Schisandra chinensis Fructus and Its Active Ingredients as Promising Resources for the Treatment of Neurological Diseases

Neurological diseases (NDs) are a leading cause of death worldwide and tend to mainly affect people under the age of 50. High rates of premature death and disability caused by NDs undoubtedly constrain societal development. However, effective therapeutic drugs and methods are very limited. Schisandra chinensis Fructus (SCF) is the dry ripe fruit of Schisandra chinensis (Turcz.) Baill, which has been used in traditional Chinese medicine for thousands of years. Recent research has indicated that SCF and its active ingredients show a protective role in NDs, including cerebrovascular diseases, neurodegenerative diseases, or depression. The key neuroprotective mechanisms of SCF and its active ingredients have been demonstrated to include antioxidation, suppression of apoptosis, anti-inflammation, regulation of neurotransmitters, and modulation of brain-derived neurotrophic factor (BDNF) related pathways. This paper summarizes studies of the role of SCF and its active ingredients in protecting against NDs, and highlights them as promising resources for future treatment. Furthermore, novel insights on the future challenges of SCF and its active ingredients are offered.


Introduction
Neurological diseases (NDs) are a major public health problem, with high prevalence, and leading to disability and mortality. The World Health Organization estimates that NDs and their sequelae affect as many as one billion people worldwide and are major factors contributing to associated disability and suffering. Cerebrovascular diseases, neurodegenerative diseases, and mental disorders, such as stroke and dementia, rank among the leading causes of death and disability, often affecting the adults in working-age [1]. The health index level of NDs is closely related to the level of regional socioeconomic development. In low-and middle-income countries, the prognosis of NDs is worse, as the resources to treat and manage patients are limited [2]. In China, the prevalence of cerebrovascular diseases has increased to 12.3‰ in rural areas, as evidenced by a survey taken every five years, from 1993 to 2013 [3]. The current number of cardiovascular and cerebrovascular diseases patients is 290 million, including 13 million stroke patients.
The treatment of NDs, including stroke and Alzheimer's disease (AD), is critical to patients' lifespan and quality of life. However, effective therapeutic drugs and methods are very limited. Even in high-income countries, stroke remains a common cause of death and disability [4], and women Table 1.

Antioxidative Effect in Neurological Diseases
Oxidative stress is one of the main causes of neural injury and neurodegeneration [54]. Moreover, because of the fact that antioxidant substances cannot easily penetrate the blood-brain barrier, brain tissue is particularly sensitive to oxidative stress [55]. The oxidizable/reducible chemical pairs, including reduced thioredoxin/oxidized thioredoxin, glutathione/glutathione disulfide, and NAD + /NADH (and NADP/NADPH), determine the overall redox potential of a cell [56].
Increasing evidence demonstrates that oxidative stress participates in the pathophysiological processes of stroke (including ischemia-reperfusion injury) and other brain injuries [57,58]. The production of reactive oxygen species (ROS) rapidly increases and overwhelms the antioxidant defenses. An excess of ROS directly modifies or degenerates cellular macromolecules, causing lipid peroxidation, protein oxidation, and DNA damage in neural tissues, and finally leading to brain injury [59,60]. In neurodegenerative diseases, the increased ROS leads to neuronal dysfunction. In the early events of AD, ROS are related to Aβ-induced nerve injury, as well as the abnormal phosphorylation of tau proteins. In addition, the accumulated ROS exacerbate dopaminergic neuronal death in the substantia nigra of PD patients [61]. In neuronal excitotoxicity, stroke, and neurodegenerative disease, increased extracellular glutamate levels bring about calcium overload, as well as mitochondrial dysfunction [62]. Therefore, redox regulation has recently been recognized as an important factor in acute and chronic NDs [63]. SCF and its ingredients were shown to manifest neuroprotective effects on NDs by attenuating oxidative stress ( Figure 2). The pharmacological data are shown in Table 2.

Antioxidative Effect in Neurological Diseases
Oxidative stress is one of the main causes of neural injury and neurodegeneration [54]. Moreover, because of the fact that antioxidant substances cannot easily penetrate the blood-brain barrier, brain tissue is particularly sensitive to oxidative stress [55]. The oxidizable/reducible chemical pairs, including reduced thioredoxin/oxidized thioredoxin, glutathione/glutathione disulfide, and NAD + /NADH (and NADP/NADPH), determine the overall redox potential of a cell [56].
Increasing evidence demonstrates that oxidative stress participates in the pathophysiological processes of stroke (including ischemia-reperfusion injury) and other brain injuries [57,58]. The production of reactive oxygen species (ROS) rapidly increases and overwhelms the antioxidant defenses. An excess of ROS directly modifies or degenerates cellular macromolecules, causing lipid peroxidation, protein oxidation, and DNA damage in neural tissues, and finally leading to brain injury [59,60]. In neurodegenerative diseases, the increased ROS leads to neuronal dysfunction. In the early events of AD, ROS are related to Aβ-induced nerve injury, as well as the abnormal phosphorylation of tau proteins. In addition, the accumulated ROS exacerbate dopaminergic neuronal death in the substantia nigra of PD patients [61]. In neuronal excitotoxicity, stroke, and neurodegenerative disease, increased extracellular glutamate levels bring about calcium overload, as well as mitochondrial dysfunction [62]. Therefore, redox regulation has recently been recognized as an important factor in acute and chronic NDs [63]. SCF and its ingredients were shown to manifest neuroprotective effects on NDs by attenuating oxidative stress ( Figure 2). The pharmacological data are shown in Table 2.   Under pathological conditions, the redox balance is disrupted. The degradation of glutathione (GSH) is accelerated when the GSH-Px activity is decreased, and the production of glutathione disulfide (GSSG) is increased [64][65][66]. The expression of enzymes with antioxidant effects, as superoxide dismutase (SOD) and catalase (CAT), are inhibited simultaneously [67][68][69]. The mitochondrial membrane potential (MMP) decreases, while reactive oxygen species (ROS) is released excessively [70,71]. Intracellular Ca 2+ influx, as well as intracellular Ca 2+ release from the endoplasmic reticulum are increased, resulting in a series of downstream pathological responses [72][73][74]. The protective effect of SCF and its active ingredients are shown in orange.

SCF and Total Lignans of SCF
SCF was supposed to be a complementary medicine in cyclophosphamide (CTX) treatment for its effect of reducing chloroacetaldehyde (CAA) production and decreasing the Cmax and AUC0-24h of 2-dechloroethylcyclophosphamide (DCCTX). With SCF treatment, brain glutathione (GSH) content increased and malondialdehyde (MDA) levels were reduced in rats with CTX-induced damage [20]. Yang et al. reported that SCF showed an antioxidant effect on AD rats by elevating superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity, and reducing MDA level [21].
The lignans extracted from SCF were identified as a potential treatment for AD, because of their protection against damage from oxidative stress. In a recent report, the total lignans of SCF (TLS) blocked the decrease of mitochondrial membrane potential (MMP) in primary mouse neuronal cells. Moreover, TLS restored the activity of total antioxidant capacity (T-AOC) in AD mice (see Sections 5.1 and 6.1 for more detail) [26]. In addition, the lignans of SCF were assumed to protect against Dgalactose (D-gal)-induced neurotoxicity in rats by maintaining GSH, MDA, and nitric oxide (NO) levels, and alleviating the decrease of SOD, catalase (CAT), and T-AOC activity. They were demonstrated to be potential candidates for the treatment of aging-associated neurodegenerative diseases [27]. Under pathological conditions, the redox balance is disrupted. The degradation of glutathione (GSH) is accelerated when the GSH-Px activity is decreased, and the production of glutathione disulfide (GSSG) is increased [64][65][66]. The expression of enzymes with antioxidant effects, as superoxide dismutase (SOD) and catalase (CAT), are inhibited simultaneously [67][68][69]. The mitochondrial membrane potential (MMP) decreases, while reactive oxygen species (ROS) is released excessively [70,71]. Intracellular Ca 2+ influx, as well as intracellular Ca 2+ release from the endoplasmic reticulum are increased, resulting in a series of downstream pathological responses [72][73][74]. The protective effect of SCF and its active ingredients are shown in orange.

SCF and Total Lignans of SCF
SCF was supposed to be a complementary medicine in cyclophosphamide (CTX) treatment for its effect of reducing chloroacetaldehyde (CAA) production and decreasing the C max and AUC0-24h of 2-dechloroethylcyclophosphamide (DCCTX). With SCF treatment, brain glutathione (GSH) content increased and malondialdehyde (MDA) levels were reduced in rats with CTX-induced damage [20]. Yang et al. reported that SCF showed an antioxidant effect on AD rats by elevating superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity, and reducing MDA level [21].
The lignans extracted from SCF were identified as a potential treatment for AD, because of their protection against damage from oxidative stress. In a recent report, the total lignans of SCF (TLS) blocked the decrease of mitochondrial membrane potential (MMP) in primary mouse neuronal cells. Moreover, TLS restored the activity of total antioxidant capacity (T-AOC) in AD mice (see Sections 5.1 and 6.1 for more detail) [26]. In addition, the lignans of SCF were assumed to protect against D-galactose (D-gal)-induced neurotoxicity in rats by maintaining GSH, MDA, and nitric oxide (NO) levels, and alleviating the decrease of SOD, catalase (CAT), and T-AOC activity. They were demonstrated to be potential candidates for the treatment of aging-associated neurodegenerative diseases [27].

Sch A and Sch B
Sch A and Sch B, derived from SCF, manifested anti-oxidative effects on AD. In research by Hu et al. Sch A significantly attenuated short-term and spatial memory impairments in AD mice by upregulating SOD, MDA, GSH-Px, GSH levels, and glutathione disulfide (GSSG) levels [30]. Furthermore, Sch B attenuated learning and memory impairment of AD mice induced by Aβ1-42. The restoration of glutamate transporter type 1 (GLT-1) and the capacity of glycogen synthase kinase3β (GSK3β) were maintained by Sch B treatment [35].
In a study by Chen et al. Sch B showed a protective effect in rats with cerebral ischemia/reperfusion (I/R) injury by strengthening the cerebral mitochondrial antioxidant effect. With the Sch B treatment, the GSH, α-TOC, and Mn-SOD expressions were increased, whereas the MDA-level and Ca 2+ -induced permeability transition was decreased [34]. In addition, Sch B relieved microglial-mediated inflammatory injury by inhibiting ROS and NADPH oxidase activity (see Section 6.2 for more detail) [36]. Sch B also modulated acetylcholine (ACh) activity in mice with dementia induced by scopolamine. The ACh level was maintained as normal, while the acetylcholinesterase (AChE) activity was inhibited by Sch B [33].

STA and SCH
STA is regarded as a neuroprotective lignin and works by attenuating the damage induced by 6-hydroxydopamine (6-OHDA) during in vivo and in vitro experiments. It alleviated neural damage by inhibiting ROS and NOS overproduction, and regulating extracellular signal-regulated kinase (ERK) phosphorylation, phosphatidylinositol 3-kinase (PI3K)/Akt ratio, and GSK3β dephosphorylation [42]. Moreover, STA restored SOD, GSH-Px, MDA, and GSH activity in AD mice, which indicated its protective effect against cognitive deficits and oxidative stress [43].
SCH is a bioactive lignan isolated from SCF. It has been suggested as a potential cognitive enhancer against AD through an antioxidative effect. As Hu et al. reported, SCH improved short-term and spatial memory impairments by upregulating SOD, GSH-Px, and GSH activity, and downregulating MDA and GSSG levels in the cerebral cortex and hippocampus of AD mice [45].

ICO and Gomisin A
ICO isolated from SCF showed an antioxidative effect on 6-OHDA-induced human neuroblastoma SH-SY5Y cell (a human derived cell line used as in vitro models of neuronal function and differentiation) death, inhibiting ROS and calcium accumulation. Additionally, ICO stimulated the expression of the antioxidant response genes NQO1 and HO-1 (see Section 5.4 for more detail) [47]. Moreover, gomisin A inhibited the ROS production, NADPH oxidase activation, and gp91phox expression induced by lipopolysaccharide (LPS) in microglia (see Section 6.3 for more detail) [50].

Suppression of Apoptosis
Apoptosis is the main mechanism behind the appearance of DNA in circulation [75]. On the one hand, apoptosis may contribute to a significant proportion of neuronal death following acute brain ischemia (ABI), which may lead to stroke [76]. On the other hand, when ischemic stroke and neurodegenerative diseases such as AD and PD occur, the apoptosis results in profound brain injury, including neuronal death and loss of neurological functions [77][78][79]. More recent advances have revealed that the cell death pathways of apoptosis, intracellular Ca 2+ homeostasis, and key metabolic pathways are regulated by mitochondria in neurologic disease [80]. More specifically, with more suppressed mitochondrial respiration comes more dysregulated calcium signaling. Furthermore, caspase-dependent and apoptosis-inducing factor-dependent apoptotic cell deaths are activated by Bax-dependent mitochondrial permeabilization [81,82]. SCF and its ingredients protect against NDs by suppressing apoptosis (Figure 3). The pharmacological data are shown in Table 3.  [85][86][87]. Bax migrates from the cytosol to the mitochondria in apoptosis [88,89]. Mitochondrial Bcl-2 exerts an anti-apoptotic effect by preventing the release of mitochondrial cytochrome c (Cyt c), and reducing the activity of caspase [90][91][92]. Cyt c released into the cytoplasm binds to apoptosis-related factor 1 (Apaf-1) in the presence of dATP, and forms apoptotic bodies with caspase-9. With the activating of caspase-9, caspase-3 is subsequently activated to induce apoptosis [93][94][95]. The protective effect of SCF and its active ingredients are shown in orange.

TLS
In a study by Jiang et al. TLS manifested a protective effect on rats with cerebral ischemia injury. The mechanism is related to increased Bcl-2 and p-Akt levels and the inhibition of apoptin Bax expression in the cerebral infarction area [28]. Moreover, TLS showed significant antiapoptotic effects in Aβ1-42-induced AD in primary mouse neuronal cells, by increasing Bcl-2 expression [26].

Sch A and Sch B
Sch A has been reported to reduce cell apoptosis and necrosis in primary cultures of rat cortical neurons after oxygen and glucose deprivation, followed by reperfusion (OGD/R). Intracellular Ca 2+ and LDH levels were decreased by Sch A treatment. Proteins play an important role in neuronal apoptosis, c-Jun NH2-terminal kinases (JNK), p38, and caspase-3 were modulated by Sch A in H293T cells [31]. Furthermore, Sch B showed antiapoptotic and anti-autophagy effects in rats with AD induced by Aβ . In these experiments, the overexpression of caspase-3 and terminal transferasemediated dUTP nick-end labeling (TUNEL) positive cells were suppressed by Sch B treatment. In addition, proteins such as HSP70 and beclin-1 were upregulated by Sch B (see Section 6.2 for more detail) [37]. With the activating of caspase-8, the following cascade reactions are promoted [85][86][87]. Bax migrates from the cytosol to the mitochondria in apoptosis [88,89]. Mitochondrial Bcl-2 exerts an anti-apoptotic effect by preventing the release of mitochondrial cytochrome c (Cyt c), and reducing the activity of caspase [90][91][92]. Cyt c released into the cytoplasm binds to apoptosis-related factor 1 (Apaf-1) in the presence of dATP, and forms apoptotic bodies with caspase-9. With the activating of caspase-9, caspase-3 is subsequently activated to induce apoptosis [93][94][95]. The protective effect of SCF and its active ingredients are shown in orange.

TLS
In a study by Jiang et al. TLS manifested a protective effect on rats with cerebral ischemia injury. The mechanism is related to increased Bcl-2 and p-Akt levels and the inhibition of apoptin Bax expression in the cerebral infarction area [28]. Moreover, TLS showed significant antiapoptotic effects in Aβ1-42-induced AD in primary mouse neuronal cells, by increasing Bcl-2 expression [26].

Sch A and Sch B
Sch A has been reported to reduce cell apoptosis and necrosis in primary cultures of rat cortical neurons after oxygen and glucose deprivation, followed by reperfusion (OGD/R). Intracellular Ca 2+ and LDH levels were decreased by Sch A treatment. Proteins play an important role in neuronal apoptosis, c-Jun NH2-terminal kinases (JNK), p38, and caspase-3 were modulated by Sch A in H293T cells [31]. Furthermore, Sch B showed antiapoptotic and anti-autophagy effects in rats with AD induced by Aβ . In these experiments, the overexpression of caspase-3 and terminal transferase-mediated dUTP nick-end labeling (TUNEL) positive cells were suppressed by Sch B treatment. In addition, proteins such as HSP70 and beclin-1 were upregulated by Sch B (see Section 6.2 for more detail) [37].

STA, Sch C, and Schizandrol B
As Sa et al.

ICO and Gomisin A
α-Isocubebenol (ICO) derived from SCF was recently shown to exert neuroprotective properties with an antiapoptotic effect. In the scopolamine-induced AD mice, ICO significantly upregulated the Bcl-2/Bax ratio. In addition, the AChE activity and decreased ERK phosphorylation induced by scopolamine were attenuated by ICO treatment [48]. In an in vitro experiment, ICO showed a protective effect on 6-OHDA-induced neural damage in SH-SY5Y cells. The mechanism was suggested to inhibit the release of the apoptosis-inducing factor from the mitochondria into the cytosol and nucleus [47]. In addition, gomisin A protected against CTX toxicity by blocking CYP3A-mediated metabolism and reducing CAA production in GH3 cells [51]. Table 3. The pharmacological data of SCF and its active ingredients in protecting against NDs by suppressing apoptosis. TUNEL-terminal transferase-mediated dUTP nick-end labeling; OGD/R-oxygen and glucose deprivation followed by reperfusion. Reducing CAA production

Anti-Inflammatory Effect
Neuroinflammation has been proven to contribute to the etiology of hypoxia-ischemia neural injury and neurodegenerative diseases [96]. Despite discrepancies in their pathophysiological timeframe and severity, NDs share common molecular mechanisms that include inflammation, mitochondrial dysfunction, and endoplasmic reticulum stress [79]. In an ischemic stroke, neuroinflammatory processes are upregulated and initiate a feedback loop of inflammatory cascades that can expand the region of damage [97]. Inflammatory molecules such as cytokines, chemokines, and reactive oxygen and nitrogen species are thought to be pivotal mediators of persistent neuronal injury [98][99][100]. SCF and its ingredients exert a neuroprotective effect on NDs by alleviating inflammation (Figure 4). The pharmacological data are shown in Table 4.

Anti-Inflammatory Effect
Neuroinflammation has been proven to contribute to the etiology of hypoxia-ischemia neural injury and neurodegenerative diseases [96]. Despite discrepancies in their pathophysiological timeframe and severity, NDs share common molecular mechanisms that include inflammation, mitochondrial dysfunction, and endoplasmic reticulum stress [79]. In an ischemic stroke, neuroinflammatory processes are upregulated and initiate a feedback loop of inflammatory cascades that can expand the region of damage [97]. Inflammatory molecules such as cytokines, chemokines, and reactive oxygen and nitrogen species are thought to be pivotal mediators of persistent neuronal injury [98][99][100]. SCF and its ingredients exert a neuroprotective effect on NDs by alleviating inflammation (Figure 4). The pharmacological data are shown in Table 4. . SCF and its active ingredients protect against inflammation in NDs. In the inflammatory response, TLR4 recognizes lipopolysaccharide (LPS), and then binds to the MyD88 Toll structure, forming a TLR-MyD active complex. Then, the complex recruits and activates the IL-1 receptor-associated kinase (IRAK), which is associated with tumor necrosis factor-associated factor 6 (TRAF6), activating the downstream mitogen-activated protein kinases (MAPK) pathway [101,102]. Meanwhile, TNFR1 binds to TNF, and interacts with receptor-interacting protein (RIP), activating the downstream inhibitory kappa B kinase (IKK) and MAPK pathway [103,104]. Phosphorylation of IκB protein leads to degradation of the protein, promotes nuclear translocation of nuclear factor-κB (NF-κB), and transfers NF-κB to the nucleus [105]. At the same time, the activation of the MAPK pathway leads to the production of activator protein-1 (AP-1), which is phosphorylated, and then enters the nucleus. Activation of NF-κB and AP-1 can lead to over-expression of the inflammatory factors, such as TNF-α, IL-1β, IL-6, IL-8, and IL-10, resulting a series of inflammatory reactions [106][107][108][109]. The protective effect of SCF and its active ingredients are shown in orange.

TLS
As Zhao et al. reported, TLS protects against cognitive deficits and neurodegeneration by inhibiting the expression of JNK/p38 and BACE1 in Aβ1-42-induced primary mouse neuronal cells. These results indicated that TLS could be applied as an active pharmaceutical ingredient for cognitive improvement in AD [26]. Furthermore, the lignans isolated from SCF, including Sch A-D, manifested SCF and its active ingredients protect against inflammation in NDs. In the inflammatory response, TLR4 recognizes lipopolysaccharide (LPS), and then binds to the MyD88 Toll structure, forming a TLR-MyD active complex. Then, the complex recruits and activates the IL-1 receptor-associated kinase (IRAK), which is associated with tumor necrosis factor-associated factor 6 (TRAF6), activating the downstream mitogen-activated protein kinases (MAPK) pathway [101,102]. Meanwhile, TNFR1 binds to TNF, and interacts with receptor-interacting protein (RIP), activating the downstream inhibitory kappa B kinase (IKK) and MAPK pathway [103,104]. Phosphorylation of IκB protein leads to degradation of the protein, promotes nuclear translocation of nuclear factor-κB (NF-κB), and transfers NF-κB to the nucleus [105]. At the same time, the activation of the MAPK pathway leads to the production of activator protein-1 (AP-1), which is phosphorylated, and then enters the nucleus. Activation of NF-κB and AP-1 can lead to over-expression of the inflammatory factors, such as TNF-α, IL-1β, IL-6, IL-8, and IL-10, resulting a series of inflammatory reactions [106][107][108][109]. The protective effect of SCF and its active ingredients are shown in orange.

TLS
As Zhao et al. reported, TLS protects against cognitive deficits and neurodegeneration by inhibiting the expression of JNK/p38 and BACE1 in Aβ1-42-induced primary mouse neuronal cells. These results indicated that TLS could be applied as an active pharmaceutical ingredient for cognitive improvement in AD [26]. Furthermore, the lignans isolated from SCF, including Sch A-D, manifested beneficial activity by inhibiting the lipopolysaccharide (LPS)-induced NO release in primary murine BV2 microglia cells [29].

Sch A, Sch B, and Sch C
Song et al. reported that Sch A can exert anti-inflammatory and neuroprotective effects on LPS-induced inflammatory injury in microglia (BV2 cells) and neurons. The potential molecular mechanism may be the inhibition of the tumor necrosis factor-associated factor 6(TRAF6)-inhibitory kappa B kinase (IKK)β/ nuclear translocation of nuclear factor-κB (NF-κB) and Janus kinase-2/signal transducer and activator of transcription-3 (Jak2/Stat3) signaling pathways [32].
Sch B has been effective at inhibiting neural inflammation during in vivo and in vitro studies. Giridharan reported that Sch B modulated receptors for advanced glycation end products (RAGE), NF-κB, and the mitogen-activated protein kinases (MAPK) signaling pathway. Moreover, an overexpression of the proteins prompting inflammation were inhibited by Sch B [37]. As Lee reported, Sch B attenuated cerebral ischemia injury in rats by suppressing the overexpression of inflammatory markers in ischemic hemispheres [39], and relieved microglial-mediated inflammatory injury by inhibiting the TLR4-dependent MyD88/IKK/NF-κB signaling pathway [36]. Moreover, Sch B showed an inhibitory effect on the LPS-induced inflammatory response by suppressing NF-κB activation, while activating PPAR-γ [38].
As Park et al. reported, Sch C was regarded as a natural antineuroinflammatory agent, protecting against lipoteichoic acid (LTA)-stimulated inflammation in mouse primary microglia. The results showed that Sch C suppressed NF-κB, AP-1, JAK-STATs, and MAPK expression, and activated cAMP/PKA/CREB and Nrf-2 signaling [41].

ICO, Gomisin A, and Gomisin N
ICO showed a protective effect on Aβ-stimulated neuroinflammation in mouse primary microglia. The research indicated that ICO provided a neuroprotective function by inhibiting IκB-α, NF-κB, and the MAPK signaling pathway [49].
As one of the major dibenzocyclooctadiene lignans isolated from SCF, gomisin A manifested as a neuroprotective treatment for LPS-stimulated inflammation on N9 microglia. The potential mechanism of gomisin A was suggested to be inhibition of the TLR4-mediated NF-κB and MAPKs signaling pathways [50]. As Araki et al. reported, gomisin N ameliorated LPS-induced inflammation in mice and BV2 cells. The research demonstrated that an elevation of the inflammatory markers induced by LPS was inhibited by gomisin N treatment [52].

Regulation of Neurotransmitters
The emotional processing and behavioral anxiety are determined by the reciprocal relationship between the central nervous system and the endocrine signals. Peptide hormones are increasingly recognized for their effects on anxiety-like behavior and reward [110]. The neurobiological bases of depression and anxiety disorders are not fully understood and the currently available treatments are not always effective [111]. In recent years, the disorders of neurotransmitters, including norepinephrine (NE), 5-hydroxytryptamine (5-HT), dopamine (DA), and gamma-aminobutyric acid (GABA) have been reported to lead to significant changes in neurodegenerative diseases and induce anxiety, depression, arousal, and alarm [112][113][114]. They are involved in the pathophysiological bases of these diseases and provide benefits in their treatment through their diverse functions [115,116]. Despite this, antidepressant and anxiolytic drug development has largely stalled [117].
SCF was demonstrated to ameliorate 4-chloro-dl-phenylalanine (PCPA) induced insomnia in rats by regulating the expression of brain neurotransmitters and their metabolites through its sedative-hypnotic effects [25]. Furthermore, SCF was used as an efficient treatment for anxiety-like behavior induced by ethanol withdrawal. The results showed that it attenuated anxiety by significantly downregulating the elevation of norepinephrine (NE) and its metabolite in the hypothalamic paraventricular nucleus [24]. According to the latest report, SCH showed a neuroprotective effect by ameliorating learning and memory impairments in APP/PSI transgenic mice. The mechanism was suggested to be regulation of neurotransmitters and their metabolites in the brain. The results indicated that SCH could be applied as an active pharmaceutical compound for neurodegenerative diseases such as PD and AD [46]. The pharmacological data are shown in Table 5.

Modulation of BDNF Related Pathways
As a growth factor dynamically expressed in the brain across postnatal development, BDNF regulates neuronal differentiation and synaptic plasticity. It is acknowledged that decreased BDNF levels lead to altered neural plasticity, contributing to disease [118]. The mechanism of BDNF release appears to be related to synaptic sprouting and strengthened synaptic connections [119]. Nowadays, depression and anxiety are becoming major burdens to society, affecting as much as 7% of the world's population [120]. BDNF has been introduced to treatment-resistant depression and it has been identified as a therapeutic target for depression [121,122]. Furthermore, it is a distinct marker of stress adaptation, extinction of fear, and neuroimmune response [123][124][125].
Yan et al. reported that SCF could improve a depression-like emotional state and associated cognitive deficits in mice with chronic unpredictable mild stress (CUMS). The mechanism was proven to regulate BDNF expression in the hippocampus as well as upregulate the TrkB/CREB/ERK and PI3K/Akt/GSK-3β pathways [22,23]. Moreover, Yuan et al. reported that nigranoic acid (SBB1, 3,4-secocycloartene triterpenoid) manifested beneficial effects in terms of enhancing mental and intellectual functions by increasing BDNF and c-fos expression in NGF-differentiated PC12 cells [53]. The pharmacological data are shown in Table 6. PCPA induced insomnia in rat In vivo Reduces the elevation of GABA, NE, DA, DOPAC, HVA 7.5 g/kg 7.5 g/kg [25] Increases 5-HT, 5-HIAA levels SCH APP/PS1 transgenic mice (induced AD) In vivo Ameliorated the cognitive impairment 2 mg/kg 2 mg/kg [46] Decreases Aβ deposition in the hippocampus Regulates serotonin, 5-HIAA, DA, NE, γ-aminobutyric acid, glutamic acid, homovanillic acid, 3,4-dihydroxyphenylacetic acid and acetylcholine levels

Conclusions and Perspectives for Future Work
SCF and its active ingredients manifest a protective effect on NDs by attenuating injury induced by overoxidative stress, apoptosis, inflammation, and neurotransmitter disorders. The most active ingredients in SCF, lignans, share the same physiologically active structure as biphenyl cycloalkenol, whose parent nucleus is biphenyl cyclooctadiene [126]. Biphenyl cyclooctadiene has a biphenyl structure, as well as the eight-membered ring structure of biphenyl and side-chain synthesis. Given its many structural forms and stereoisomers, it is acknowledged as the key structure displaying antioxidation, antiapoptosis, and antiviral effects [127]. In future studies, attention should be paid to the components of the key active structures, so as to screen out lead compounds. The structure of the lead compounds should be optimized to enhance metabolic stability and improve bioavailability, in order to provide new candidates for the clinical treatment of NDs.
The pathogenesis of NDs has been further elucidated in recent years, such as the mitochondrial mechanism of neuroglial crosstalk after stroke [128], phagocytosis of reactive astrocytes following brain ischemia [129], purinergic signaling in reactive astrocytes of AD [130], endothelial cytoskeletal reorganization in blood-brain barrier disruption [131], cerebral cavernous malformations in stroke, and seizure [132,133]. Furthermore, more therapeutic targets of NDs have been discovered recently, such as TRPA1 [134], IL-27 [135], TIM-3 [136], tau [137], and histamine H3 receptor [138]. As biologically active drugs, in future work, SCF and its active ingredients should be applied to many more target-screening models.