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Review

Neuroprotective Potential of Major Alkaloids from Nelumbo nucifera (Lotus): Mechanisms and Therapeutic Implications

by
Douyang Zhao
1,
Linlin Ma
1,2,
Jeremy Brownlie
2,
Kathryn Tonissen
1,2,
Yang Pan
3 and
Yunjiang Feng
1,2,*
1
Institute for Biomedicine and Glycomics, Griffith University, Brisbane 4111, Australia
2
School of Environment and Science, Griffith University, Brisbane 4111, Australia
3
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(17), 8280; https://doi.org/10.3390/ijms26178280
Submission received: 18 July 2025 / Revised: 19 August 2025 / Accepted: 22 August 2025 / Published: 26 August 2025
(This article belongs to the Special Issue Molecular Mechanisms of Neurological and Psychiatric Disease, 2nd Edition)
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Abstract

Nelumbo nucifera (lotus) has long been used in traditional medicine across Asia, and its bioactive alkaloids have recently garnered attention for their neuroprotective properties. This review summarizes the current research on the mechanisms by which lotus-derived alkaloids, particularly neferine, nuciferine, liensinine, and isoliensinine, protect neural tissues. These compounds exhibit a wide range of pharmacological activities, including antioxidant and anti-inflammatory effects, regulation of calcium signaling and ion channels, promotion of neurogenesis, and modulation of key neurotransmitter systems, such as dopaminergic, cholinergic, and GABAergic pathways. Notably, they attenuate tau hyperphosphorylation, reduce oxidative stress-induced neuronal apoptosis, and enhance neurotrophic signaling via BDNF-related pathways. While antioxidant and anti-inflammatory actions are the most extensively studied, emerging evidence also highlights their roles in autophagy modulation and mitochondrial protection. Together, these findings suggest that lotus alkaloids are promising candidates for the prevention and treatment of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases. Further investigation is warranted to explore the synergistic mechanisms and potential clinical applications of these compounds.

1. Introduction

Traditional Chinese Medicine (TCM) has utilized botanical remedies for thousands of years, with plant-derived compounds playing a central role in the treatment of various ailments [1]. Nelumbo nucifera, commonly known as the Indian lotus, padma, Chinese water lily, and sacred lotus, is a perennial aquatic plant of the family Nymphaeaceae [2,3]. Although the family contains only one genus (Nelumbo), it comprises two species: N. nucifera Gaertn. (Asian lotus) and N. lutea Pear. (American lotus). N. nucifera is widely distributed across China, Thailand, India and Japan [4]. The majority of N. nucifera parts are edible, but its rhizomes and seeds are the most commonly used in traditional diets [5,6]. Lotus rhizomes, which are morphologically modified underground stems, are typically yellow and have a stout and creeping appearance [7,8]. Lotus seeds typically have an oval or round shape, measuring approximately 1.2 to 1.8 cm in length and 0.8 to 1.4 cm in diameter, with an average weight ranging from 1.1 to 1.4 g (Figure 1) [5]. The plant also features large, floating, orbicular leaves that can reach diameters of up to 60 cm [2,9]. While the rhizome and seeds are valued for their nutritional content, the lotus flower is often used for decorative purposes due to its low nutritional value [7,10].
Historically, lotus seeds have been used in TCM to treat a range of conditions, including hypertension, nausea, vomiting of blood, red eyes, and swelling [11,12]. Their medicinal use was first documented in the Shi Xing Ben Cao (Edible Materia Medica) during the Tang dynasty (circa 1400 AD), and they have been used continuously for over 400 years in China [4]. The Ben Cao Gang Mu General Outline (Compendium of Materia Medica, 1596) noted that the lotus embryo helps clear internal heat, calm the mind, and promote homeostasis [13]. In Yi Lin Zuan Yao (1647), a soup prepared from lotus embryos and Ba-Ceng-Sha was described as a remedy for purifying the heart and kidneys [4]. Modern applications continue to emphasize their calming effects, including the treatment of insomnia, anxiety, and restlessness [14,15]. Lotus seed tea, especially when combined with goji berries, is also promoted for enhancing cognitive function, calming the nervous system, and improving sleep quality [16,17].
Beyond the embryo and seeds, other parts of N. nucifera, notably the leaves and rhizomes, are widely used in traditional medicine [18,19]. Lotus leaves have been employed to regulate cholesterol levels, alleviate summer heat-induced dehydration, and treat diarrhea caused by damp-heat, spleen deficiency, and hematochezia [20]. They are also believed to enhance cerebral blood circulation and support cognitive functions [21,22]. Lotus rhizomes are traditionally used for chronic diseases, such as cancer and diabetes, and have been shown to exhibit hepatoprotective, cardioprotective, and hypoglycemic effects [23,24,25]. When consumed as lotus root soup, they are thought to boost energy, promote circulation, and support overall brain health [14,15,26].
The primary pharmacological activity of N. nucifera is largely attributed to its alkaloid content. Preliminary studies have identified several bioactive alkaloids, including nuciferine, neferine, and liensinine, which modulate key molecular pathways implicated in neurodegeneration, thereby demonstrating their potential as neuroprotective agents. Recent research has shown that neferine can attenuate oxidative stress and preserve neuronal integrity [27,28,29,30,31]. Additionally, emerging evidence suggests that these alkaloids may influence dopaminergic and serotonergic signaling pathways, offering therapeutic potential for alleviating anxiety, insomnia, and other neuropsychiatric symptoms [32,33].
While both traditional use and modern studies underscore the broad pharmacological potential of Nelumbo nucifera, most contemporary research has concentrated on its anti-cancer and cardioprotective effects. In this review, we have placed greater emphasis on a comprehensive perspective while acknowledging the more specific focus of previous reviews, including that of Ren et al. [34]. Furthermore, despite accumulating evidence supporting the neuroprotective potential of lotus alkaloids, a comprehensive synthesis of their pharmacological properties, molecular mechanisms, and therapeutic applications in neurodegenerative disorders remains lacking [35]. This review aims to address this gap by systematically evaluating the current body of research on alkaloids derived from N. nucifera, emphasizing their neuroprotective effects. Through this analysis, we aim to provide a more coherent understanding of their potential in preventing or ameliorating neurological damage and identify key directions for future investigations.

2. Method and Materials

An extensive literature search was conducted using Google Scholar with the keyword “lotus alkaloid neuroprotection,” which initially yielded 1810 results. To refine the scope, the search was restricted to publications from 2014 to 2024, narrowing the dataset to 1570 papers. Only peer-reviewed journal articles published in English were included, further narrowing the pool of publications to around 1000 papers. Abstracts were screened for relevance, resulting in approximately 500 papers selected for full-text assessment. Ultimately, only manuscripts aligned with the review’s objectives and providing substantive data were retained for analysis. To further refine the literature pool, additional keyword combinations were employed, including “lotus alkaloid oxidation neuroprotection,” “lotus alkaloid neuroinflammation,” “lotus alkaloid autophagy neuroprotection,” “lotus alkaloid neurogenesis,” and “lotus alkaloid mitochondria neuroprotection”. These searches helped identify studies that specifically addressed the mechanistic underpinnings of neuroprotection by lotus-derived alkaloids. Based on these selection criteria, 173 peer-reviewed articles were ultimately included and cited in this review.

3. Chemical Constituents of Lotus Alkaloids

Alkaloids are the major secondary metabolites in Lotus, accounting for approximately 2.43% of its dry weight [27,28,29]. To date, 51 alkaloids, divided into four classes, have been identified, including 1-benzylisoquinoline (Figure S1), aporphines (Figure S2), bisbenzylisoquinolines (Figure S3), and tribenzylisoquinolines (Figure S4), with more than half belonging to the isoquinoline class [4,36]. Neferine, liensinine, isoliensinine, nuciferine, O-nornuciferine, dehydronuciferine, pronuciferine, and roemerine are recognized as key bioactive alkaloids present in Nelumbo nucifera, which have been demonstrated in the present study to exert neuroprotective effects (Figure 2). Neferine, liensinine, and isoliensinine are classified as bisbenzylisoquinoline alkaloids, whereas nuciferine, O-nornuciferine, dehydronuciferine, pronuciferine, and roemerine belong to the aporphine alkaloid class. In the present review, their neuroprotective effects will be discussed in detail within the mechanism section, with an emphasis on their roles in modulating neurodegenerative diseases. For clarity, these eight alkaloids are highlighted as the primary focus of discussion, while the chemical structures of the other alkaloids are provided in the Supplementary Materials to improve readability.

4. Mechanism of Neuroprotection

Several mechanisms have been demonstrated to be involved in neuroprotection, including anti-inflammation, autophagy regulation, antioxidation, mitochondrial regulation, ion channel regulation, and neurogenesis (Table 1, Table 2, Table 3, Table 4 and Table 5). These mechanisms can work synergistically to enhance neuroprotection, although their interactions are complex and remain to be fully elucidated. In this section, we discuss how lotus alkaloids protect neuronal cells through these mechanisms and explore the interplay between them.

4.1. Anti-Inflammatory Effects and Autophagy Regulation

Inflammation is a natural defense mechanism that facilitates the clearance of cellular debris after injury or necrosis [37]. However, prolonged or excessive neuroinflammation may induce cerebrum damage and cerebrovascular dysfunction, ultimately triggering neuronal apoptosis [38]. Moreover, the resulting inflammatory cascade further propagates neuroinflammation, creating a self-amplifying cycle [37,39]. Chronic neuroinflammation is a hallmark of neurodegenerative diseases, particularly Parkinson’s disease [40,41].
Microglia, the resident immune cells of the CNS, play a pivotal role in neuroinflammation. Although they act as the first line of defense, their overactivation may result in the progression of Parkinson’s disease [40]. One key player in this process is inducible nitric oxide synthase (iNOS), which catalyzes the production of nitric oxide (NO) and is a major mediator of inflammation [42]. Overexpression of iNOS leads to excessive NO production, resulting in tissue damage and chronic inflammation [42]. In vivo studies have demonstrated that lotus alkaloids suppress iNOS activity. Liensinine (20 mg/kg and 40 mg/kg) significantly reduced iNOS levels and cerebral inflammation in mice [43]. Similarly, neferine (10 μM) suppressed iNOS expression and the release of pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), in LPS-stimulated BV-2 microglial cells [40], supporting its potent anti-inflammatory effects (Table 1).
Table 1. Neuroprotective effects of lotus alkaloids via anti-inflammatory mechanisms. ↓ indicates decrease.
Table 1. Neuroprotective effects of lotus alkaloids via anti-inflammatory mechanisms. ↓ indicates decrease.
CompoundDoseModelMechanismReference(s)
Neferine10 µM LPS-treated BV-2 cells↓ INOS
↓ interleukin-6
↓ TNFα 		[40,44]
Nuciferine5–20 μM LPS-stimulated BV2 microglia cells↓ IL-1β
↓ PGE2
↓ TNFα
↓ NO secretion
↓ NF-κB		[45]
Liensinine20 and 40 mg/kg Sepsis-associated encephalopathy mice cerebrum↓ iNOS activities
↓ inflammatory responses		[43,46]
Liensinine, neferine, and isoliensinine5.02 μM, 4.13 μM and 4.36 µM (IC50 values)Mouse macrophage cell line↓ NO production
↓ NF-κB
↓ IL-1β
↓ PGE2
↓ TNFα 		[47]
The anti-inflammatory effects of lotus alkaloids, including those described above, could involve NF-κB signaling, an important transcription factor that upregulates the expression of genes involved in stimulating inflammation, such as TNF-α, IL-1β, PGE2 (Prostaglandin E2), and iNOS expression (Table 1) [48]. NF-κB can be activated by various mechanisms, but one common mechanism is via phosphorylation and subsequent degradation of IκBα (inhibitor of kappa B alpha), an inhibitor protein that binds to the NF-κB transcription factor and prevents its translocation to the nucleus [49].
NF-κB pathway activation can be simulated by many factors, including LPS, which results in the rapid secretion of cytokines and other pro-inflammatory mediators [48]. Treatment of BV2 microglial cells with 5–20 μM nuciferine significantly decreased the secretion of LPS-induced inflammatory mediators, including TNF-α, IL-1β, and PGE2, by inhibiting IκBα phosphorylation, thus preventing the activation of NF-κB (Figure 3) [45,46]. Treatment of BV2 cells with 10 μM neferine also inhibited the expression of LPS-induced inflammatory cytokines, including TNF-α and IL-6 [40]. Liensinine, neferine, and isoliensinine at 5.02 µM, 4.13 µM, and 4.36 µM (IC50 values) were also shown to inhibit LPS-induced NO production in the RAW 264.7 mouse macrophage cell line, and to suppress the release of inflammatory markers such as TNF-α, IL-1β, and IL-6 by suppressing the NF-κB pathway [47]. Therefore, the main lotus alkaloids may act by inhibiting the NF-κB signaling pathway to downregulate the expression of inflammatory mediators.
Autophagy is a fundamental catabolic process essential for neuronal homeostasis, mediating the clearance of dysfunctional organelles and protein aggregates. Its regulatory role in neuroimmune signaling, particularly in suppressing excessive neuroinflammation through modulation of inflammasome activity and cytokine release, is critical for CNS integrity. Impairment of autophagy is increasingly implicated in the pathogenesis of neurodegenerative diseases, underscoring its potential as a therapeutic target for conditions such as Alzheimer’s and Parkinson’s diseases [50,51]. Additionally, autophagy modulates cytokine production and facilitates the resolution of inflammation. The formation of autophagosomes contributes to the clearance of pro-inflammatory stimuli, thereby mitigating sustained neuroinflammation [51,52,53,54].
Dysregulation of autophagy plays a central role in the development of neurological disorders and is associated with depression [55]. LC3B-II and Beclin-1 are critical proteins involved in autophagy [56,57]. Previous studies have demonstrated that total alkaloids from lotus embryos increased autophagy by significantly increasing the expression of LC3B-II and Beclin-1 in the hippocampus of LPS-treated mice (200 mg kg−1) and BV2 microglial cells (20 μM) (Table 2) [58]. Previous studies have suggested that endoplasmic reticulum (ER) stress is closely associated with the development of depression-like behaviors induced by various physiological and environmental stressors [59]. According to the same study, total alkaloid extracts reduced LPS-induced depressive behavior by decreasing ER stress and increasing autophagy. Based on these findings, the authors proposed that consuming lotus embryo tea may be a promising strategy for preventing depression [58,59].
Table 2. Neuroprotective effects of lotus alkaloids via autophagy regulation. ↓ indicates decrease while ↑ suggests increase.
Table 2. Neuroprotective effects of lotus alkaloids via autophagy regulation. ↓ indicates decrease while ↑ suggests increase.
CompoundDoseModelMechanismReference
Neferine12.8 µMPC-12 cells↓ 50% level of Huntingtin Protein [60]
Liensinine100 µMAβ transgenic GMC101 nematodes↑ autophagy-related genes
↑ autophagosome formation		[61]
Total alkaloids of lotus embryo 200 mg kg−1
20 μM		LPS-treated mice
BV2 microglial cell		↑ autophagy
↑ LC3B-II and Beclin-1
↓ depression		[58]
Defects in autophagy are commonly observed in various chronic inflammatory diseases [62,63]. Impaired autophagic mechanisms can lead to the accumulation of damaged cellular components, thereby exacerbating chronic inflammation [63,64,65]. Therefore, autophagy regulation may offer a novel approach for modulating neurodegenerative disorders by clearing aggregate-prone proteins [66]. For example, neferine (12.8 µM) can clear 50% of Huntingtin protein level through an autophagy-related gene 7 (ATG7)-dependent mechanism [60]. This effect was mediated through the mTOR-AMPK-dependent pathway (Figure 3), a key signaling pathway that upregulates autophagy-related genes [67,68,69]. Similarly, in a transgenic nematode model of Alzheimer’s disease that overexpressed Amyloid-beta (Aβ) proteins, liensinine (100 µM) significantly decreased the accumulation of Amyloid-beta and tau proteins, thereby inhibiting abnormal autophagosome formation and avoiding subsequent apoptosis [61]. This effect was linked to liensinine’s ability to upregulate autophagy genes, including lgg-1, unc-51, pha-4, atg-9, and ced-9 [61,70,71].
Inflammation and autophagy are linked cellular responses to stress and are required for maintaining cellular homeostasis. Inflammation can stimulate autophagy processes [72], which, in turn, can reduce inflammation and protect the cells. Conversely, during periods of chronic inflammation, autophagy is impaired, leading to increased inflammation and cellular damage [65,73]. Maintaining a balance between autophagy and inflammation is essential for overall health and recovery from infection or injury. Given the promising effects of lotus alkaloid extracts on both autophagy and inflammation, these compounds are increasingly being considered as effective therapeutics for treating a range of neurological and neurodegenerative conditions.

4.2. Oxidative Stress Protection and Mitochondrial Function Regulation

Oxidative stress can be harmful to sugars, lipids, proteins, and DNA, triggering neuroinflammation and leading to significant neuronal cell injury [74,75]. Excessive accumulation of reactive oxygen species (ROS) may result in hyperoxia—a state of elevated oxygen levels—which can be even more harmful, promoting neurotoxicity and ultimately inducing neuronal apoptosis [76,77]. The brain is especially vulnerable to ROS due to its high demand for oxygen [78]. Therefore, overproduction of ROS has been increasingly associated with aging and age-related diseases [79,80]. Oxidative stress is closely associated with mitochondrial dysfunction. Accumulated oxidative stress can lead to mitochondrial dysfunction, which in turn triggers irreversible mutations and dysfunction [81,82]. Mitochondria, which utilize nearly 85% of the oxygen in cells, are the primary sites of ROS production [83]. Most ROS are generated by “leakage” of electrons from the mitochondrial respiratory chain [83,84], leading to the formation of incompletely reduced oxygen species such as hydrogen peroxide (H2O2), the radical anion O2− radical, and the nitric oxide radical (NO•) [78,83]. They are highly reactive radicals that can impose severe oxidative stress on cells [78,85].
Lotus alkaloids have demonstrated antioxidant defense against ROS in neuronal cells (Table 3). In an LPS-activated microglial cell model, liensinine, neferine, and isoliensinine scavenged 50% ·OH at concentrations of 5.4, 6.9, and 6.6 μM, and 50% ONOO− radicals at 10.5, 7.8, and 10.3 μM [44]. In SH-SY5Y neuroblastoma cells, 10 µM liensinine and neferine decreased ROS levels by 15.31% and 20.37%, respectively [61]. Another study on SH-SY5Y cells showed that pronuciferine at 5 and 10 µM significantly suppressed neuronal death caused by H2O2 and increased SH-SY5Y cell proliferation by 45% [86]. CAT (catalase), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) are key antioxidant enzymes that protect cells from oxidative stress by neutralizing reactive oxygen species (ROS) [87,88]. In a high-fat diet-induced obese mouse model, nuciferine at 40 mg/kg ameliorated high-fat diet-induced insulin resistance and increased the levels of antioxidant enzymes SOD, CAT, and GSH-Px (Figure 4) [89]. This effect was attributed to the activation of the AMPK/SIRT1 pathway. According to two studies, activation of the AMPK/SIRT1 pathway reduces Aβ1-42 accumulation and phosphorylated tau (p-tau) expression, which in turn increases the levels of antioxidant enzymes [87,90]. To summarize, several lotus alkaloids exhibit potent antioxidant properties that protect neurons from oxidative stress by scavenging ROS and modulating key antioxidant enzymes.
Table 3. Neuroprotective effects of lotus alkaloids via antioxidation. ↑ indicates increase while ↓ suggests decrease.
Table 3. Neuroprotective effects of lotus alkaloids via antioxidation. ↑ indicates increase while ↓ suggests decrease.
CompoundDoseModelMechanismReference
Pronuciferine5 µM SH-SY5Y cells↓ neuronal death caused by H2O2,
↑ cell proliferation by 45%		[86]
Liensinine, neferine, and isoliensinine5.4, 6.9, and 6.6 μMLPS-activated microglial cells↓ 50% ·OH[44]
10.5, 7.8, and 10.3 μM ↓ 50% ONOO−
Liensinine and neferine10 µMAPP695swe SH-SY5Y cells↑ 15.31% oxidative stress resistance
↓ 20.37% ROS levels		[61]
Nuciferine40 mg/kgHigh-fat diets obese mice↓ 69.55% GSH,
↓ 60.05% SOD
↓ 3.59% CAT		[89]
Mitochondria are essential organelles that produce energy in the form of adenosine triphosphate (ATP) through oxidative phosphorylation [91]. The brain uses approximately 25% of the body’s total energy, which is primarily supplied by mitochondria [80]. The brain and neurons depend heavily on ATP production, which also results in the creation of ROS [92,93,94]. Overproduction of ROS can lead to mitochondrial dysfunction, affecting ATP production and further increasing ROS generation, creating a vicious cycle [95,96]. Mitochondrial dysfunction has been implicated in many neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s diseases [97]. This dysfunction often includes an impaired mitochondrial membrane potential, reduced ATP production, and increased ROS generation [98,99]. Lotus alkaloids have been shown to promote mitochondrial function (Table 4). In PC12 cells, 10 µM neferine increased the mitochondrial membrane potential and ATP levels and decreased mitochondrial ROS levels [100]. In an induced cerebral ischemia mouse model, neferine (50 mg/kg) improved mitochondrial structure, respiration, and Na+-K+-ATPase activity. This protective effect was linked to the activation of the p62–Keap1–Nrf2 pathway (Figure 4) by stimulating the nuclear translocation of Nrf2 (a transcription factor), which further activates its downstream heme oxygenase-1 (HO-1) and other antioxidant genes [100]. This highlights the critical role of oxidative stress reduction in preserving mitochondrial integrity.
Table 4. Neuroprotective effects of lotus alkaloids via mitochondria regulation. ↑ indicates increase while ↓ suggests decrease.
Table 4. Neuroprotective effects of lotus alkaloids via mitochondria regulation. ↑ indicates increase while ↓ suggests decrease.
CompoundDoseModelMechanismReference
Liensinine40 mg/kg Sepsis-associated encephalopathy mice↓ cerebrum mitochondria apoptosis[43]
Neferine50 mg/kgRats with induced cerebral ischaemia↑ mitochondrial structures
↑ mitochondrial respiration		[100]
10 µMPC12 cells ↑ mitochondrial membrane potentials
↓ mitochondrial ROS
Furthermore, mitochondria are highly susceptible not only to oxidative damage but also to the activation of apoptotic signaling pathways. Bax and Bcl-2 are pivotal regulators of mitochondrial-mediated apoptosis, with Bax promoting cell death in response to stress, and Bcl-2 protecting cells by inhibiting pro-apoptotic signals [101,102]. Liensinine at 40 mg/kg attenuated mitochondrial apoptosis in the cerebrum of sepsis-associated encephalopathy (SAE) mice by upregulating BCL-2 expression and downregulating Bax expression, thereby inhibiting mitochondrial apoptosome formation [43]. Consistent with previous studies, this study demonstrated that the reduction in oxidative stress in SAE mice was associated with liensinine-induced upregulation of Nrf2, which promoted its nuclear translocation and subsequently enhanced the transcription of downstream antioxidant enzymes. These findings emphasize the critical role of lotus alkaloids in alleviating oxidative stress and mitochondrial dysfunction through the activation of the Nrf2 pathway [43,103].
To conclude, several studies have demonstrated that lotus alkaloids exert protective effects against oxidative stress and mitochondrial dysfunction, primarily through the activation of the Nrf2 signaling pathway [43,100]. Oxidative stress and mitochondrial dysfunction are closely interconnected, with each capable of exacerbating the other. When mitochondrial function is compromised, ROS generation increases, which in turn exacerbates mitochondrial damage, creating a vicious cycle [95,104]. Therefore, mitochondrial dysfunction and abnormalities in antioxidants can increase oxidative stress and lead to neuronal death. Lotus alkaloids that target both mitochondrial regulation and enhance antioxidant defenses are promising candidates for neuroprotection.

4.3. Regulation of Ion Channels

Oxidative stress not only damages proteins, lipids, DNA, and cellular signaling molecules, but also impairs ion channel function [105]. Ion channels, which are transmembrane proteins that selectively conduct Na+, K+, Ca2+, and Cl− ions, play an important role in brain homeostasis [106,107]. Dysfunction of these channels, such as altered ion permeability or selectivity, contributes to neurodegeneration by interacting with multiple pathogenic mechanisms. For example, disrupted balance of ion homeostasis can promote excitotoxicity and mitochondrial dysfunction; loss of membrane potential can affect neuronal firing and signal transmission, impairing brain network activity; ion dysregulation can alter protein folding and degradation pathways, exacerbating the accumulation of toxic aggregates like α-synuclein or amyloid-β (Aβ); and ion channel dysfunction in glial cells can trigger neuroinflammation [108,109,110].
Calcium signaling is especially vital in neurons. While it plays a crucial role in neuroprotection, dysregulated calcium influx can lead to excitotoxicity, oxidative stress, and neurodegeneration, which are implicated in conditions like Alzheimer’s and Parkinson’s diseases [111,112]. Ca2+ overload through over-activated calcium channels induced by Aβ can lead to a cascade of ROS-mediated oxidative stress, resulting in cerebral neuronal loss [113,114]. Notably, it was found Ca2+ overload in Aβ25–35-treated PC12 cells was significantly reduced to 72.8%, 46.9%, and 81.7% by liensinine, isoliensinine, and neferine (10 μM), respectively (Table 5) [115,116]. This protective effect was attributed to the inhibition of tau protein hyperphosphorylation by downregulating the Ca2+-CaM/CaMKII pathway (Figure 5) [115,117]. Hyperphosphorylation of tau protein in the brain results in the formation of neurofibrillary tangles, which are a hallmark of Alzheimer’s disease and other tauopathies, ultimately resulting in cerebral neuronal loss [116,118].
Table 5. Neuroprotective effects of lotus alkaloids via ion-channel modulation. ↑ indicates increase while ↓ suggests decrease.
Table 5. Neuroprotective effects of lotus alkaloids via ion-channel modulation. ↑ indicates increase while ↓ suggests decrease.
CompoundDoseModelMechanismReference
Neferine, Liensinine, Isoliensinine10 μMPC12 cells damaged by Aβ25–35↓ Ca2+ level
72.8% and 46.9% 		[115]
Neferine50 mg/kgPermanent middle cerebral artery occlusion (pMCAO) rats↓ Ca2+ ↑ Hsp70
↓ NO		[119]
Neuronal nitric oxide synthase (nNOS) is a key enzyme responsible for the production of nitric oxide (NO) in neurons and plays crucial roles in neurotransmission, synaptic plasticity, and vascular regulation. However, dysregulated nNOS activity, particularly in response to calcium overload, can contribute to neurodegeneration [120,121]. Intracellular Ca2+ accumulation is a major trigger for nNOS activation, leading to excessive NO production and oxidative stress (Figure 5). Elevated Ca2+ levels are associated with increased neurotoxicity and dysfunction of heat shock protein 70 kDa (Hsp70) [122]. Hsp70, which is localized in the endoplasmic reticulum and mitochondria, plays a crucial role in protein folding, cellular stress protection, and apoptosis inhibition [119,123]. A study in permanent middle cerebral artery occlusion (pMCAO) rats demonstrated that neferine (50 mg/kg) reduced intracellular Ca2+ levels and upregulated Hsp70 expression. This effect was mediated by the downregulation of calpain-1 (a calcium-activated protease) and 4-HNE (a lipid peroxidation product), along with a concomitant reduction in NO production (Figure 5) [119]. Both calpain-1 and 4-HNE play significant roles in neuronal injury, particularly in calcium dysregulation and oxidative stress-related neurodegeneration [124,125]. These findings suggest that neferine mitigates calcium overload and oxidative stress by upregulating Hsp70 expression, thereby protecting against organelle damage and apoptosis [119]. Collectively, these results highlight the therapeutic potential of lotus-derived alkaloids in neurodegenerative diseases characterized by calcium dysregulation.

4.4. Regulation of Neurogenesis

Neurogenesis, the process of generating new neurons, declines with age [126]. While many current treatments for neurodegenerative diseases aim to prevent neuronal loss, enhancing neurogenesis offers a complementary approach to support brain repair [127,128]. Neurogenesis-related genes accelerate the differentiation of neural stem cells into new neurons [129].
Therefore, compounds that promote neurogenesis or enhance the expression of neurogenesis-related proteins may hold therapeutic potential for age-related neurodegenerative diseases (Table 6) [128,130]. Microtubule-associated protein 2 (MAP-2) and myelin basic protein (MBP) are essential proteins for neural development and function. MAP-2 protein stabilizes microtubules in neuronal dendrites, playing a critical role in maintaining neuronal structure and supporting dendritic growth and maturation [131,132]. In contrast, MBP protein is vital for myelin sheath formation by oligodendrocytes, ensuring proper insulation of axons and efficient nerve signal conduction in the central nervous system [133,134]. Together, they serve as functional markers of neuronal and glial cell identity and maturation. In hypoxic-ischemic-injured rats, neferine (50 mg/kg) reduced neuronal loss, promoted morphological recovery and myelination, and alleviated white matter injury in the cerebrum [135]. These effects were attributed to a significant increase in the expression of MAP-2 and MBP proteins by neferine (Figure 6) [135].
Table 6. Neuroprotective effects of lotus alkaloids via promotion of neurogenesis. ↑ indicates increase while ↓ suggests decrease.
Table 6. Neuroprotective effects of lotus alkaloids via promotion of neurogenesis. ↑ indicates increase while ↓ suggests decrease.
CompoundDoseModelMechanismReference
Neferine50 mg/kgNeonatal hypoxic-ischemic-injured rats ↓ neuronal loss,
↑ morphological recovery of the brain
↑ MAP-2 and MBP
↑ myelination		[135]
N. nucifera leaf water extracts 10 to 20 μg/mL Scopolamine-treated mice↑ hippocampus neurogenesis[136]
Pronuciferine0.1 to 10 μM SH-SY5Y cells ↑ 17% to 20% BDNF level [86]
Roemerine20 mM and 10 mM SH-SY5Y cells↑ 73% and 36% BDNF expression[137]
Brain-derived neurotrophic factor (BDNF) is a major neurotrophic factor involved in neurogenesis, which plays an important role in developing and maintaining neuronal structures, neuronal differentiation, survival, and synaptic plasticity [138,139,140,141]. Nuciferine (10 or 20 μg/mL) has been shown to promote hippocampus neurogenesis in scopolamine-treated mice by elevating BDNF level and restoring the expression of neurogenesis-associated markers, including DCX, nestin, and NeuN, markers of early, mid, and late stages of neuronal development, respectively, in the hippocampus [136]. Similarly, pronuciferine (0.1–10 μM) increased BDNF levels in SH-SY5Y cells by 17% to 20% [86]. These effects were associated with the activation of key signaling pathways, MAPK/ERK and PI3K/Akt by BDNF, ultimately leading to the activation of the transcription factor CREB (cAMP Response Element-Binding Protein) (Figure 6) [136]. CREB is a critical regulator of genes involved in neuronal survival, growth, synaptic plasticity, and neurogenesis [142,143]. Therefore, BDNF serves not only as a neurotrophic support molecule but also as a powerful modulator of gene expression that is essential for brain development, function, and adaptation.
To conclude, lotus alkaloids, particularly neferine and nuciferine, have shown promising neurogenic potential by modulating key molecular and cellular mechanisms involved in brain development and repair. These compounds upregulated the expression of MAP-2 and MBP, indicating enhanced neuronal differentiation and myelination. Mechanistically, lotus alkaloids activate neurotrophic signaling pathways, such as BDNF/TrkB, which in turn stimulates downstream activation of the PI3K/Akt and MAPK cascades. These findings suggest that lotus alkaloids may serve as valuable neuroprotective and regenerative agents in the context of neurodegenerative diseases.

4.5. Multimodal Actions of Lotus Alkaloids on Neurotransmitter Systems: Possible Neuroprotective Effects

Lotus alkaloids exhibit a diverse range of neurobiological effects and interact with multiple neurotransmitter systems, including dopaminergic, GABAergic, and cholinergic pathways. Their multifaceted mechanism potentially confers enhanced neuroprotective and cognitive benefits compared to single-target botanical compounds, which may explain the diverse neurological effects observed in their applications in traditional medicines.
Lotus alkaloids offer potential therapies for neurodegenerative conditions, such as Parkinson’s disease, either by modulating dopamine receptors or by elevating intracellular dopamine levels, addressing the progressive dopamine depletion that is a central pathophysiological feature of Parkinson’s disease [144,145,146]. D2 dopamine receptor agonists are widely used in the clinical management of Parkinson’s disease due to their ability to directly stimulate postsynaptic dopamine receptors, thereby bypassing the need for endogenous dopamine synthesis and release from degenerating nigrostriatal neurons. This mechanism provides more stable dopaminergic stimulation and contributes to improved symptom control, particularly in the early stages of the disease [147,148]. Among lotus-derived alkaloids, O-nornuciferine has been characterized as a potent agonist of both D1 and D2 dopamine receptors, exhibiting superior binding affinity (D1 IC50 = 2.09 μM and D2 IC50 = 1.14 μM) when compared to eight other lotus-derived alkaloids evaluated (ranging from 4.01 μM to 38.47 μM) [33]. A compound that targets both D1 and D2 receptors represents a pharmacologically appealing strategy for treating Parkinson’s disease, potentially offering broader symptom relief than D2-only drugs [149]. Additionally, experimental models have demonstrated that neferine administration effectively increases dopamine concentrations within the substantia nigra in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease mouse models, suggesting a direct modulatory effect on dopamine metabolism or neuroprotection of dopaminergic neurons [150].
Acetylcholinesterase inhibitors (AChEIs) represent an extensively investigated therapeutic approach for Alzheimer’s disease, based on the dual role of acetylcholinesterase (AChE) in both degrading acetylcholine and accelerating the formation of amyloid fibrils, which are critical pathological features of Alzheimer’s disease [151,152]. Phytochemical studies have identified dehydronuciferine as the most potent AChE inhibitor among eight aporphine alkaloids isolated from lotus, with an IC50 of 25 μg/mL [152]. Furthermore, both neferine and liensinine inhibited AChE activity (IC50 = 14.19 and 0.34 μM, respectively) in a rat model of AD [153]. These findings suggest that lotus alkaloids may provide cognitive benefits by preserving cholinergic neurotransmission.
In several neurodegenerative disorders, disruption of GABAergic function contributes to a constellation of symptoms, including motor dysfunction, cognitive deterioration, and seizure activity [154]. Therapeutic approaches targeting GABA receptors may modulate excessive excitatory neurotransmission and potentially alleviate symptoms of Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease [155]. Traditional uses of Nelumbo nucifera, particularly the leaves, include calming the mind and alleviating insomnia [13]. These ethnopharmacological applications have been supported by mechanistic studies demonstrating that the total alkaloids from lotus leaves can increase GABA levels in the brain, promote Cl− influx via GABAA receptors, and elevate serotonin and dopamine levels. Such neurotransmitter modulation is consistent with the regulation of sleep–wake cycles and reduction of anxiety. The sedative and anxiolytic effects of these alkaloids were confirmed through behavioral assays, including open-field, light/dark box, and pentobarbital-induced sleep tests, with effects significantly attenuated by GABAA receptor antagonists [21,32]. These findings suggest that lotus leaf alkaloids exert their central nervous system effects primarily via GABAergic and monoaminergic pathways, providing a pharmacological basis for their traditional use in promoting relaxation and improving sleep quality.

5. Conclusions and Limitations

To date, 51 lotus alkaloids have been isolated; however, only a limited number have been assessed for their neuroprotective properties. Among these, neferine, liensinine, and nuciferine have demonstrated a range of neuroprotective effects through various mechanisms (Figure 7). The most common effects include anti-inflammatory and antioxidant effects, while the promotion of neurogenesis and mitochondrial regulation represents promising avenues for future research. Although the precise interactions among these mechanisms remain unclear, their interplay likely exerts a synergistic effect on neuroprotection. For instance, a strong interrelationship exists between antioxidant effects and mitochondrial regulation, while a robust association is observed between anti-inflammatory mechanisms and autophagy regulation.
Current evidence indicates that the major alkaloids of N. nucifera exhibit minimal cytotoxicity in a range of normal and specialized cell types. No significant toxic effects or adverse interactions have been reported at experimentally relevant concentrations. A detailed summary of the available cytotoxicity data is provided in the Supplementary Material. These findings support their favorable safety profile and justify further investigation of their pharmacological potential.
While this review highlights recent advances in understanding the neuroprotective mechanisms of lotus alkaloids, it has several limitations. The majority of evidence is derived from preclinical models, with a notable lack of human studies evaluating efficacy, safety, and pharmacokinetics. In addition, most studies investigate isolated mechanisms in controlled systems, whereas in vivo, the interplay between oxidative stress, inflammation, apoptosis, and neurogenesis is likely to be more complex. Future research should therefore prioritize translational studies, including well-designed clinical trials, structural optimization of active compounds, and integrative multi-omics approaches, to elucidate synergistic pathways and improve therapeutic potential.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijms26178280/s1, References [156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176] are cited in the supplementary materials.

Author Contributions

D.Z. wrote the manuscript and drew illustrations. L.M., J.B., K.T., Y.P. and Y.F. supervised the writing of the manuscript and contributed to the development of its contents. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

Douyang Zhao would like to acknowledge Griffith University for providing Griffith University Postgraduate Research Scholarship and Griffith University International Postgraduate Research Scholarship. Figure 3, Figure 4, Figure 5 and Figure 6 are created in Chemdraw Pro version 12.0.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
AβAmyloid beta
AChEAcetylcholinesterase
AChEIAcetylcholinesterase inhibitor
BDNFBrain-derived neurotrophic factor
Ca2+Calcium ion
CaMKIICalcium/calmodulin-dependent protein kinase II
CATCatalase
CREBcAMP response element-binding protein
D1Dopamine freceptor D1
D2Dopamine receptor D2
EREndoplasmic reticulum
GABAGamma-aminobutyric acid
GSH-PxGlutathione peroxidase
Hsp70Heat shock protein 70 kDa
HO-1Heme oxygenase-1
IC50Half maximal inhibitory concentration
INOSInducible nitric oxide synthase
IL-6Interleukin-6
IκBαInhibitor of kappa B alpha
MAP-2Microtubule-associated protein 2
MAPKMitogen-activated protein kinase
MBPMyelin basic protein
MPTP1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
nNOSNeuronal nitric oxide synthase
NONitric oxide
Nrf2Nuclear factor erythroid 2–related factor 2
pMCAOPermanent middle cerebral artery occlusion
PI3KPhosphatidylinositol 3-kinase
ROSReactive oxygen species
SH-SY5YHuman neuroblastoma cell line SH-SY5Y
SODSuperoxide dismutase
TrkBTropomyosin receptor kinase B
TNF-αTumor necrosis factor-alpha
4-HNE4-Hydroxynonenal

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Figure 1. Major morphological features of lotus (Nelumbo nucifera) used in traditional medicine. This anatomical illustration shows the key structural components of the lotus plant used for medicinal purposes, specifically the flower, broad leaves, rhizome structures that form root nodules, and circular seedpod. To the right are enlarged images of the key reproductive structures: (top) the mature seed with the epicarp (external layer) intact; (middle) a horizontal cross-section of the seed showing the large starch-rich cotyledon surrounding a cavity that encases the plumule; and (bottom) the plumule, which is the developmental core from which the embryo develops.
Figure 1. Major morphological features of lotus (Nelumbo nucifera) used in traditional medicine. This anatomical illustration shows the key structural components of the lotus plant used for medicinal purposes, specifically the flower, broad leaves, rhizome structures that form root nodules, and circular seedpod. To the right are enlarged images of the key reproductive structures: (top) the mature seed with the epicarp (external layer) intact; (middle) a horizontal cross-section of the seed showing the large starch-rich cotyledon surrounding a cavity that encases the plumule; and (bottom) the plumule, which is the developmental core from which the embryo develops.
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Figure 2. Key bioactive alkaloids present in Nelumbo nucifera with neuroprotective effects.
Figure 2. Key bioactive alkaloids present in Nelumbo nucifera with neuroprotective effects.
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Figure 3. Lotus alkaloids exert neuroprotection by regulating inflammation triggered by LPS. Nuciferine, neferine, and isoliensinine attenuate inflammatory responses by inhibiting the phosphorylation and subsequent proteasomal degradation of inhibitor of kappa B alpha (IκBα), thereby suppressing the activation of the NF-κB signaling pathway. This results in the downregulation of inducible nitric oxide synthase (iNOS) expression and inflammatory mediators, including TNF-α, IL-1β, PGE2, and NO production, thereby decreasing inflammation. Furthermore, neferine inhibits mechanistic Target of Rapamycin (mTOR) activation, thereby reducing autophagy dysfunction.
Figure 3. Lotus alkaloids exert neuroprotection by regulating inflammation triggered by LPS. Nuciferine, neferine, and isoliensinine attenuate inflammatory responses by inhibiting the phosphorylation and subsequent proteasomal degradation of inhibitor of kappa B alpha (IκBα), thereby suppressing the activation of the NF-κB signaling pathway. This results in the downregulation of inducible nitric oxide synthase (iNOS) expression and inflammatory mediators, including TNF-α, IL-1β, PGE2, and NO production, thereby decreasing inflammation. Furthermore, neferine inhibits mechanistic Target of Rapamycin (mTOR) activation, thereby reducing autophagy dysfunction.
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Figure 4. Lotus alkaloids exert neuroprotection by regulating oxidation and mitochondrial function. Nuciferine, neferine, and liensinine exert antioxidant effects by activating the AMP-activated protein kinase/Sirtuin 1 (AMPK/SIRT1) signaling pathway, which promotes the removal of Keap1/p62 and further nuclear translocation of nuclear factor erythroid-related factor 2 (Nrf2), thereby activating mitochondrial biogenesis. Simultaneously, this activation enhances the transcriptional upregulation of antioxidant enzymes, including heme oxygenase-1 (HO-1), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px), ultimately leading to a reduction in intracellular reactive oxygen species (ROS) levels.
Figure 4. Lotus alkaloids exert neuroprotection by regulating oxidation and mitochondrial function. Nuciferine, neferine, and liensinine exert antioxidant effects by activating the AMP-activated protein kinase/Sirtuin 1 (AMPK/SIRT1) signaling pathway, which promotes the removal of Keap1/p62 and further nuclear translocation of nuclear factor erythroid-related factor 2 (Nrf2), thereby activating mitochondrial biogenesis. Simultaneously, this activation enhances the transcriptional upregulation of antioxidant enzymes, including heme oxygenase-1 (HO-1), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px), ultimately leading to a reduction in intracellular reactive oxygen species (ROS) levels.
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Figure 5. Lotus alkaloids exert neuroprotective effects by regulating calcium homeostasis. Ca2+ overload can be significantly reduced by liensinine and isoliensinine, which downregulate the Calcium–Calmodulin/Calcium–Calmodulin-Dependent Protein Kinase II (Ca2+-CaM/CaMKII) and inhibit tau protein hyperphosphorylation, thereby decreasing the formation of helical filaments. Neferine also attenuates intracellular Ca2+ accumulation and upregulates Hsp70 (heat shock protein 70 kDa) expression by downregulating calcium-dependent cysteine protease (calpain-1), thereby inhibiting apoptosis. Furthermore, the downregulation of neuronal nitric oxide (nNOS) simultaneously reduces 4-hydroxynonenal (4-HNE) and nitric oxide (NO) production, thereby alleviating oxidative stress.
Figure 5. Lotus alkaloids exert neuroprotective effects by regulating calcium homeostasis. Ca2+ overload can be significantly reduced by liensinine and isoliensinine, which downregulate the Calcium–Calmodulin/Calcium–Calmodulin-Dependent Protein Kinase II (Ca2+-CaM/CaMKII) and inhibit tau protein hyperphosphorylation, thereby decreasing the formation of helical filaments. Neferine also attenuates intracellular Ca2+ accumulation and upregulates Hsp70 (heat shock protein 70 kDa) expression by downregulating calcium-dependent cysteine protease (calpain-1), thereby inhibiting apoptosis. Furthermore, the downregulation of neuronal nitric oxide (nNOS) simultaneously reduces 4-hydroxynonenal (4-HNE) and nitric oxide (NO) production, thereby alleviating oxidative stress.
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Figure 6. Lotus alkaloids exert neuroprotection by promoting neurogenesis. Pronuciferine and nuciferine increase brain-derived neurotrophic factor (BDNF) levels by activating the TrkB receptor, which in turn triggers key signaling pathways such as mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), and Phosphatidylinositol 3-kinase (PI3K/Akt). This subsequently activates the transcription factor cAMP Response Element-Binding Protein (CREB), which promotes the expression of neurogenic genes, including microtubule-associated protein 2 (MAP-2) and Myelin basic protein (MBP), thereby enhancing neurogenesis.
Figure 6. Lotus alkaloids exert neuroprotection by promoting neurogenesis. Pronuciferine and nuciferine increase brain-derived neurotrophic factor (BDNF) levels by activating the TrkB receptor, which in turn triggers key signaling pathways such as mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), and Phosphatidylinositol 3-kinase (PI3K/Akt). This subsequently activates the transcription factor cAMP Response Element-Binding Protein (CREB), which promotes the expression of neurogenic genes, including microtubule-associated protein 2 (MAP-2) and Myelin basic protein (MBP), thereby enhancing neurogenesis.
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Figure 7. Summary of neuroprotective mechanisms of lotus alkaloids. Created in BioRender. Zhao, D. (2025) https://BioRender.com/cj686yy (accessed on 14 July 2025).
Figure 7. Summary of neuroprotective mechanisms of lotus alkaloids. Created in BioRender. Zhao, D. (2025) https://BioRender.com/cj686yy (accessed on 14 July 2025).
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MDPI and ACS Style

Zhao, D.; Ma, L.; Brownlie, J.; Tonissen, K.; Pan, Y.; Feng, Y. Neuroprotective Potential of Major Alkaloids from Nelumbo nucifera (Lotus): Mechanisms and Therapeutic Implications. Int. J. Mol. Sci. 2025, 26, 8280. https://doi.org/10.3390/ijms26178280

AMA Style

Zhao D, Ma L, Brownlie J, Tonissen K, Pan Y, Feng Y. Neuroprotective Potential of Major Alkaloids from Nelumbo nucifera (Lotus): Mechanisms and Therapeutic Implications. International Journal of Molecular Sciences. 2025; 26(17):8280. https://doi.org/10.3390/ijms26178280

Chicago/Turabian Style

Zhao, Douyang, Linlin Ma, Jeremy Brownlie, Kathryn Tonissen, Yang Pan, and Yunjiang Feng. 2025. "Neuroprotective Potential of Major Alkaloids from Nelumbo nucifera (Lotus): Mechanisms and Therapeutic Implications" International Journal of Molecular Sciences 26, no. 17: 8280. https://doi.org/10.3390/ijms26178280

APA Style

Zhao, D., Ma, L., Brownlie, J., Tonissen, K., Pan, Y., & Feng, Y. (2025). Neuroprotective Potential of Major Alkaloids from Nelumbo nucifera (Lotus): Mechanisms and Therapeutic Implications. International Journal of Molecular Sciences, 26(17), 8280. https://doi.org/10.3390/ijms26178280

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