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Review

The Role of Saponins in the Treatment of Neuropathic Pain

by 1,†, 1,†, 1,2 and 1,*
1
Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
2
School of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou 310053, China
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2022, 27(12), 3956; https://doi.org/10.3390/molecules27123956
Received: 30 April 2022 / Revised: 17 June 2022 / Accepted: 17 June 2022 / Published: 20 June 2022
(This article belongs to the Special Issue Molecular Targets in Neuroscience and Neurotherapeutics)

Abstract

:
Neuropathic pain is a chronic pain caused by tissue injury or disease involving the somatosensory nervous system, which seriously affects the patient’s body function and quality of life. At present, most clinical medications for the treatment of neuropathic pain, including antidepressants, antiepileptic drugs, or analgesics, often have limited efficacy and non-negligible side effects. As a bioactive and therapeutic component extracted from Chinese herbal medicine, the role of the effective compounds in the prevention and treatment of neuropathic pain have gradually become a research focus to explore new analgesics. Notably, saponins have shown analgesic effects in a large number of animal models. In this review, we summarized the most updated information of saponins, related to their analgesic effects in neuropathic pain, and the recent progress on the research of therapeutic targets and the potential mechanisms. Furthermore, we put up with some perspectives on future investigation to reveal the precise role of saponins in neuropathic pain.

1. Introduction

Pain was defined in 2020 by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage”, which is divided into acute pain and chronic pain [1]. Under physiological conditions, acute pain is the body’s nociception that protects the organization from further injury of noxious stimuli by triggering the body’s reflex defense behavior, which plays a positive role in ensuring individual safety and health. However, chronic pain still exists for a long time after injury repairment, and has lost the significance of protecting individuals. It makes patients feel uncomfortable or painful, resulting in many physiological and psychological disorders that greatly affect the quality of life of patients [2]. Neuropathic pain is one of the chronic pains, and is caused by somatic sensory nervous system injury or disease [3,4]. The incidence of neuropathic pain in the population is as high as 7–10% [5]. The main features include spontaneous pain, unpleasant abnormal sensation (paresthesia), enhanced response to pain stimuli (hyperalgesia), and pain to stimuli that usually do not cause pain (allodynia) [3]. Neuropathic pain often causes comorbidity of emotional disorders. A total of 50–60% of patients have anxiety disorder and 36–71% have depression disorder, which seriously affect the physical and mental health and quality of life of patients [6,7]. Classical analgesics have poor therapeutic effects on neuropathic pain. At present, the recommended therapeutic drugs mainly include tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, pregabalin, and gabapentin, but these drugs are only effective for about 50% of patients and have limited pain relief. Moreover, long-term administration will cause many intolerable side effects [8,9]. Therefore, the clinical treatment of neuropathic pain still faces great challenges.
Recently, the effective components, extracted from Chinese herbal medicine, for the prevention and treatment of neuropathic pain have gradually become the research focus to explore new analgesics. Saponins are widely distributed in nature, including fungi, ferns, plants, animals, and marine life [10]. The word “saponins” is a free translation from the English name Saponin, which is derived from the Latin “Sapo”, which means soap. In the chemical structure of saponins, due to the lipophilicity of the aglycone to different degrees, the sugar chain has strong hydrophilicity, and the aqueous solution can produce persistent, soap-like foam after shaking. Saponins have a wide range of physiological activities. A large body of studies have shown that saponins extracted from many Chinese herbal medicines have potential analgesic effects in various neuropathic pain models, which brought great potential for the development of new analgesic drugs. Therefore, we conducted a literature review to examine the role of saponins in the treatment of neuropathic pain. The search was performed in the PubMed and CNKI databases with the following keywords: saponins and neuropathic pain or pain. Relevant articles, including research papers, reviews, and their selective references, were examined systematically and are cited in the present review. This review focuses on the research progress of saponins in neuropathic pain. In addition, the chemical structure, mechanism of action, and experimental models of their biologically active ingredients are also introduced and discussed.

2. The Chemical Properties of Saponins

Saponins are a class of compounds with diverse structures, consisting of sapogenin and glycosyl groups [11]. The common ones of the saccharides that make up saponins are D-glucose, D-galactose, D-xylose, L-arabinose, and L-rhamnose, etc. According to the different structures of sapogenin, saponins are usually divided into two categories: triterpene saponins and steroidal saponins.
The triterpene aglycon structure of triterpene saponins is different. According to the basic carbon skeleton of the aglycon, triterpenoids can be divided into chain triterpenes, monocyclic triterpenes, bicyclic triterpenes, tricyclic triterpenes, tetracyclic triterpenes, and pentacyclic triterpenes. In nature, plants are dominated by tetracyclic triterpenes and pentacyclic triterpenes, among which the former mainly include lanostane, euphorane, dammarane, and cucurbitane, as well as protostance, meliacane, cycloartane, etc. (Figure 1A); and the later mainly include oleanane, ursane, lupinane, friedelane, fernane, isofernane, hopane, and isohopane (Figure 1B), and so on [11,12,13]. The steroidal saponins are formed by the condensation of steroidal sapogenins and glycosyl groups. It consists of 27 carbon atoms, and their basic carbon skeleton is a derivative of spirostane. According to the configuration of C25 in the spirostane structure and the cyclization state of the F ring, they are further divided into four types: spirostanol, isospirostanol, furostanol, and pseudospirostanol (Figure 1C) [14].
Triterpene saponins mostly consist of carboxyl groups and are acidic, so they are often called acidic saponins; while steroidal saponins, on the contrary, are neutral saponins. There also exist some differences in the division of triterpene saponins and steroidal saponins in nature. The former is mainly derived from dicotyledonous plants, and the common branches are in Leguminosae, Araliaceae, Campanulaceae, Cucurbitaceae, Ranunculaceae, Umbelliferae, and Rhamnaceae, etc.; the latter is mainly obtained from monocotyledonous plants, such as Liliaceae, Dioscoreaceae, Solanaceae, Amaryllidaceae, Agaveaceae, Scrophulariaceae, and Rhamnaceae, etc. [15,16].
Saponins possess a wide range of biological activities, such as anti-inflammatory, antitumor, antibacterial, antiviral, immune regulation, analgesic, neuroprotective, hepatoprotective, antihyperlipidemic, hypocholesterolemic, hypotensive, and so on [17,18,19,20]. Next, we will focus on their effects and mechanisms in the treatment of neuropathic pain (Table 1).

3. Preclinical Evidence for Saponins in Neuropathic Pain

3.1. Ginsenosides

Ginsenosides are the major biologically active components of Ginseng, which have a wide range of pharmacological activities. According to the skeleton of their aglycones, ginsenosides can be classified into two groups, tetracyclic triterpene dammarane-type saponins (protopanaxadiol (PPD)-, protopanaxatriol (PPT)-type) (Figure 2A) and tetracyclic triterpene oleanane-type saponins [48,49,50]. So far, more than 100 different ginsenoside monomers have been isolated, such as ginsenosides Rb1, Rb2, Rc, Rd, Re, Rg1, and Rf, the pharmacological and pharmacokinetic properties of which are different [51,52].
Data based on animal models have shown that ginsenosides play a beneficial role in neuropathic pain. In a study conducted by Jee Youn Lee et al. [21], peripheral and central neuropathic pain was induced by tail nerve injury or contusive spinal cord injury (SCI) in male SD rats, respectively. Remarkable analgesic effects were shown after the application of oral total saponin extract (TSE), ginsenoside Rb1. The research found that TSE and ginsenoside Rb1 inhibited the activation of microglia/astrocytes, and attenuated inflammatory factors levels, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Further results demonstrated that TSE, ginsenoside Rb1, and Rb1-metabolite-compound, K, also exerted analgesic effects that might be mediated through the estrogen receptor. Other research conducted by Gao Chao et al. reported that intrathecal injection of ginsenoside Rg1 significantly inhibited chronic constrictive injury (CCI)-induced thermal hyperalgesia in a dose-dependent manner. It might be mediated by inhibiting the expression of phosphorylated p38 mitogenactivated protein kinase (p-p38MAPK) and nuclear factor kappa-B (NF-κB) subunit phosphorylated p65, and the activation of ionized calcium binding adaptor molecule-1 (IBA-1) in the spinal microglia, resulting in downregulation of the central sensitization [22]. In addition, other studies showed that ginsenoside Rf robustly decreased IL-1β and IL-6, but increased the expression of IL-10 in the dorsal root ganglion (DRG), in both the spinal cord and DRG of CCI rats [23]. Thus, ginsenoside Rf may adjust the balance between proinflammatory and anti-inflammatory factors to promote its antinociceptive effect in neuropathic pain.
Many studies have revealed the key role of proinflammatory cytokines in the pathophysiology of neuropathic pain [53,54,55,56]. The above studies all explained that related ginsenosides inhibited inflammation through different pathways to relieve neuropathic pain. Furthermore, other studies have shown that ginsenoside Rb1 inhibits neuronal apoptosis [24] and promotes the neurogenesis and regulates the expressions of brain-derived neurotrophic factor (BDNF) and caspase-3 to play a neuroprotective effect [57]. On the other hand, clinically chronic pain patients are often accompanied by depression, and some depressive patients also have chronic somatic pain symptoms [58]. Therefore, the relationship between pain and the occurrence of depression has become the focus of recent studies. It has shown that intraperitoneal injection of ginsenoside Rg2 not only alleviates the mechanical allodynia and thermal hyperalgesia, but also relieves anxiety and depression in CCI rats [59], though its underlying mechanism needs to be further explored. So far, most of the analgesic mechanisms of ginsenosides in the neuropathic pain are limited to the exploration of inflammatory factors, lacking in-depth analysis of its targeted molecular targets. In addition, whether the regulatory effects of ginsenosides are related with different neuropathic pain-related brain regions is still largely unknown. Further studies focusing on these points may provide a research basis for the precise regulation of drugs.

3.2. Saikosaponins

Saikosaponins are derived from Bupleurum or Bupleurum scorzonerifolium in the Umbelliferae, one of the traditional Chinese herbal medicines, and are the main active ingredients of Bupleurum [60]. So far, more than 100 kinds of saikosaponins have been isolated from Bupleurum, the main ones of which are oleanane and ursolic pentacyclic triterpene saponins [61,62,63,64,65]. According to their chemical structure, saikosaponins are divided into -A, -B, -C, -D, -M, -N, -P, and -T categories, and Saikosaponin D (SSD) is considered to be the most active one, followed by Saikosaponin A (SSA) [66,67]. Their chemical structures are shown in Figure 2B.
Both in vivo and in vitro experimental studies have shown that saikosaponins can inhibit the activation of transient receptor potential ankyrin 1 (TRPA1) and significantly reduce the nociceptive response of animals induced by allyl isothiocyanate (AITC) [25]. Molecular docking and site-directed mutagenesis analyses demonstrated that saikosaponins bind to the TRPA1 hydrophobic pocket near the Asn855 residue, which once mutated to Ser and was previously united with enhanced pain perception in humans [25,68]. Gyeongbeen also reported that multiple administrations of SSD could significantly relieve mechanical hypersensitivity induced by vincristine, which was carried out partially by suppressing the activity of TRPA1 [25]. Therefore, it can be further speculated that SSD might play a certain therapeutic role in the neuropathic pain that is induced by chemotherapeutics, diabetes, or CCI, in which the expression and sensitivity of TRPA1 were changed as well, resulting in abnormal pain response and perception [69,70,71,72,73]. However, the analgesic effect of SSD is different between streptozotocin (STZ)- and paclitaxel-induced pain models. Short-term oral administration was effective in the former, while multiple administrations were required for the pain relief of the latter [26]. This indicates that the analgesic effect of SSD may not only act as an antagonist of TRPA1, but also exert anti-inflammatory activity to reduce the oxidative stress caused by nerve damage. Related research reported that SSD could restrain the translocation of the glucocorticoid receptor to the mitochondria, and decrease the H2O2-induced phosphorylation of extracellular-regulated kinase (ERK), c-Jun N-terminal kinase (c-JNK), and p38MAPK to downregulate the activity of neuronal PC12 cells [27,74,75].
It is well known that activation of NF-κB in both DRG and spinal cord neurons is associated with the transduction and processing of nociceptive messages. Therefore, inhibition of NF-κB can alleviate chronic painful states [76]. Studies have shown that SSA alleviates neuropathic pain by inhibiting CCI-induced elevation of p-p38 MAPK and NF-κB levels in the spinal cord [28]. In addition, cytokine dysregulation is one of the characteristic manifestations of neuropathic pain symptoms [77]. It could also be found that SSA significantly inhibited the expression of certain immune-related cytotoxic factors, including COX-2 and iNOS, and, likewise, the pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6. Meanwhile, the expression of the important anti-inflammatory cytokine IL-10 was significantly upregulated, suggesting that it had anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated macrophages [29,30]. Further research showed that SSA blocked the NF-κB signaling pathway by preventing phosphorylation of the NF-κB inhibitor α (IκBα), thereby allowing p65 NF-κB to remain in the cytoplasm, preventing it from translocating to the nucleus. In addition, SSA inhibited the MAPK signaling pathway by downregulating the phosphorylation of p38 MAPK, c-JNK, and ERK to exert the anti-inflammatory activity [30]. On the basis, SSA appeared to counteract the neurological function deficits after traumatic brain injury via inbiting aquaporin-4 (AQP-4) and matrix metalloprotein-9 (MMP-9) to account for its neuroprotective effects [31]. On the other hand, a study of Seong Shoon Yoon et al. expressed that SSA exhibited a significant inhibitory effect on morphine-reinforced behavior and drug addiction predominantly via mediating GABAB receptors [78,79]. Davoud Ahmadimoghaddam et al. reported that Bupleurum falcatum L. roots essential oil, of which SSA was one of the main constituents [32], exerted its antinociceptive and antiallodynic effects through the regulation of L-arginine-NO-cGMP-KATP channel pathways, as well as interaction with opioid, peroxisome proliferator-activated, and cannabinoid receptors [32]. The voltage-gated sodium channel Nav1.7 is a tetrodotoxin-sensitive sodium channel subtype and is encoded by SCN9A. It is well known that the dysfunction of Nav1.7 has the correlation with pain disorders [80]. Relevant research showed that SSA displayed the analgesic effects on the thermal pain and formalin-induced pain in mice via strong inhibitory effect on the peak currents of Nav1.7 [33].
The above studies have shown that SSD and SSA can exert analgesic effects in different neuropathic pain models through multiple pathways, and their mechanisms of action have similarities and differences. In the follow-up, we can combine their structural characteristics with the mechanisms of action for deep analysis to provide a research basis for the precise regulation of the targets.

3.3. Astragalosides

Astragali Radix, the dried roots of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao, or Astragalus membranaceus (Fisch.) Bge., is known as a high-grade traditional Chinese medicine [81]. There are three main types of compounds in astragalus: saponins, flavonoids, and polysaccharides, and triterpene saponins are the major constituents [82,83,84]. It is reported that more than 40 kinds of saponins have been isolated and identified from the dried astragalus roots via HPLC and GC-MS, such as astragalosides I–VIII, acetylastragaloside, isoastragaloside I, III, astramembrannin II, cycloastragenol, cycloascauloside B, brachyoside B, astrasieversianin X, etc. [85,86,87,88]. Among these, astragaloside IV (AS-IV) is known as the major active ingredient and qualitative control biomarker. AS-IV is 3-O-beta-d-xylopyranosyl-6-O-beta-d-glucopyranosyl-cycloastragenol (Figure 2C), the molecular formula is C41H68O14 [89].
It is generally accepted that the transient receptor potential vanilloid 1 (TRPV1) channel is a polymodal receptor for various stimuli such as noxious heat and capsaicin, and is also an important pain sensor [90,91]. TRPV1 is overexpressed in Aδ fibers and C fibers in the situation of inflammation or nerve injury [92]. In addition, purinergic P2 × 3 receptors are ligand-gated nonselective cation channels, highly selectively expressed in small-diameter and medium-diameter sensory neurons related to nociceptive information, and play a key role in the generation and maintenance of pathological pain [93,94]. In the research by Guo-Bing Shi et al., AS-IV not only dramatically downregulated the expression of TRPV1 in Aδ fibers to remarkably upregulate the nociceptive threshold, but also inhibited P2 × 3 expression in DRG neurons to attenuate the mechanical allodynia [34]. Meanwhile, AS-IV restored the histological structure of the damaged sciatic nerve by accumulating glial cell-derived neurotrophic factor family receptorα1 (GFRα1), the glial cell derived neurotrophic factor (GDNF) selective receptor, in the debris of myelin between the Schwann cells and the damaged axon [34]. It also reduced the levels of GFRα1 and GDNF in DRG, which were highly expressed and induced by CCI, contributing to the restoration of injured nerve fibers [95,96].
In the peripheral nervous system, the appropriate dose of AS-IV could also greatly promote the regeneration of peripheral nerves [35]. Growth-associated protein 43 is lower in spinal cord segments L4–6 but active in growing neuronal axons in normal Balb/c mice. As a particular biomarker in nerve injury, it plays a vital role in nerve growth, and strongly associates with neuronal axon growth [36,89,97,98]. Previous research showed that AS-IV significantly upregulated the expression of growth-related protein 43 in regenerated nerve tissue, thereby increasing the number and diameter of myelinated nerve fibers in the sciatic nerve of mice, while elevating motor nerve conduction velocity and action potential amplitude [36]. Moreover, AS-IV also conducted analgesic effects on peripheral neuropathy in STZ-induced diabetic rats. Firstly, it reduced blood glucose and glycosylated hemoglobin (HbA1C) levels, and increased plasma insulin levels in diabetic rats [37]. It is crucial to control the levels of HbA1C because its concentration is closely related to the incidence of diabetes-related complications, which has been proven by clinical trials [99]. Secondly, AS-IV enhanced the activity of glutathione peroxidase in nerves, suppressed the activation of aldose reductase in erythrocytes, and decreased the accumulation of advanced glycation end products in both nerves and erythrocytes, which might not only activate the cellular antioxidant defense system, but also aggrandize the ability of antioxidative stress injury on peripheral nerves. Thirdly, AS-IV acted as the AR inhibitor, and then enhanced Na+, K+-ATPase activity, improved the delayed motor nerve conduction velocity, increased nerve blood flow, and prevented structural nerve fiber damage to correct peripheral nerve defects [37].

3.4. Diosgenin

Diosgenin is a naturally occurring steroidal sapogenin and is abundant in nature. Primary sources of diosgenin include the three Dioscorea species and one Heterosmilax species, namely, D. zingiberensis, D. septemloba, D. collettii, and H. yunnanensis [100]. Diosgenin can also be obtained from fenugreek (T. foenum graecum Linn) and Costus speciosus [101,102,103]. It is a C27 spiroketal steroid sapogenin, 3β-hydroxy-5-spirostene (Figure 2D), and its molecular formula is C27H42O3 [104]. As a representational phytosteroid, diosgenin is an important basic raw material for the production of steroid hormone drugs and has received increasing attention in the pharmaceutical industry for decades [105]. In addition, diosgenin itself has a wide range of biological effects. The following studies mainly describe its role in neuropathic pain.
Neuropathic pain, one of the common complications of diabetes mellitus, manifests as increased sensitivity to noxious stimuli [106]. To evaluate the effects of diosgenin in the treatment of diabetes-induced neuropathic pain, an in vivo study was performed on a rat model of STZ-induced diabetes. It was demonstrated that diosgenin upturned mechanical and thermal nociceptive thresholds and lowered pain scores at the late phase of the formalin test in diabetic rats [38]. Since elevated oxidative stress is one of the key factors in diabetes-related neurological dysfunction, it can lead to vascular dysfunction, resulting in intraneural hypoxia, which can lead to impaired motor and sensory nerve function [107,108]. Studies showed that diosgenin could reduce the content of malondialdehyde (MDA) in serum, DRG, and sciatic nerve of diabetic rats and restored the activities of superoxide dismutase (SOD) and catalase, thereby inhibiting oxidative stress and enhancing the function of the antioxidant defense system [38]. Furthermore, NF-κB, an important nuclear transcription factor, is responsible for the control of genes encoding inflammation and nociception-related mediators [109]. Upregulation of NF-κB in the DRG neurons of diabetic rats has been proven, and its inhibition significantly reduces nociceptive responses [110,111,112]. It reported that diosgenin downregulated the NF-κB p65/p50 signaling pathway in the LPS-induced lung injury model [113]. However, based on the available reports, there is no specific experimental research regarding whether diosgenin exerts its analgesic effect in diabetes-induced neuropathic pain by regulating NF-κB, and related research needs to be further developed. Nerve growth factor (NGF), as a neurotrophic factor, is a protein factor that plays a vital role in the maintenance of the growth, development, and function of sympathetic and sensory neurons. It stimulates the axon growth, maintains the axon size, prevents the postinjury death of mature neurons, and regulates various functions of the nervous system, including synaptic plasticity and neurotransmission [114,115]. In diabetic neuropathy, the function of NGF is impaired and the expression of NGF-related genes is modified, which are important factors in the progress of diabetic neuropathic pain. A study conducted by Tong Ho KANG et al. revealed that diosgenin upregulated the level of NGF in the sciatic nerve of diabetic rats. The comparable effects also reported that diosgenin increased the neurite outgrowth of PC12 cells, enhanced the sciatic nerve conduction velocity of diabetic mice by inducing NGF, reduced myelin disturbance, increased the area of myelinated axons, and improved the signal transmission of damaged axons, thereby alleviating diabetic neuropathic pain [39].
In addition to the diabetic neuropathy model, the role of diosgenin in the treatment of neuropathic pain has also been reported in the CCI rat model. In 2017, Wei-Xin Zhao et al. performed an in vivo study, and the results demonstrated that diosgenin could upregulate CCI-reduced mechanical withdrawal threshold and thermal withdrawal latency. This was due to the fact that diosgenin not only inhibited CCI-induced elevation of proinflammatory cytokines TNF-α, IL-1β and IL-2, but also suppressed oxidative stress in the spinal cord. Moreover, diosgenin remarkably restrained the expression of p-p38 MAPK and NF-κB in the spinal cord and eased neuropathic pain in CCI rats by inhibiting the activation of p38 MAPK and NF-κB signaling pathways [40]. In other research [41], sciatic-crushed-nerve injury in rats decreased the sciatic function index, which was widely used to evaluate functional gait [116], increased the c-Fos expression in the ventrolateral periaqueductal gray and paraventricular nucleus, restrained recovery of locomotor function caused by the overexpression of BDNF, and aggrandized expressions of COX-2 and iNOS that responded to inflammation. Fortunately, diosgenin was able to significantly improve the above pathological states, and exploited potential abilities in pain control and functional recovery after peripheral nerve injury.

3.5. Saponin-Rich Extracts of O. sanctum

In addition to the analgesic effects of the above four plant saponins that have been identified with clear structures, saponin-rich extracts of O. sanctum have also been found with similar effects. O. sanctum is the aerial part of Ocimum basilicum, a plant of the Labiatae family. Modern pharmacological studies have illustrated that the chemical composition of O. sanctum is complex and the types are diverse, including volatile oils, flavonoids and their glycosides, coumarins, phenylpropanoids, and fatty acids, mainly volatile oils and flavonoids and their glycosides [117]. In addition, a variety of saponins have been isolated from the alcoholic extract of O. sanctum [118], the most important of which are pentacyclic triterpenoid saponins that are dominated by ursolic and oleanolic acids [119,120,121], and have a wide range of pharmacological effects.
Oxidative stress [122] and alterations in calcium homeostasis [123] are thought to be closely associated with neuropathic pain. During neurological disorders, dysfunction of the intracellular calcium regulatory system produces oxidative stress [124], and increases in free radicals lead to neuronal degeneration and apoptosis. On the other hand, metabolic abnormalities [125], formation of protein aggregates [126], and changes in membrane permeability [127] caused by oxidative stress all increase calcium levels, and they act together to promote the deterioration of neuropathic pain. O. sanctum has a good antioxidant effect [128,129], protects against free radical damage [130], and is able to reduce calcium levels [42]. O. sanctum is used as a neurotonic in parts of India for the relief of headache, joint pain, and muscle pain. In the experiments conducted by Muthuraman et al., the administration of O. sanctum attenuated sciatic nerve transection-induced peripheral neuropathy and motor in-co-ordination, attenuated the amputation-induced reduction in thiobarbituric acid reactive species, total calcium, and glutathione levels in a dose-dependent manner [42]. It suggested that the analgesic effect of O. sanctum might be related to its antioxidation and reduction of calcium levels. Additionally, in other studies, treatment with O. sanctum and its saponin-rich fraction reduced neuropathic pain caused by chronic constrictive injury and chemotherapeutic agent vincristine, associated with its effects on the oxidative stress and calcium levels [42,43]. Based on the above findings, it can be observed that the downregulation of calcium levels by O. sanctum administration may be due to a direct effect on or secondary to a decrease in oxidative stress. Then, it produces an antinociceptive or antiapoptotic effect on neurons. It has been reported that Saponins have antioxidant [131] and calcium lowering effects [132]. Thus, the antinociceptive effect of O. sanctum saponins may be constructed through direct or indirect reduction of calcium levels.
There is also evidence that O. sanctum leaves and seeds reduce uric acid levels in rabbits [133], and elevated uric acid levels are associated with gouty arthritis and other joint inflammation [134]. The ethanolic extract of O. sanctum can be antinociceptive, and involves the interaction of neurotransmitter systems such as opioid receptors and norepinephrine [135]. These studies support the traditional use of O. sanctum for the treatment of inflammation and pain, without excluding the effects of other active ingredients such as flavonoids and phenols.

4. Conclusions and Perspective

In this review, we summarized the role of five well-studied and representative saponins in reducing neuropathic pain with the following key points: (1) Saponins can effectively reduce neuropathic pain in different nerve injury models, such as the spared nerve injury, spinal nerve ligation, partial sciatic nerve injury, diabetes-induced neuropathy, chemotherapy-induced neuropathy, and CCI models. (2) The analgesic effects of saponins are mainly related to their anti-inflammatory, immunol regulatory, antioxidative stress and neuroprotective activities.
Of course, further prospective research is also needed to address the following problems. Luckily, with the development of advanced technology, we can combine these technical methods to promote the further development of related research listed below (Figure 3):
(1) Saponins are widely distributed in nature. In addition to the above five saponins, there are some other less studied saponins (saponins from Tribulus terrestris [44], escin [45,46], etc.) that have been found to have therapeutic effects in animal models of neuropathic pain. Therefore, according to the species characteristics of plants, more saponin compounds can be explored to provide a material basis for new drug research. Facing more and more different types and structures of saponins, knowing how to efficiently and quickly screen out the effective parts is an urgent problem to be solved. In addition, the extraction rate of some saponins from plants is not high enough, so it is possible to synthesize saponins based on their chemical structural characteristics.
In order to quickly and efficiently screen out biologically active saponins, high content screening technology can be used. It can realize multitarget, multiparameter detection of saponins. Moreover, combined with computer-aided drug design technology, the structure optimization and target docking of saponin derivatives can be achieved, which provides a theoretical basis for the synthesis of saponin derivatives with an efficient analgesic effect.
(2) At present, the research on the mechanism of action of saponins extracted from traditional Chinese medicine in neuropathic pain is relatively scattered, relatively independent, and the research depth is not enough. In the follow-up, the relationship between the structural properties of saponins and their targets need to be analyzed, and the effective sites of action may be synthesized and modified to provide a research basis for multitarget therapy. In-depth analysis of the pathogenesis of neuropathic pain, a full understanding of its circuit abnormalities, and an insight into the circuit basis and function characteristics of saponins to relieve pain can provide directions for the subsequent development of targets. Combined with optogenetics, pharmacogenetics, and other regulatory methods, deep and systematic research for this purpose can be well conducted.
(3) The ultimate goal of drug discovery is to treat diseases, so clinical research is of great importance. Some analgesics currently in clinical use have the problems of low safety, large side effects, and unsatisfactory analgesic effects. The current literature supporting saponins for the treatment of neuropathic pain are limited to animal models, and future studies are needed to evaluate the efficacy of these saponins in the clinic.
In view of the shortcomings of current clinical drugs, it is possible to consider the study of the combination of existing drugs and traditional Chinese medicines containing saponins or extracted saponins to offer more alternatives for the treatment of neuropathic pain. Research has demonstrated that ginsenoside Rf potentiates U50-induced analgesia and inhibits tolerance to its analgesia via nonopioid, non-dihydropyridine-sensitive Ca2+, and non-benzodiazepine-GABAergic mechanisms in mice [47]. Meanwhile, combination therapy can reverse drug resistance to a certain extent. In addition, electroacupuncture treatment of neuropathic pain and pain-induced negative emotions are gradually extensive [136,137]. With the improvement of new materials and pharmaceutical preparation technology, the technology of electroacupuncture with drug-loading capabilities, such as saponins, has gradually become possible. The synergistic and targeted delivery of acupuncture and medicine provides a new prospect for the treatment of neuropathic pain.
Overall, even with the aforementioned obstacles and problems, saponins remain the valuable drug candidates for the treatment of neuropathic pain. It is believed that with the provision of future research technologies and in-depth research, the reliability of saponins against neuropathic pain will be greatly improved, which will promote their application in actual neuropathic pain treatment.

5. Strengths and Limitations of the Review

The strength of this review is its systematical and comprehensive summary of the effects and mechanisms of different saponins on neuropathic pain. At the same time, according to the current research technologies and progress, some limitations of the previous research are pointed out and some constructive opinions are put forward.
On the other hand, this paper also has a limitation. This review is based on the structure and type of saponins, which leads to the inability to systematically summarize the role of saponins in different types of neuropathic pain, which are only introduced separately in each part.

Author Contributions

Conceptualization: B.T. and Z.C.; Writing: B.T., X.W., J.Y., Z.C.; Supervision: Z.C. All authors have read and agreed to the published version of the manuscript.

Funding

This project was supported by grants from the Natural Science Foundation of Zhejiang Province (LD22H310003, LY22H280008) and the Research Project of Zhejiang Chinese Medical University (2021JKJNTZ010B, 2021JKJNTZ011B, 2021JKGJYY027).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Not applicable.

References

  1. Raja, S.N.; Carr, D.B.; Cohen, M.; Finnerup, N.B.; Flor, H.; Gibson, S.; Keefe, F.J.; Mogil, J.S.; Ringkamp, M.; Sluka, K.A.; et al. The revised International Association for the Study of Pain definition of pain: Concepts, challenges, and compromises. Pain 2020, 161, 1976–1982. [Google Scholar] [CrossRef] [PubMed]
  2. St John Smith, E. Advances in understanding nociception and neuropathic pain. J. Neurol. 2018, 265, 231–238. [Google Scholar] [CrossRef] [PubMed][Green Version]
  3. Zilliox, L.A. Neuropathic Pain. Continuum 2017, 23, 512–532. [Google Scholar] [CrossRef] [PubMed]
  4. Meacham, K.; Shepherd, A.; Mohapatra, D.P.; Haroutounian, S. Neuropathic Pain: Central vs. Peripheral Mechanisms. Curr. Pain Headache Rep. 2017, 21, 28. [Google Scholar] [CrossRef] [PubMed]
  5. Van Hecke, O.; Austin, S.K.; Khan, R.A.; Smith, B.H.; Torrance, N. Neuropathic pain in the general population: A systematic review of epidemiological studies. Pain 2014, 155, 654–662. [Google Scholar] [CrossRef]
  6. Cohen, S.P.; Mao, J. Neuropathic pain: Mechanisms and their clinical implications. BMJ 2014, 348, f7656. [Google Scholar] [CrossRef][Green Version]
  7. Finnerup, N.B.; Attal, N.; Haroutounian, S.; McNicol, E.; Baron, R.; Dworkin, R.H.; Gilron, I.; Haanpää, M.; Hansson, P.; Jensen, T.S.; et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015, 14, 162–173. [Google Scholar] [CrossRef][Green Version]
  8. Jensen, T.S.; Finnerup, N.B. Allodynia and hyperalgesia in neuropathic pain: Clinical manifestations and mechanisms. Lancet Neurol. 2014, 13, 924–935. [Google Scholar] [CrossRef]
  9. Hansson, P.T.; Attal, N.; Baron, R.; Cruccu, G. Toward a definition of pharmacoresistant neuropathic pain. Eur. J. Pain 2009, 13, 439–440. [Google Scholar] [CrossRef]
  10. Papadopoulou, K.; Melton, R.E.; Leggett, M.; Daniels, M.J.; Osbourn, A.E. Compromised disease resistance in saponin-deficient plants. Proc. Natl. Acad. Sci. USA 1999, 96, 12923–12928. [Google Scholar] [CrossRef][Green Version]
  11. Vincken, J.P.; Heng, L.; de Groot, A.; Gruppen, H. Saponins, classification and occurrence in the plant kingdom. Phytochemistry 2007, 68, 275–297. [Google Scholar] [CrossRef] [PubMed]
  12. Lin, M.; Yang, S.; Huang, J.; Zhou, L. Insecticidal Triterpenes in Meliaceae: Plant Species, Molecules and Activities: Part I; (Aphanamixis-Chukrasia). Int. J. Mol. Sci. 2021, 22, 13262. [Google Scholar] [CrossRef] [PubMed]
  13. Connolly, J.D.; Hill, R.A. Triterpenoids. Nat. Prod. Rep. 2008, 25, 794–830. [Google Scholar] [CrossRef] [PubMed]
  14. Luo, L.M.; Qin, L.; Pei, G.; Huang, S.G.; Zhou, X.J.; Chen, N.H. Advances in studies on steroidal saponins and their pharmacological activities in genus Lilium. Zhongguo Zhong Yao Za Zhi 2018, 43, 1416–1426. [Google Scholar] [CrossRef] [PubMed]
  15. Shi, J.; Arunasalam, K.; Yeung, D.; Kakuda, Y.; Mittal, G.; Jiang, Y. Saponins from edible legumes: Chemistry, processing, and health benefits. J. Med. Food 2004, 7, 67–78. [Google Scholar] [CrossRef] [PubMed]
  16. Man, S.; Gao, W.; Zhang, Y.; Huang, L.; Liu, C. Chemical study and medical application of saponins as anti-cancer agents. Fitoterapia 2010, 81, 703–714. [Google Scholar] [CrossRef]
  17. Hassan, H.S.; Sule, M.I.; Musa, A.M.; Musa, K.Y.; Abubakar, M.S.; Hassan, A.S. Anti-inflammatory activity of crude saponin extracts from five Nigerian medicinal plants. Afr. J. Tradit. Complementary Altern. Med. 2012, 9, 250–255. [Google Scholar] [CrossRef][Green Version]
  18. Singh, D.; Chaudhuri, P.K. Structural characteristics, bioavailability and cardioprotective potential of saponins. Integr. Med. Res. 2018, 7, 33–43. [Google Scholar] [CrossRef]
  19. Xu, G.B.; Xiao, Y.H.; Zhang, Q.Y.; Zhou, M.; Liao, S.G. Hepatoprotective natural triterpenoids. Eur. J. Med. Chem. 2018, 145, 691–716. [Google Scholar] [CrossRef]
  20. Fang, Z.; Li, J.; Yang, R.; Fang, L.; Zhang, Y. A Review: The Triterpenoid Saponins and Biological Activities of Lonicera Linn. Molecules 2020, 25, 3773. [Google Scholar] [CrossRef]
  21. Lee, J.Y.; Choi, H.Y.; Park, C.S.; Kim, D.H.; Yune, T.Y. Total saponin extract, ginsenoside Rb1, and compound K alleviate peripheral and central neuropathic pain through estrogen receptors on rats. Phytother. Res. 2021, 35, 2119–2132. [Google Scholar] [CrossRef] [PubMed]
  22. Gao, C.; Guo, X.; Weng, L.; Zhou, W.; Shen, Y.; Yu, Y.; Han, Y. Effect of ginsenoside Rg1 on activity of spinal microglia and expression of p38 mitogen-activated protein kinase/nuclear transcription factor-kappa B in neuropathic pain rats. Int. J. Anesth. Resus 2017, 38, 1084. [Google Scholar] [CrossRef]
  23. Li, Y.; Chen, C.; Li, S.; Jiang, C. Ginsenoside Rf relieves mechanical hypersensitivity, depression-like behavior, and inflammatory reactions in chronic constriction injury rats. Phytother. Res. 2019, 33, 1095–1103. [Google Scholar] [CrossRef] [PubMed]
  24. Huang, F.; Li, Y.N.; Yin, F.; Wu, Y.T.; Zhao, D.X.; Li, Y.; Zhang, Y.F.; Zhu, Q.S. Ginsenoside Rb1 inhibits neuronal apoptosis and damage, enhances spinal aquaporin 4 expression and improves neurological deficits in rats with spinal cord ischemiareperfusion injury. Mol. Med. Rep. 2015, 11, 3565–3572. [Google Scholar] [CrossRef][Green Version]
  25. Lee, G.; Choi, J.; Nam, Y.J.; Song, M.J.; Kim, J.K.; Kim, W.J.; Kim, P.; Lee, J.S.; Kim, S.; No, K.T.; et al. Identification and characterization of saikosaponins as antagonists of transient receptor potential A1 channel. Phytother. Res. 2020, 34, 788–795. [Google Scholar] [CrossRef]
  26. Lee, G.; Nam, Y.-J.; Kim, W.J.; Shin, B.H.; Lee, J.S.; Park, H.T.; Kim, P.; Lee, J.H.; Choi, Y. Saikosaponin D Ameliorates Mechanical Hypersensitivity in Animal Models of Neuropathic Pain. Planta Med. Int. Open 2020, 7, e145–e149. [Google Scholar] [CrossRef]
  27. Li, Z.Y.; Jiang, Y.M.; Liu, Y.M.; Guo, Z.; Shen, S.N.; Liu, X.M.; Pan, R.L. Saikosaponin D acts against corticosterone-induced apoptosis via regulation of mitochondrial GR translocation and a GR-dependent pathway. Prog. Neuropsychopharmacol. Biol. Psychiatry 2014, 53, 80–89. [Google Scholar] [CrossRef]
  28. Zhou, X.; Cheng, H.; Xu, D.; Yin, Q.; Cheng, L.; Wang, L.; Song, S.; Zhang, M. Attenuation of neuropathic pain by saikosaponin a in a rat model of chronic constriction injury. Neurochem. Res. 2014, 39, 2136–2142. [Google Scholar] [CrossRef]
  29. Lu, C.N.; Yuan, Z.G.; Zhang, X.L.; Yan, R.; Zhao, Y.Q.; Liao, M.; Chen, J.X. Saikosaponin a and its epimer saikosaponin d exhibit anti-inflammatory activity by suppressing activation of NF-kappaB signaling pathway. Int. Immunopharmacol. 2012, 14, 121–126. [Google Scholar] [CrossRef]
  30. Zhu, J.; Luo, C.; Wang, P.; He, Q.; Zhou, J.; Peng, H. Saikosaponin A mediates the inflammatory response by inhibiting the MAPK and NF-kappaB pathways in LPS-stimulated RAW 264.7 cells. Exp. Ther. Med. 2013, 5, 1345–1350. [Google Scholar] [CrossRef][Green Version]
  31. Mao, X.; Miao, G.; Tao, X.; Hao, S.; Zhang, H.; Li, H.; Hou, Z.; Tian, R.; Lu, T.; Ma, J.; et al. Saikosaponin a protects TBI rats after controlled cortical impact and the underlying mechanism. Am. J. Transl. Res. 2016, 8, 133–141. [Google Scholar] [PubMed]
  32. Ahmadimoghaddam, D.; Zarei, M.; Mohammadi, S.; Izadidastenaei, Z.; Salehi, I. Bupleurum falcatum L. alleviates nociceptive and neuropathic pain: Potential mechanisms of action. J. Ethnopharmacol. 2021, 273, 113990. [Google Scholar] [CrossRef] [PubMed]
  33. Xu, Y.; Yu, Y.; Wang, Q.; Li, W.; Zhang, S.; Liao, X.; Liu, Y.; Su, Y.; Zhao, M.; Zhang, J. Active components of Bupleurum chinense and Angelica biserrata showed analgesic effects in formalin induced pain by acting on Nav1.7. J. Ethnopharmacol. 2021, 269, 113736. [Google Scholar] [CrossRef] [PubMed]
  34. Shi, G.B.; Fan, R.; Zhang, W.; Yang, C.; Wang, Q.; Song, J.; Gao, Y.; Hou, M.X.; Chen, Y.F.; Wang, T.C.; et al. Antinociceptive activity of astragaloside IV in the animal model of chronic constriction injury. Behav. Pharm. 2015, 26, 436–446. [Google Scholar] [CrossRef] [PubMed]
  35. Cheng, C.Y.; Yao, C.H.; Liu, B.S.; Liu, C.J.; Chen, G.W.; Chen, Y.S. The role of astragaloside in regeneration of the peripheral nerve system. J. Biomed. Mater. Res. A 2006, 76, 463–469. [Google Scholar] [CrossRef]
  36. Zhang, X.; Chen, J. The mechanism of astragaloside IV promoting sciatic nerve regeneration. Neural Regen. Res. 2013, 8, 2256–2265. [Google Scholar] [CrossRef] [PubMed]
  37. Yu, J.; Zhang, Y.; Sun, S.; Shen, J.; Qiu, J.; Yin, X.; Yin, H.; Jiang, S. Inhibitory effects of astragaloside IV on diabetic peripheral neuropathy in rats. Can. J. Physiol. Pharm. 2006, 84, 579–587. [Google Scholar] [CrossRef]
  38. Kiasalari, Z.; Rahmani, T.; Mahmoudi, N.; Baluchnejadmojarad, T.; Roghani, M. Diosgenin ameliorates development of neuropathic pain in diabetic rats: Involvement of oxidative stress and inflammation. Biomed. Pharm. 2017, 86, 654–661. [Google Scholar] [CrossRef]
  39. Kang, T.H.; Moon, E.; Hong, B.N.; Choi, S.Z.; Son, M.; Park, J.H.; Kim, S.Y. Diosgenin from Dioscorea nipponica ameliorates diabetic neuropathy by inducing nerve growth factor. Biol. Pharm. Bull. 2011, 34, 1493–1498. [Google Scholar] [CrossRef][Green Version]
  40. Zhao, W.X.; Wang, P.F.; Song, H.G.; Sun, N. Diosgenin attenuates neuropathic pain in a rat model of chronic constriction injury. Mol. Med. Rep. 2017, 16, 1559–1564. [Google Scholar] [CrossRef]
  41. Lee, B.K.; Kim, C.J.; Shin, M.S.; Cho, Y.S. Diosgenin improves functional recovery from sciatic crushed nerve injury in rats. J. Exerc. Rehabil. 2018, 14, 566–572. [Google Scholar] [CrossRef] [PubMed]
  42. Muthuraman, A.; Diwan, V.; Jaggi, A.S.; Singh, N.; Singh, D. Ameliorative effects of Ocimum sanctum in sciatic nerve transection-induced neuropathy in rats. J. Ethnopharmacol. 2008, 120, 56–62. [Google Scholar] [CrossRef] [PubMed]
  43. Kaur, G.; Jaggi, A.S.; Singh, N. Exploring the potential effect of Ocimum sanctum in vincristine-induced neuropathic pain in rats. J. Brachial Plex. Peripher. Nerve Inj. 2010, 5, 3. [Google Scholar] [CrossRef] [PubMed][Green Version]
  44. Gautam, M.; Ramanathan, M. Saponins of Tribulus terrestris attenuated neuropathic pain induced with vincristine through central and peripheral mechanism. Inflammopharmacology 2019, 27, 761–772. [Google Scholar] [CrossRef] [PubMed]
  45. Zhang, L.; Chen, X.; Wu, L.; Li, Y.; Wang, L.; Zhao, X.; Zhao, T.; Zhang, L.; Yan, Z.; Wei, G. Ameliorative effects of escin on neuropathic pain induced by chronic constriction injury of sciatic nerve. J. Ethnopharmacol. 2021, 267, 113503. [Google Scholar] [CrossRef] [PubMed]
  46. Yan, F.; Chen, D.; Xie, J.; Zeng, W.; Li, Q. Escin alleviates chemotherapy-induced peripheral neuropathic pain by inducing autophagy in the spinal cord of rats. Nan Fang Yi Ke Da Xue Xue Bao 2020, 40, 1634–1638. [Google Scholar] [PubMed]
  47. Nemmani, K.V.; Ramarao, P. Ginsenoside Rf potentiates U-50,488H-induced analgesia and inhibits tolerance to its analgesia in mice. Life Sci. 2003, 72, 759–768. [Google Scholar] [CrossRef]
  48. Christensen, L.P. Ginsenosides chemistry, biosynthesis, analysis, and potential health effects. Adv. Food Nutr. Res. 2009, 55, 1–99. [Google Scholar] [CrossRef]
  49. Zheng, M.; Xin, Y.; Li, Y.; Xu, F.; Xi, X.; Guo, H.; Cui, X.; Cao, H.; Zhang, X.; Han, C. Ginsenosides: A Potential Neuroprotective Agent. BioMed Res. Int. 2018, 2018, 8174345. [Google Scholar] [CrossRef][Green Version]
  50. Hou, M.; Wang, R.; Zhao, S.; Wang, Z. Ginsenosides in Panax genus and their biosynthesis. Acta Pharm. Sin. B 2021, 11, 1813–1834. [Google Scholar] [CrossRef]
  51. Lee, H.S.; Lee, H.J.; Yu, H.J.; Ju do, W.; Kim, Y.; Kim, C.T.; Kim, C.J.; Cho, Y.J.; Kim, N.; Choi, S.Y.; et al. A comparison between high hydrostatic pressure extraction and heat extraction of ginsenosides from ginseng (Panax ginseng CA Meyer). J. Sci. Food Agric. 2011, 91, 1466–1473. [Google Scholar] [CrossRef] [PubMed]
  52. Nag, S.A.; Qin, J.J.; Wang, W.; Wang, M.H.; Wang, H.; Zhang, R. Ginsenosides as Anticancer Agents: In vitro and in vivo Activities, Structure-Activity Relationships, and Molecular Mechanisms of Action. Front. Pharmacol. 2012, 3, 25. [Google Scholar] [CrossRef] [PubMed][Green Version]
  53. Wolf, G.; Yirmiya, R.; Goshen, I.; Iverfeldt, K.; Holmlund, L.; Takeda, K.; Shavit, Y. Impairment of interleukin-1 (IL-1) signaling reduces basal pain sensitivity in mice: Genetic, pharmacological and developmental aspects. Pain 2003, 104, 471–480. [Google Scholar] [CrossRef]
  54. Miyoshi, K.; Obata, K.; Kondo, T.; Okamura, H.; Noguchi, K. Interleukin-18-mediated microglia/astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injury. J. Neurosci. 2008, 28, 12775–12787. [Google Scholar] [CrossRef]
  55. Ji, R.R.; Chamessian, A.; Zhang, Y.Q. Pain regulation by non-neuronal cells and inflammation. Science 2016, 354, 572–577. [Google Scholar] [CrossRef] [PubMed][Green Version]
  56. Sommer, C.; Leinders, M.; Üçeyler, N. Inflammation in the pathophysiology of neuropathic pain. Pain 2018, 159, 595–602. [Google Scholar] [CrossRef]
  57. Gao, X.-Q.; Yang, C.-X.; Chen, G.-J.; Wang, G.-Y.; Chen, B.; Tan, S.-K.; Liu, J.; Yuan, Q.-L. Ginsenoside Rb1 regulates the expressions of brain-derived neurotrophic factor and caspase-3 and induces neurogenesis in rats with experimental cerebral ischemia. J. Ethnopharmacol. 2010, 132, 393–399. [Google Scholar] [CrossRef]
  58. Adamo, D.; Calabria, E.; Coppola, N.; Pecoraro, G.; Mignogna, M.D. Vortioxetine as a new frontier in the treatment of chronic neuropathic pain: A review and update. Ther. Adv. Psychopharmacol. 2021, 11, 1–19. [Google Scholar] [CrossRef]
  59. Zhang, Q.L.; Li, S.Y.; Li, P. Effects of ginsenoside-Rg2 on mechanical allodynia, heat hyperalgeia, depressive state of rats with chronic sciatic nerve constriction injury. Zhongguo Ying Yong Sheng Li Xue Za Zhi 2019, 35, 228–231. [Google Scholar] [CrossRef]
  60. Ruizhen, C.; Chunyan, Z. Research progress on pharmacological activities of Saikosaponins from Radix Bupleurum. Occup. Health 2021, 37, 568–576. [Google Scholar] [CrossRef]
  61. He, Y.; Hu, Z.; Li, A.; Zhu, Z.; Yang, N.; Ying, Z.; He, J.; Wang, C.; Yin, S.; Cheng, S. Recent Advances in Biotransformation of Saponins. Molecules 2019, 24, 2365. [Google Scholar] [CrossRef] [PubMed][Green Version]
  62. Li, X.; Li, X.; Huang, N.; Liu, R.; Sun, R. A comprehensive review and perspectives on pharmacology and toxicology of saikosaponins. Phytomedicine 2018, 50, 73–87. [Google Scholar] [CrossRef] [PubMed]
  63. Ashour, M.L.; Wink, M. Genus Bupleurum: A review of its phytochemistry, pharmacology and modes of action. J. Pharm. Pharm. 2011, 63, 305–321. [Google Scholar] [CrossRef] [PubMed]
  64. Ebata, N.; Nakajima, K.; Hayashi, K.; Okada, M.; Maruno, M. Saponins from the root of Bupleurum falcatum. Phytochemistry 1996, 41, 895–901. [Google Scholar] [CrossRef]
  65. Li, X.Q.; Song, Y.N.; Wang, S.J.; Rahman, K.; Zhu, J.Y.; Zhang, H. Saikosaponins: A review of pharmacological effects. J. Asian Nat. Prod. Res. 2018, 20, 399–411. [Google Scholar] [CrossRef]
  66. Wong, V.K.; Zhou, H.; Cheung, S.S.; Li, T.; Liu, L. Mechanistic study of saikosaponin-d (Ssd) on suppression of murine T lymphocyte activation. J Cell Biochem. 2009, 107, 303–315. [Google Scholar] [CrossRef]
  67. Wang, Y.L.; He, S.X.; Luo, J.Y. Progress in research on antitumor activity of saikosaponin and its mechanism. J. Chin. Integr. Med. 2006, 4, 98–100. [Google Scholar] [CrossRef]
  68. Gupta, R.; Saito, S.; Mori, Y.; Itoh, S.G.; Okumura, H.; Tominaga, M. Structural basis of TRPA1 inhibition by HC-030031 utilizing species-specific differences. Sci. Rep. 2016, 6, 37460. [Google Scholar] [CrossRef][Green Version]
  69. Wang, S.; Kobayashi, K.; Kogure, Y.; Yamanaka, H.; Yamamoto, S.; Yagi, H.; Noguchi, K.; Dai, Y. Negative Regulation of TRPA1 by AMPK in Primary Sensory Neurons as a Potential Mechanism of Painful Diabetic Neuropathy. Diabetes 2018, 67, 98–109. [Google Scholar] [CrossRef][Green Version]
  70. Nativi, C.; Gualdani, R.; Dragoni, E.; Di Cesare Mannelli, L.; Sostegni, S.; Norcini, M.; Gabrielli, G.; la Marca, G.; Richichi, B.; Francesconi, O.; et al. A TRPA1 antagonist reverts oxaliplatin-induced neuropathic pain. Sci. Rep. 2013, 3, 2005. [Google Scholar] [CrossRef][Green Version]
  71. Nassini, R.; Gees, M.; Harrison, S.; De Siena, G.; Materazzi, S.; Moretto, N.; Failli, P.; Preti, D.; Marchetti, N.; Cavazzini, A.; et al. Oxaliplatin elicits mechanical and cold allodynia in rodents via TRPA1 receptor stimulation. Pain 2011, 152, 1621–1631. [Google Scholar] [CrossRef] [PubMed]
  72. Descoeur, J.; Pereira, V.; Pizzoccaro, A.; Francois, A.; Ling, B.; Maffre, V.; Couette, B.; Busserolles, J.; Courteix, C.; Noel, J.; et al. Oxaliplatin-induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors. EMBO Mol. Med. 2011, 3, 266–278. [Google Scholar] [CrossRef] [PubMed]
  73. Anderson, D.W.; Bradbury, K.A.; Schneider, J.S. Broad neuroprotective profile of nicotinamide in different mouse models of MPTP-induced parkinsonism. Eur. J. Neurosci. 2008, 28, 610–617. [Google Scholar] [CrossRef] [PubMed]
  74. Yuan, B.; Yang, R.; Ma, Y.; Zhou, S.; Zhang, X.; Liu, Y. A systematic review of the active saikosaponins and extracts isolated from Radix Bupleuri and their applications. Pharm. Biol. 2017, 55, 620–635. [Google Scholar] [CrossRef] [PubMed][Green Version]
  75. Lin, X.; Wu, S.; Wang, Q.; Shi, Y.; Liu, G.; Zhi, J.; Wang, F. Saikosaponin-D Reduces H2O2-Induced PC12 Cell Apoptosis by Removing ROS and Blocking MAPK-Dependent Oxidative Damage. Cell Mol. Neurobiol. 2016, 36, 1365–1375. [Google Scholar] [CrossRef]
  76. Sun, T.; Song, W.G.; Fu, Z.J.; Liu, Z.H.; Liu, Y.M.; Yao, S.L. Alleviation of neuropathic pain by intrathecal injection of antisense oligonucleotides to p65 subunit of NF-κB. Br. J. Anaesth. 2006, 97, 553–558. [Google Scholar] [CrossRef][Green Version]
  77. Ramesh, G.; MacLean, A.G.; Philipp, M.T. Cytokines and chemokines at the crossroads of neuroinflammation, neurodegeneration, and neuropathic pain. Mediat. Inflamm. 2013, 2013, 480739. [Google Scholar] [CrossRef][Green Version]
  78. Yoon, S.S.; Seo, J.W.; Ann, S.H.; Kim, H.Y.; Kim, H.S.; Cho, H.Y.; Yun, J.; Chung, E.Y.; Koo, J.S.; Yang, C.H. Effects of saikosaponin A on cocaine self-administration in rats. Neurosci. Lett. 2013, 555, 198–202. [Google Scholar] [CrossRef]
  79. Yoon, S.S.; Kim, H.S.; Cho, H.Y.; Yun, J.; Chung, E.Y.; Jang, C.G.; Kim, K.J.; Yang, C.H. Effect of saikosaponin A on maintenance of intravenous morphine self-administration. Neurosci. Lett. 2012, 529, 97–101. [Google Scholar] [CrossRef]
  80. Minett, M.S.; Nassar, M.A.; Clark, A.K.; Passmore, G.; Dickenson, A.H.; Wang, F.; Malcangio, M.; Wood, J.N. Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons. Nat. Commun. 2012, 3, 791. [Google Scholar] [CrossRef][Green Version]
  81. Chen, Z.; Liu, L.; Gao, C.; Chen, W.; Vong, C.T.; Yao, P.; Yang, Y.; Li, X.; Tang, X.; Wang, S.; et al. Astragali Radix (Huangqi): A promising edible immunomodulatory herbal medicine. J. Ethnopharmacol. 2020, 258, 112895. [Google Scholar] [CrossRef] [PubMed]
  82. Fu, J.; Wang, Z.; Huang, L.; Zheng, S.; Wang, D.; Chen, S.; Zhang, H.; Yang, S. Review of the botanical characteristics, phytochemistry, and pharmacology of Astragalus membranaceus (Huangqi). Phytother. Res. 2014, 28, 1275–1283. [Google Scholar] [CrossRef] [PubMed]
  83. Song, J.Z.; Mo, S.F.; Yip, Y.K.; Qiao, C.F.; Han, Q.B.; Xu, H.X. Development of microwave assisted extraction for the simultaneous determination of isoflavonoids and saponins in radix astragali by high performance liquid chromatography. J. Sep. Sci. 2007, 30, 819–824. [Google Scholar] [CrossRef] [PubMed]
  84. Ma, X.Q.; Shi, Q.; Duan, J.A.; Dong, T.T.; Tsim, K.W. Chemical analysis of Radix Astragali (Huangqi) in China: A comparison with its adulterants and seasonal variations. J. Agric. Food Chem. 2002, 50, 4861–4866. [Google Scholar] [CrossRef]
  85. Wang, Y.; Liu, L.; Ma, Y.; Guo, L.; Sun, Y.; Liu, Q.; Liu, J. Chemical Discrimination of Astragalus mongholicus and Astragalus membranaceus Based on Metabolomics Using UHPLC-ESI-Q-TOF-MS/MS Approach. Molecules 2019, 24, 4064. [Google Scholar] [CrossRef][Green Version]
  86. Liu, D.-l.; Bao, H.-Y.; Liu, Y. Progress on Chemical Constituents and Pharmacological Effects of Astragali Radix in Recent Five Years. Food Drug 2014, 16, 68–70. [Google Scholar]
  87. Polat, E.; Bedir, E.; Perrone, A.; Piacente, S.; Alankus-Caliskan, O. Triterpenoid saponins from Astragalus wiedemannianus Fischer. Phytochemistry 2010, 71, 658–662. [Google Scholar] [CrossRef]
  88. Verotta, L.; Guerrini, M.; El-Sebakhy, N.A.; Assad, A.M.; Toaima, S.M.; Radwan, M.M.; Luo, Y.D.; Pezzuto, J.M. Cycloartane and oleanane saponins from egyptian astragalus spp. as modulators of lymphocyte proliferation. Planta Med. 2002, 68, 986–994. [Google Scholar] [CrossRef]
  89. Zhang, J.; Wu, C.; Gao, L.; Du, G.; Qin, X. Astragaloside IV derived from Astragalus membranaceus: A research review on the pharmacological effects. Adv. Pharm. 2020, 87, 89–112. [Google Scholar] [CrossRef]
  90. Yang, F.; Xiao, X.; Lee, B.H.; Vu, S.; Yang, W.; Yarov-Yarovoy, V.; Zheng, J. The conformational wave in capsaicin activation of transient receptor potential vanilloid 1 ion channel. Nat. Commun. 2018, 9, 2879. [Google Scholar] [CrossRef]
  91. Tominaga, M.; Caterina, M.J.; Malmberg, A.B.; Rosen, T.A.; Gilbert, H.; Skinner, K.; Raumann, B.E.; Basbaum, A.I.; Julius, D. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 1998, 21, 531–543. [Google Scholar] [CrossRef][Green Version]
  92. Mitchell, K.; Bates, B.D.; Keller, J.M.; Lopez, M.; Scholl, L.; Navarro, J.; Madian, N.; Haspel, G.; Nemenov, M.I.; Iadarola, M.J. Ablation of rat TRPV1-expressing Adelta/C-fibers with resiniferatoxin: Analysis of withdrawal behaviors, recovery of function and molecular correlates. Mol. Pain 2010, 6, 94. [Google Scholar] [CrossRef] [PubMed][Green Version]
  93. Li, X.; Kang, L.; Li, G.; Zeng, H.; Zhang, L.; Ling, X.; Dong, H.; Liang, S.; Chen, H. Intrathecal leptin inhibits expression of the P2X2/3 receptors and alleviates neuropathic pain induced by chronic constriction sciatic nerve injury. Mol. Pain 2013, 9, 65. [Google Scholar] [CrossRef] [PubMed][Green Version]
  94. Lin, J.; Li, G.; Den, X.; Xu, C.; Liu, S.; Gao, Y.; Liu, H.; Zhang, J.; Li, X.; Liang, S. VEGF and its receptor-2 involved in neuropathic pain transmission mediated by P2X2/3 receptor of primary sensory neurons. Brain Res. Bull. 2010, 83, 284–291. [Google Scholar] [CrossRef] [PubMed]
  95. Dong, Z.Q.; Ma, F.; Xie, H.; Wang, Y.Q.; Wu, G.C. Down-regulation of GFRalpha-1 expression by antisense oligodeoxynucleotide attenuates electroacupuncture analgesia on heat hyperalgesia in a rat model of neuropathic pain. Brain Res. Bull. 2006, 69, 30–36. [Google Scholar] [CrossRef]
  96. Dong, Z.Q.; Ma, F.; Xie, H.; Wang, Y.Q.; Wu, G.C. Changes of expression of glial cell line-derived neurotrophic factor and its receptor in dorsal root ganglions and spinal dorsal horn during electroacupuncture treatment in neuropathic pain rats. Neurosci. Lett. 2005, 376, 143–148. [Google Scholar] [CrossRef]
  97. Shen, Y.; Meiri, K. GAP-43 dependency defines distinct effects of netrin-1 on cortical and spinal neurite outgrowth and directional guidance. Int. J. Dev. Neurosci. 2012, 31, 11–20. [Google Scholar] [CrossRef]
  98. Mendonca, H.R.; Araujo, S.E.; Gomes, A.L.; Sholl-Franco, A.; da Cunha Faria Melibeu, A.; Serfaty, C.A.; Campello-Costa, P. Expression of GAP-43 during development and after monocular enucleation in the rat superior colliculus. Neurosci. Lett. 2010, 477, 23–27. [Google Scholar] [CrossRef]
  99. Davidson, J.A. Treatment of the patient with diabetes: Importance of maintaining target HbA(1c) levels. Curr. Med. Res. Opin. 2004, 20, 1919–1927. [Google Scholar] [CrossRef]
  100. Yi, T.; Fan, L.L.; Chen, H.L.; Zhu, G.Y.; Suen, H.M.; Tang, Y.N.; Zhu, L.; Chu, C.; Zhao, Z.Z.; Chen, H.B. Comparative analysis of diosgenin in Dioscorea species and related medicinal plants by UPLC-DAD-MS. BMC Biochem. 2014, 15, 19. [Google Scholar] [CrossRef][Green Version]
  101. Arya, P.; Kumar, P. Diosgenin a steroidal compound: An emerging way to cancer management. J. Food Biochem. 2021, 45, e14005. [Google Scholar] [CrossRef]
  102. Chen, Y.; Tang, Y.-M.; Yu, S.-L.; Han, Y.-W.; Kou, J.-P.; Liu, B.-L.; Yu, B.-Y. Advances in the pharmacological activities and mechanisms of diosgenin. Chin. J. Nat. Med. 2015, 13, 578–587. [Google Scholar] [CrossRef]
  103. Al-Habori, M.; Raman, A.; Lawrence, M.J.; Skett, P. In vitro effect of fenugreek extracts on intestinal sodium-dependent glucose uptake and hepatic glycogen phosphorylase A. Int. J. Exp. Diabetes Res. 2001, 2, 91–99. [Google Scholar] [CrossRef][Green Version]
  104. Fan, R.; He, W.; Fan, Y.; Xu, W.; Xu, W.; Yan, G.; Xu, S. Recent advances in chemical synthesis, biocatalysis, and biological evaluation of diosgenin derivatives—A review. Steroids 2022, 180, 108991. [Google Scholar] [CrossRef]
  105. Fernandes, P.; Cruz, A.; Angelova, B.; Pinheiro, H.M.; Cabral, J.M.S. Microbial conversion of steroid compounds: Recent developments. Enzym. Microb. Tech. 2003, 32, 688–705. [Google Scholar] [CrossRef]
  106. Obrosova, I.G. Update on the pathogenesis of diabetic neuropathy. Curr. Diabetes Rep. 2003, 3, 439–445. [Google Scholar] [CrossRef]
  107. Kasznicki, J.; Kosmalski, M.; Sliwinska, A.; Mrowicka, M.; Stanczyk, M.; Majsterek, I.; Drzewoski, J. Evaluation of oxidative stress markers in pathogenesis of diabetic neuropathy. Mol. Biol. Rep. 2012, 39, 8669–8678. [Google Scholar] [CrossRef][Green Version]
  108. Vincent, A.M.; Russell, J.W.; Low, P.; Feldman, E.L. Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr. Rev. 2004, 25, 612–628. [Google Scholar] [CrossRef]
  109. Wang, C.; Ning, L.P.; Wang, Y.H.; Zhang, Y.; Ding, X.L.; Ge, H.Y.; Arendt-Nielsen, L.; Yue, S.W. Nuclear factor-kappa B mediates TRPV4-NO pathway involved in thermal hyperalgesia following chronic compression of the dorsal root ganglion in rats. Behav. Brain Res. 2011, 221, 19–24. [Google Scholar] [CrossRef]
  110. Zhang, Y.P.; Song, C.Y.; Yuan, Y.; Eber, A.; Rodriguez, Y.; Levitt, R.C.; Takacs, P.; Yang, Z.; Goldberg, R.; Candiotti, K.A. Diabetic neuropathic pain development in type 2 diabetic mouse model and the prophylactic and therapeutic effects of coenzyme Q10. Neurobiol. Dis. 2013, 58, 169–178. [Google Scholar] [CrossRef]
  111. Kumar, A.; Negi, G.; Sharma, S.S. Suppression of NF-κB and NF-κB regulated oxidative stress and neuroinflammation by BAY 11-7082 (IκB phosphorylation inhibitor) in experimental diabetic neuropathy. Biochimie 2012, 94, 1158–1165. [Google Scholar] [CrossRef]
  112. Kawamura, N.; Dyck, P.J.; Schmeichel, A.M.; Engelstad, J.K.; Low, P.A.; Dyck, P.J. Inflammatory mediators in diabetic and non-diabetic lumbosacral radiculoplexus neuropathy. Acta Neuropathol. 2008, 115, 231–239. [Google Scholar] [CrossRef]
  113. Gao, M.; Chen, L.; Yu, H.; Sun, Q.; Kou, J.; Yu, B. Diosgenin down-regulates NF-kappaB p65/p50 and p38MAPK pathways and attenuates acute lung injury induced by lipopolysaccharide in mice. Int. Immunopharmacol. 2013, 15, 240–245. [Google Scholar] [CrossRef]
  114. Gao, Z.; Feng, Y.; Ju, H. The Different Dynamic Changes of Nerve Growth Factor in the Dorsal Horn and Dorsal Root Ganglion Leads to Hyperalgesia and Allodynia in Diabetic Neuropathic Pain. Pain Physician 2017, 20, E551–E561. [Google Scholar]
  115. Calissano, P.; Amadoro, G.; Matrone, C.; Ciafrè, S.; Marolda, R.; Corsetti, V.; Ciotti, M.T.; Mercanti, D.; Di Luzio, A.; Severini, C.; et al. Does the term ‘trophic’ actually mean anti-amyloidogenic? The case of NGF. Cell Death Differ. 2010, 17, 1126–1133. [Google Scholar] [CrossRef]
  116. Byun, Y.H.; Lee, M.H.; Kim, S.S.; Kim, H.; Chang, H.K.; Lee, T.H.; Jang, M.H.; Shin, M.C.; Shin, M.S.; Kim, C.J. Treadmill running promotes functional recovery and decreases brain-derived neurotrophic factor mRNA expression following sciatic crushed nerve injury in rats. J. Sports Med. Phys. Fit. 2005, 45, 222–228. [Google Scholar]
  117. Liu, M.; Luo, F.; Qing, Z.; Yang, H.; Liu, X.; Yang, Z.; Zeng, J. Chemical Composition and Bioactivity of Essential Oil of Ten Labiatae Species. Molecules 2020, 25, 4862. [Google Scholar] [CrossRef]
  118. Palida, A.; Mi, R.; Cong, Y.; Yi, B.; Wang, X. Isolation and identification of chemical constituents in Ocimum bacilicum. West China J. Pharm. Sci. 2007, 22, 489–490. [Google Scholar] [CrossRef]
  119. Kaur, G.; Bali, A.; Singh, N.; Jaggi, A.S. Ameliorative potential of Ocimum sanctum in chronic constriction injury-induced neuropathic pain in rats. An. Acad. Bras. Ciênc. 2015, 87, 417–429. [Google Scholar] [CrossRef][Green Version]
  120. Anandjiwala, S.; Kalola, J.; Rajani, M. Quantification of eugenol, luteolin, ursolic acid, and oleanolic acid in black (Krishna Tulasi) and green (Sri Tulasi) varieties of Ocimum sanctum Linn. using high-performance thin-layer chromatography. J. AOAC Int. 2006, 89, 1467–1474. [Google Scholar] [CrossRef][Green Version]
  121. Rao, A.R.; Veeresham, C.; Asres, K. In vitro and in vivo inhibitory activities of four Indian medicinal plant extracts and their major components on rat aldose reductase and generation of advanced glycation endproducts. Phytother. Res. 2013, 27, 753–760. [Google Scholar] [CrossRef]
  122. Carrasco, C.; Naziroǧlu, M.; Rodríguez, A.B.; Pariente, J.A. Neuropathic Pain: Delving into the Oxidative Origin and the Possible Implication of Transient Receptor Potential Channels. Front. Physiol. 2018, 9, 95. [Google Scholar] [CrossRef]
  123. Bourinet, E.; Altier, C.; Hildebrand, M.E.; Trang, T.; Salter, M.W.; Zamponi, G.W. Calcium-permeable ion channels in pain signaling. Physiol. Rev. 2014, 94, 81–140. [Google Scholar] [CrossRef]
  124. Katsuyama, Y.; Sato, Y.; Okano, Y.; Masaki, H. Intracellular oxidative stress induced by calcium influx initiates the activation of phagocytosis in keratinocytes accumulating at S-phase of the cell cycle after UVB irradiation. J. Dermatol. Sci. 2021, 103, 41–48. [Google Scholar] [CrossRef]
  125. Gibson, G.E. Interactions of oxidative stress with cellular calcium dynamics and glucose metabolism in Alzheimer’s disease. Free Radic. Biol. Med. 2002, 32, 1061–1070. [Google Scholar] [CrossRef]
  126. Goodwin, J.; Nath, S.; Engelborghs, Y.; Pountney, D.L. Raised calcium and oxidative stress cooperatively promote alpha-synuclein aggregate formation. Neurochem. Int. 2013, 62, 703–711. [Google Scholar] [CrossRef]
  127. Carbonera, D.; Azzone, G.F. Permeability of inner mitochondrial membrane and oxidative stress. Biochim. Biophys. Acta 1988, 943, 245–255. [Google Scholar] [CrossRef]
  128. George, S.; Chaturvedi, P. Protective role of Ocimum canum plant extract in alcohol-induced oxidative stress in albino rats. Br. J. Biomed. Sci. 2008, 65, 80–85. [Google Scholar] [CrossRef]
  129. Kelm, M.A.; Nair, M.G.; Strasburg, G.M.; DeWitt, D.L. Antioxidant and cyclooxygenase inhibitory phenolic compounds from Ocimum sanctum Linn. Phytomedicine 2000, 7, 7–13. [Google Scholar] [CrossRef]
  130. Balanehru, S.; Nagarajan, B. Protective effect of oleanolic acid and ursolic acid against lipid peroxidation. Biochem. Int. 1991, 24, 981–990. [Google Scholar]
  131. Hu, S.; Wu, Y.; Zhao, B.; Hu, H.; Zhu, B.; Sun, Z.; Li, P.; Du, S. Panax notoginseng Saponins Protect Cerebral Microvascular Endothelial Cells against Oxygen-Glucose Deprivation/Reperfusion-Induced Barrier Dysfunction via Activation of PI3K/Akt/Nrf2 Antioxidant Signaling Pathway. Molecules 2018, 23, 2781. [Google Scholar] [CrossRef] [PubMed][Green Version]
  132. Neco, P.; Rose, B.; Huynh, N.; Zhang, R.; Bridge, J.H.; Philipson, K.D.; Goldhaber, J.I. Sodium-calcium exchange is essential for effective triggering of calcium release in mouse heart. Biophys. J. 2010, 99, 755–764. [Google Scholar] [CrossRef] [PubMed][Green Version]
  133. Sarkar, A.; Pandey, D.N.; Pant, M.C. A report on the effects of Ocimum sanctum (Tulsi) leaves and seeds on blood and urinary uric acid, urea and urine volume in normal albino rabbits. Indian J. Physiol. Pharmacol. 1990, 34, 61–62. [Google Scholar] [PubMed]
  134. Dalbeth, N.; Choi, H.K.; Joosten, L.A.B.; Khanna, P.P.; Matsuo, H.; Perez-Ruiz, F.; Stamp, L.K. Gout. Nat. Rev. Dis. Prim. 2019, 5, 69. [Google Scholar] [CrossRef] [PubMed]
  135. Khanna, N.; Bhatia, J. Antinociceptive action of Ocimum sanctum (Tulsi) in mice: Possible mechanisms involved. J. Ethnopharmacol. 2003, 88, 293–296. [Google Scholar] [CrossRef]
  136. Zhang, X.H.; Feng, C.C.; Pei, L.J.; Zhang, Y.N.; Chen, L.; Wei, X.Q.; Zhou, J.; Yong, Y.; Wang, K. Electroacupuncture attenuates neuropathic pain and comorbid negative behavior: The involvement of the dopamine system in the amygdala. Front. Neurosci. 2021, 15, 657507. [Google Scholar] [CrossRef]
  137. Shao, F.; Du, J.; Wang, S.; Cerne, R.; Fang, J.; Shao, X.; Jin, X.; Fang, J. Electroacupuncture alleviates anxiety-like behavior in pain aversion rats by attenuating the expression of neuropeptide Y in anterior cingulate cortex. Clin. Complementary Med. Pharmacol. 2022, 2, 100019. [Google Scholar] [CrossRef]
Figure 1. Chemical structures of different subgroups of tetracyclic triterpenoid saponins (A), pentacyclic triterpenoid saponins (B), and steroidal saponins (C).
Figure 1. Chemical structures of different subgroups of tetracyclic triterpenoid saponins (A), pentacyclic triterpenoid saponins (B), and steroidal saponins (C).
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Figure 2. Chemical structures of ginsenosides (A), saikosaponins (B), astragaloside IV (C), and diosgenin and dioscin (D) (Note: PPD, protopanaxadiol; PPT, protopanaxatriol; Glc, glucoside; Rha, rhamnoside; Fuc, fructoside).
Figure 2. Chemical structures of ginsenosides (A), saikosaponins (B), astragaloside IV (C), and diosgenin and dioscin (D) (Note: PPD, protopanaxadiol; PPT, protopanaxatriol; Glc, glucoside; Rha, rhamnoside; Fuc, fructoside).
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Figure 3. Schematic diagram of the direction of in-depth analysis of saponins in the treatment of neuropathic pain in future research.
Figure 3. Schematic diagram of the direction of in-depth analysis of saponins in the treatment of neuropathic pain in future research.
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Table 1. Effects of saikosaponins on neuropathic pain.
Table 1. Effects of saikosaponins on neuropathic pain.
Saponins Animals/CellsDose mg/kgEffects/Behavioral EvaluationMechanisms of ActionReference
total saponin extract (TSE), ginsenoside Rb1, Rb1 metabolite compound Kmale Sprague–Dawley ratsTSE 50 mg/kg, Rb1 12.5 mg/kg, compound K 7 mg/kg (p.o.)↓TNI-induced mechanical, cold, and warm allodynia; ↓SCI-induced mechanical allodynia and thermal hyperalgesia; →Basso–Beattie–Bresnahan locomotor scale↓IL-1β, IL-6, iNOS, COX-2; ↓microglialand astrocyte activationJee Youn Lee [21]
ginsenoside Rg1male Sprague–Dawley rats2, 5, 10 ug/uL (intrathecal injection); 4 days↓CCI-induced thermal hyperalgesia;↓IBA-1, OX-42; ↓microglialover-activation; ↓p38MAPK/NF-κB signaling pathway Gao Chao [22]
ginsenoside Rfmale Sprague–Dawley rats 0.5, 1.5, 3 mg/kg (i.p.); 1 day, 7 days, 14 days, 21 days↓CCI-induced mechanical hyperalgesia; ↓CCI-induced immobility in the forced swimming test↓IL-1β and IL-6 in both the spinal cord and the DRG; ↑IL-10 in the DRG but not in the spinal cord Yangyi Li [23]
ginsenoside Rb1male and female Sprague-Dawley rats 10 mg/kg (i.p.); 1–7 days↑SCI-induced reduction of Basso–Beattie–Bresnahan locomotor scale ↓neuronal damage; ↓apoptotic rate in spinal cord neurons. ↑ AQP4 expressionFei Huang [24]
saikosaponin A; saikosaponin B1; saikosaponin B2; saikosaponin C; saikosaponin D; saikosaponin F; B. falcatum extract male ICR mice/HEK293 cells B. falcatum extract 50 mg/kg, saikosaponin D 20 mg/kg (p.o.)↓AITC-induced nociceptive behaviors; ↓vincristine-induced mechanical hypersensitivitysaikosaponins are TRPA1 antagonists Gyeongbeen Lee [25]
saikosaponin Dmale ICR mice 10 mg/kg (p.o.), 1 day and 15 days↓ STZ-induced mechanical hypersensitivity and paclitaxel-induced mechanical allodynia ____Gyeongbeen Lee [26]
saikosaponin DPC12 cells 200, 300, 400 μg/mL ↓H2O2-induced decrease in cell viability; ↓apoptosis rate; ↓caspase-3 activation and poly-ADP-ribose polymerase cleavage; improved the nuclear morphology↓H2O2-induced release of malonic dialdehyde MDA and lactate dehy-drogenase; ↑SOD; ↓apoptotic rate; ↓ H2O2-induced p-ERK, p-c-JNK, p-p38MAPKXuemei Lin [27]
saikosaponin Amale Sprague–Dawley rats6.25, 12.50, 25.00 mg/kg (i.p.), 14 days↓CCI-induced mechanical allodynia and thermal hyperalgesia ↓TNF-α, IL-1β, IL-2 in spinal cord; ↓p38MAPK/NF-κB signaling pathwayXin Zhou [28]
saikosaponin A; saikosaponin Dmale BALB/c mice; male Sprague–Dawley rats; Raw264.7 cells20, 10, 5 mg/kg (p.o.); ↓carrageenan-induced rat paw edema; ↓acetic acid-induced evans blue dye leakage↓NO, PGE2, IL-6, TNF-α, iNOS, COX-2 in LPS-induced RAW264.7 cells; ↓NF-κB signaling pathwayChun-Ni Lu [29]
saikosaponin A Raw264.7 cells3.125, 6.25, 12.5, 25 μM ____↓IL-1β, IL-6 TNF-α, iNOS, COX-2 in LPS-induced RAW264.7 cells; ↓MAPK/NF-κB signaling pathwayJie Zhu [30]
saikosaponin A male Sprague–Dawley rats20 mg/kg (i.v.); 3 days↑neurological functions andcognition; ↓brain edema and blood brain barrier permeability after controlled cortical impact↓AQP-4, MMP-9, MAPK, c-JNK, TNF-α, IL-6; ↓MAPK signaling pathwayXiang Mao [31]
Bupleurum falcatum L. roots essential oil (BFEO); Saikosaponin A male Swiss miceBFEO 25, 50, 100 mg/kg (p.o.); SA 6, 12, 25 mg/kg (p.o.) ↑the antinociceptive activity in formalin-induced paw licking test, ↓mechanical allodynia, →locomotor action↑the L-arginine–NO–cGMP-KATP channel pathway Davoud Ahmadimoghaddam [32]
saikosaponin Amale Kunming mice; Nav1.7-CHO cells2.5, 5, 10 mg/kg (i.g); 100 nM; ↓thermal pain and formalin-induced nociceptive responsesinhibitory effect on Nav1.7Yijia Xu [33]
astragaloside IVmale Sprague–Dawley rats15, 30, 60 mg/kg (i.p.), 23 days↓CCI-induced mechanical allodynia and thermal hyperalgesia; ↑CCI-induced reduction of nerve conduction velocity; →locomotor action↓P2 × 3, TRPA1 and TRPV1 in the DRG; restoring the histological structure of the damaged sciatic nerve by accumulating GFRα1Guo-Bing Shi [34]
astragaloside IVSprague–Dawley rats 0, 50, 100, 200μM↑regeneration rate across the wide gap; ↑myelinated axons; ↑evoked action potential; ↓nerve regenerationplays a dual role in anastomosisChun-Yuan Cheng [35]
astragaloside IVBALB/c mice2.5, 5, 10 mg/kg (i.p.)↑denervating the left sciatic nerve-induced the number and diameter of myelinated nerve fibers; ↑motor nerve conduction velocity and action potential amplitude in the sciatic nerve↑growth-associated protein-43 expression; ↑pheral nerve regeneration and functional reconstructionXiaohong Zhang [36]
astragaloside IVmale Sprague–Dawley rats3, 6, 12 mg/kg (p.o.), 12 days↑pain threshold in STZ-diabetic rats; ↑motor nerve conduction velocity↓blood glucose concentration and HbA1C levels; ↑plasma insulin levels, the activity of glutathione peroxidase in nerves; ↓ the activation of aldose reductase in erythrocytes and advanced glycation end products; ↑Na+,K+-ATPase activityJunxian Yu [37]
diosgeninmale albino Wistar rats 40 mg/kg (i.g), 35 days↓mechanical hyperalgesia and thermal hyperalgesia and pain score in STZ-diabetic rats;↓MDA, ↑SOD and catalase activity; ↓NF-κB and IL-1βZahra Kiasalari [38]
diosgeninmale ICR mice, male Sprague–Dawley rats; PC12 cells, C6 glioma cells10 mg/kg (p.o.); 0.1–10 mg/mL↑NGF levels in alloxan-diabetic rats; ↑nerveconduction velocities reverses functional and ultrastructural changes and induces neural regenerationTong Ho Kang [39]
diosgeninmale Sprague–Dawley rats10, 20, 40 mg/kg (i.p.), 14 days↓CCI-induced mechanical allodynia and thermal hyperalgesia.↓TNF-α, IL-1β, IL-2, and oxidative stress; ↓p38MAPK/NF-κB signaling pathwayWei-Xin Zhao [40]
diosgeninmale Sprague–Dawley rats25, 50, 100 mg/kg (p.o.), 7 days↑functional locomotor recovery following sciatic crushed nerve injury↓nerve injury-induced increase in BDNF, TrkB, COX-2, and iNOS expressionsByung-Ki Lee [41]
ocimum sanctum, saponin-rich extractsWistar albino rats 100 and 200 mg/kg (p.o.), 14 days ↓CCI-induced cold-allodynia, heat-hyperalgesia, mechanical hyperalgesia and tail cold-hyperalgesia ↓oxidative stress and calcium levelsGurpreet Kaur [42]
ocimum sanctum, saponin-rich extractsWistar albino rats 100 and 200 mg/kg (p.o.), 14 days ↓ vincristine-induced cold-allodynia, heat-hyperalgesia, mechanical hyperalgesia and tail cold-hyperalgesia ↓oxidative stress and calcium levelsGurpreet Kaur [43]
saponins of Tribulus terrestrisWistar rats of either sex25, 50, 100 mg/kg (p.o.)↓vincristine-induced mechanical hyperalgesia and allodynia; ↓chemical-induced nociception ↓TNF-α, IL-1β, and IL-6; ↑ nerve conduction velocity, neurotransmitters, l-glutamic acid and l-aspartic acidMrinmoy Gautam [44]
escinmale Kunming mice, male Sprague–Dawley rats; PC12 cells7, 14, 28 mg/kg (i.g.), 14 days; 15, 25, 35 mg/kg (i.g.), 3 days; 2.5, 5, 10 μM ↓CCI-induced thermal hyperalgesia; ↓ formalin-induced nociceptive responses↓TLR-4/NF-κB signal pathway; ↓GFAP, NGFLiudai Zhang [45]
escinmale Sprague–Dawley rats 4 mg/kg (i.p.), 7 days↓Paclitaxel-induced mechanical allodynia and thermal hyperalgesia ↑LC3II expression, ↓p62expression levels Yan Fang [46]
ginsenoside RfSwiss male mice 10−14, 10−12, and 10−10 mg/kg, (i.p.), 6 days; 10−12–10−2 mg/mL↑U50-induced analgesia, ↓tolerancenonopioid and non-dihydropyridine-sensitive Ca2+ channel mechanisms; non-benzodiazepine-GABAAergic mechanisms Kumar V.S. Nemmani [47]
Note: ↑ increase/enhanced/upregulate; ↓ decrease/inhibit/prevent/attenuate/downregulate; TSE, total saponin extract; TNI, tail nerve injury; SCI, spinal cord injury; CCI, chronic constrictive injury; DRG, the dorsal root ganglion; AITC, allyl isothiocyanate; STZ, streptozotocin; LPS, lipopolysaccharide; BFEO, Bupleurum falcatum L. roots essential oil.
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Tan, B.; Wu, X.; Yu, J.; Chen, Z. The Role of Saponins in the Treatment of Neuropathic Pain. Molecules 2022, 27, 3956. https://doi.org/10.3390/molecules27123956

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Tan B, Wu X, Yu J, Chen Z. The Role of Saponins in the Treatment of Neuropathic Pain. Molecules. 2022; 27(12):3956. https://doi.org/10.3390/molecules27123956

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Tan, Bei, Xueqing Wu, Jie Yu, and Zhong Chen. 2022. "The Role of Saponins in the Treatment of Neuropathic Pain" Molecules 27, no. 12: 3956. https://doi.org/10.3390/molecules27123956

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