Traditional Chinese medicine on epilepsy: focus on N-methyl-D-aspartate receptors and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors

Abstract

N-methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) mediate the majority of excitatory synaptic transmission in central nervous system. Dysfunction of these receptors may result in various diseases, including epilepsy. In recent years, a growing number of studies have targeted NMDARs and AMPARs to screen for antiepileptic agents that are both efficacious and well-tolerated. This review summarizes compounds, herbal extracts, and herbal complexes of traditional Chinese medicine (TCM) that have demonstrated antiepileptic effects through their modulation of NMDARs and AMPARs over the past 25 years. Furthermore, this review also systematically synthesizes the molecular mechanisms underlying these drugs, with the aim of facilitating the rational design and translational development of future antiepileptic therapeutic agents.

Introduction

Epilepsy is a prevalent disorder of the central nervous system, affecting approximately 70 million individuals globally. The incidence rate is notably higher among infants and the elderly [1], 2]. Despite the availability of over 30 approved antiepileptic medications, which function by suppressing neuronal hyperexcitation, approximately one-third of patients continue to experience drug-resistant epilepsy. This highlights a significant need for more effective therapeutic strategies [3], [4], [5], [6].

The abnormal neuronal discharge resulting from an imbalance between excitatory and inhibitory synaptic transmission constitutes the key mechanism underlying epileptic seizures [7], 8]. Iontropic glutamate receptors (iGluRs), functioning as non-selective cation channels, underlie the excitatory synaptic transmission. N-methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), which are prototypical iGluRs, mediate the bulk of postsynaptic depolarization; their dysregulation constitutes a mechanistic nexus for epileptogenesis [9], [10], [11].

NMDARs are composed of four subunits, two GRIN1 with two GRIN2A-D or GRIN3A-B [12]. NMDARs, especially those containing GluN2A subunits, play a crucial role in epilepsy [13], [14], [15]. Its excessive activation can lead to neuronal hyperexcitability, promoting epileptic seizures. GRIN2A gene mutation is an important cause of inherited epilepsy [16]. Abnormal localization of GluN2A NMDARs outside synapses can disrupt synaptic function, leading to refractory epilepsy and neurodevelopmental disorders [15]. Epilepsy occurs in 58 % of individuals with pathogenic GRIN mutations, and some patients are resistant to conventional antiepileptic drugs [17]. Compared to other GRIN subtypes such as GRIN1 and GRIN2B, GRIN2A mutations more frequently lead to epilepsy phenotypes [17], [18], [19]. AMPARs are also comprised tetrameric combinations of GluA1–4 subunits [12], and their plasticity (such as increased expression) directly participates in the occurrence of epilepsy [20], [21], [22]. Positron emission tomography (PET) revealed a significant increase in AMPARs density on the surface of cortical cells in patients with focal epilepsy [22]. In generalized epilepsy, synchronous neuronal firing increases AMPARs, while steady-state plasticity downregulates its expression to maintain balance [20]. Additionally, AMPARs with GluA2 subunit deficiency increases calcium permeability and exacerbates neuronal hyperexcitability [23]. An imbalance in the NMDAR/AMPAR ratio within neural networks may increase susceptibility to epilepsy. For instance, the synaptic protein complex LGI1-ADAM22 plays a crucial role in coordinating the spatial ratio of NMDAR/AMPAR, thereby maintaining signal equilibrium. The absence of the LGI1-ADAM22 complex can lead to the onset of epilepsy [24], 25]. Existing evidence demonstrates that perampanel (AMPARs antagonist) suppresses epileptiform discharges from pediatric drug-resistant cortex, and that memantine (NMDARs antagonist) counters GRIN2D-linked encephalopathy [26], [27], [28]. These findings highlight the promise of NMDARs and AMPARs as targets for antiepileptic therapy [29], 30] (Figure 1).

Figure 1:

The mechanisms underlying epilepsy mediated by NMDARs and AMPARs.

Traditional Chinese medicine (TCM) is recognized as an effective complementary and alternative therapeutic approach. TCM has been used for centuries to treat central nervous system disorders, such as epilepsy, Alzheimer’s disease (AD), and stroke, consistently demonstrating distinctive therapeutic benefits [31], [32], [33]. In recent years, understanding the molecular mechanisms by which TCM compounds modulate NMDARs and AMPARs activity has become an important area of research.

This review systematically summarizes advances since the year 2000 in the antiepileptic effects of TCM monomers, herbal extracts, and herbal complexes that target NMDARs and AMPARs, thus to guide the rational design and development of novel antiepileptic agents.

Monomers, herbal extracts, and herbal complexes

Monomers represent individual active constituents within complex herbal formulations, possessing defined chemical structures and pharmacological actions [34]. Compared to traditional compound formulas, monomers clearly identified components facilitate quality control and mechanism-of-action research. Examples include flavonoids, alkaloids, and terpenoids as common types of monomers [35]. Monomers have attracted considerable attention in medical research and drug development in recent years due to their unique therapeutic potential and relatively well-defined mechanisms. Numbers of studies are endeavoring to isolate natural molecules – monomers – of unequivocal chemical structure from plants, animals, or minerals, which have potent anti-epileptic efficacy with minimal side effects [36]. For instance, gastrodin, by modulating GABA receptors and suppressing abnormal neuronal discharges, has been formulated into approved clinical preparations [37]. Moreover, Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has been approved as an adjunctive therapy for refractory epilepsy [38], 39].

Herbal extracts refer to single compounds or complex constituents with defined biological activity and pharmacological effects, obtained through specific separation methods from traditional Chinese medicinal materials. Herbal extracts are usually obtained through systematic isolation from aqueous or ethanolic extracts of traditional Chinese herbal medicine. The raw material undergoes sequential extraction, filtration, purification, and concentration to yield either homologous or diverse bioactive constituent ensembles – herbal extracts, such as polysaccharides and saponins [40]. Herbal extracts are complex, with active constituents often referred to as a “mystery box”. The systematic screening of active constituents in extracts remains challenging. However, herbal extracts offer a shortcut for new drug development and possess significant potential for clinical translation.

Herbal complexes are therapeutic formulations composed of multiple herbs combined according to TCM principles. They contain diverse and complex chemical compositions, in which active components interact to exert synergistic therapeutic effects. Orally administered herbal complexes remain a commonly used adjunctive therapy for epilepsy prevention. Systematic investigation of these formulations offers a unique opportunity to elucidate the multi-target, multi-pathway mechanisms underlying TCM’s efficacy, including the synergistic modulation of NMDARs and AMPARs by their constituent compounds [41], 42].

Methods

To examine the therapeutic potential of NMDARs and AMPARs as molecular targets for TCM in epilepsy, this review synthesizes recent evidence on the mechanisms by which TCM monomers, herbal extracts, and herbal complexes modulate these receptors to exert anti-epileptic effects. This description of TCM drugs integrates analyses of clinical efficacy, pharmacokinetic profiles, blood-brain barrier (BBB) permeability, and toxicological data. A literature search was conducted on the China National Knowledge Infrastructure (CNKI) and PubMed (NCBI) databases for relevant articles published from January 1, 2000, to the present. The search terms included “Chinese herbal medicine”, “iGluRs”, “NMDA”, “AMPA”, “epilepsy”, and “seizures”. All publications relevant to the aforementioned topics were included. This encompassed epilepsy-focused studies that reported comprehensive datasets derived from both cellular and animal models.

Retrieved results

Over the past 25 years, global research has yielded numerous preclinical and mechanistic studies on the application of TCM in NMDAR-associated epilepsy models. These investigations are categorized into studies on monomers (n=18), herbal extracts (n=6), and herbal complexes (n=6), demonstrating a growing publication output. In parallel, seven studies have explored TCM interventions targeting AMPAR-related seizure models, which can be similarly subdivided into monomers (n=7) and herbal extracts (n=1). Although the body of research focused on AMPARs remains substantially smaller than its NMDAR-focused counterpart, it has recently exhibited a pronounced upward trend (Figure 2).

Figure 2:

The quantitative synthesis of the literature published between 2000 and 2025 on the use of TCM targeting NMDARs or AMPARs for the treatment of epilepsy.

Monomers targeting NMDARs/AMPARs in epilepsy

The monomers that target NMDARs/AMPARs were classified into seven major categories based on structural skeletons and biogenetic relationships: triterpenoid saponins, flavonoids, alkaloids, terpenoids, monoterpene glycosides, lignans, simple aromatics and phenolic acids (Figure 3). These compounds were found to suppress seizure activity in cellular and animal models of epilepsy by modulating the expression or function of NMDARs and/or AMPARs (Table 1).

Figure 3:

The classification profile of the compounds.

Table 1:

The functions and mechanisms of monomers in treating NMDARs/AMPARs-mediated epilepsy.

Compound	CAS	Clustering	Cell or animal model	Receptor	Mechanism of action	References
SSa	20736-09-8	Triterpenoid saponins	Low Mg2 -induced hippocampal neurons	NMDARs	Channel currents↓	[44]
Rg3	14197-60-5	Triterpenoid saponins	Mg2+-free-induced hippocampal neurons	NMDARs	Channel currents↓ Ca2+ influx↓	[51]–53]
JuB	55466-05-2	Triterpenoid saponins	Febrile seizure mice, heated acute brain slices	AMPARs	Channel currents↓ Ca2+ influx↓ Synaptic transmission↓ Excitability of neurons↓	[57]
RT	153-18-4	Flavonoids	KA-induced rats	NMDARs/AMPARs	GluN2A expressions↑ GluN2B expression↓ GluA1 and GluA2 expressions↑ EAATs expressions↑ GS expressions↑ Glutamatergic hyperactivity↓	[62]
KF	520-18-3	Flavonoids	PTZ-induced mice, primary cortical neurons, tsA201 cells transfected with GluA1/GluA2	AMPARs	Channel currents↓ Ca2+ influx↓ Binding to GluA1/GluA2	[63]
RIN	76-66-4	Alkaloids	Pilocarpine-induced rats, acute brain slices	NMDARs	Channel currents↓ GluN2B expression↓	[64]
Hup A	102518-79-6	Alkaloids	NMDA-induced rats, NMDA or glutamate-induced Guinea pig neurons	NMDARs	Ca2+ influx↓	[65], 66]
STA	471-87-4	Alkaloids	PTZ-induced mice	NMDARs	GluN1, GluN2A and GluN2B expression↓	[67]
PALM	3486-67-7	Alkaloids	PTZ or EKP-induced larval zebrafish, 6 Hz-induced mice, timed intravenous PTZ mice	AMPARs	Binding to AMPARs (Thr501, Arg506, and Tyr723)	[68]
AGPL	5508-58-7	Terpenoids	MES-induced and PTZ-induced mice, NMDA-induced SH-SY5Y cells	NMDARs	NMDA-induced cytotoxicity↓	[69]
6-GIN	23513-14-6	Terpenoids	PTZ-induced zebrafish	NMDARs	GRIN2B mRNA expression↓ Binding to NMDARs (ATD and glutamate binding sites)	[70]
EDB	464-43-7	Terpenoids	Pilocarpine or KA-induced rats and mice, Mg2+-free-induced hippocampal neurons	NMDARs	Ca2+ influx↓	[71]
CBD	13956-29-1	Terpenoids	NMDA-induced mice	NMDARs	Activity of NMDARs↓ (by antagonizing σ1R)	[72]
CBD	13956-29-1	Terpenoids	Febrile seizure mice, heated acute brain slices	AMPARs	Channel currents↓ Synaptic transmission↓ Excitability of neurons↓ Binding to GluA1/GluA2	[73]
PF	23180-57-6	Monoterpene glycosides	Morphine-induced mice	NMDARs	Modulate GluN2A and GluN2B activity	[74]
ATG	7770-78-7	Lignans	HEK293 cells transfected with GluA1	AMPARs	Binding to GluA2 Antagonizing GluA1 Ca2+ influx↓	[75]
α-Asarone	2883-98-9	Simple aromatics & phenolic acids	PTZ-induced rats	NMDARs	GRIN1 mRNA expression↓	[76]
EA	476-66-4	Simple aromatics & phenolic acids	PTZ-induced mice	NMDARs	GluN2A and GluN2B expression↓	[77]
SA	530-59-6	Simple aromatics & phenolic acids	Timed intravenous PTZ mice	NMDARs	GluN2A and GluN2B expression↓	[78]
SH	83766-73-8	Simple aromatics & phenolic acids	KA-induced rats	AMPARs/NMDARs	GluA1 and GluA2 expression↑ GluN2A expression↑ GluN2B expression↓ Glutamate and glutaminase↓ EAAT1/2/3 and GS↑	[79]

SSa, Saikosaponin a; Rg3, Ginsenoside Rg3; JuB, Jujuboside; RT, Rutin; KF, Kaempferol; RIN, Rhynchophylline; Hup A, Huperzine; STA, Stachydrine; PALM, Palmatine; AGPL, Andrographolide; 6-GIN, 6-Gingerol; EDB, Edaravone Dexborneol; CBD, Cannabidiol; PF, Paeoniflorin; ATG, (−)-Arctigenin; EA, Ellagic; SA, Sinapinic; SH, sodium houttuyfonate; NMDARs, N-methyl-D-aspartate receptors; AMPARs, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; KA, kainic acid; EAATs, excitatory amino acid transporters; GS, glutamine synthetase; PTZ, pentylenetetrazol; NMDA, N-methyl-D-aspartate

Triterpenoid saponins

Saikosaponin A (SSA)

SSA is a triterpenoid saponin derived from the traditional Chinese medicinal herb Bupleurum chinense DC. [43]. Whole-cell voltage-clamp recording has revealed that SSa inhibits epileptiform activity in a low-Mg²⁺-induced rat hippocampal neuronal model. It suppresses both NMDAR-mediated currents and the persistent sodium current (I NaP) [44]. Consequently, SSa reduces spontaneous recurrent epileptiform discharges (SREDs) and mitigates the severity of status epilepticus (SE) [44].

Although SSa demonstrates favorable pharmacokinetic properties, including rapid absorption, elimination, and good BBB permeability [45], its development as an NMDAR-targeting drug is limited by significant associated toxicities. Saikosaponins, including SSa, exhibit hepatotoxicity, neurotoxicity, and hemolytic activity [46], [47], [48]. A primary mechanism underlying their hepatotoxicity is the disruption of lysophosphatidylcholine and bile-acid homeostasis [47], 49], 50].

Ginsenoside Rg3 (Rg3)

The principal bioactive components of ginseng, ginsenosides, have important protective roles within the central nervous system. Among them, Rg3 has been shown to exert anticonvulsant effects. Whole-cell patch-clamp studies have demonstrated that Rg3 inhibits NMDAR-mediated currents and reduces SREDs in an in vitro model of epilepsy [51]. Ginseng total saponins (GTS) and Rg3 reduce Ca²⁺ influx through NMDARs in hippocampal neurons [52]. Specifically, Rg3 acts as an antagonist at the glycine-binding site of the NMDAR, thereby attenuating receptor overactivation and downstream glutamate signaling [53].

In toxicity evaluations, the oral median lethal dose (LD₅₀) of Rg3 exceeded 1,600 mg/kg in mice and 800 mg/kg in rats, with no fatalities or overt signs of toxicity observed [54]. Clinical trials have demonstrated that continuous administration of Rg3 for more than six months is not associated with any serious adverse events [55]. However, the oral bioavailability of Rg3 is notably low (<5 %), primarily due to extensive first-pass metabolism in the intestine. Furthermore, Rg3 is undetectable in brain tissue, whereas its metabolite, compound K, effectively crosses the BBB [56]. Thus, the pharmacological effects of Rg3 in the central nervous system are likely mediated by compound K, although its specific actions on NMDARs require further investigation.

Jujuboside B (JUB)

JuB is a saponin monomer derived from the dried mature seeds of the Ziziphus jujuba var. spinosa, a plant from the Rhamnaceae family, commonly known as the spiny date seed. Its pharmacological actions are akin to those of Z. jujuba saponin A, which possesses sedative and hypnotic effects. Recent studies have shown that JuB can effectively penetrate the BBB and act against febrile seizures [57]. JuB extends the latency to onset and reduces the severity of febrile seizures in a mouse pup model. At an intraperitoneal (i.p.) dose of 30 mg/kg, it is 90 % effective in preventing generalized convulsive seizures [57]. The mechanism underlying these protective effects involves a reduction in neuronal excitability. Specifically, in acutely isolated hippocampal brain slices, JuB suppresses the excitability of CA1 pyramidal neurons by inhibiting AMPAR currents and AMPAR-mediated synaptic transmission, as well as by decreasing intracellular free Ca²⁺ levels [57].

Pharmacokinetic studies have shown that the oral bioavailability of JuB in rats is only 3.6 %. JuB is mainly distributed in plasma and cleared rapidly [58], [59], [60]. Despite its potent sedative effects, the toxicological profile of JuB remains unexplored. Furthermore, JuB requires comprehensive safety evaluations.

Flavonoids

Rutin (RT)

RT is the quercetin rutinoside, a flavonoid compound extracted from plants. In the buds of the Sophora japonica L., known as “Huai Mi”, the RT content can exceed 20 %. RT exhibits therapeutic potential in the treatment of neurodegenerative disorders [61]. In acute kainic acid (KA)-induced epilepsy models, RT supplementation downregulates hippocampal expression of glutaminase and GluN2B, while also suppressing astrocyte activation [62]. Furthermore, RT upregulates the expression of excitatory amino acid transporters (EAATs), glutamine synthetase (GS), GluA1, GluA2, and GluN2A [62]. Collectively, these actions mitigate KA-induced acute seizures and neuronal loss through a reduction in glutamatergic hyperactivity and inhibition of the IL-1R1/TLR4-mediated neuroinflammatory cascade [62]. Notably, no acute or chronic toxicity has been documented for rutin RT [80].

Kaempferol (KF)

KF, the principal bioactive constituent of Kaempferia galanga L. and the marker for safflower authentication, exerts robust anticonvulsant and neuroprotective effects. In an acute pentylenetetrazol (PTZ) model, oral administration of KF (100 mg/kg/day for 3 days) reduced the incidence of generalized tonic-clonic seizures to 78.6 %, prolonged seizure latency, and mitigated neuronal damage, edema, and necrosis [63]. At the cellular level, 10 μM KF suppressed the excitability of primary cortical neurons and attenuated glutamate-evoked intracellular Ca²⁺ surges, thereby limiting Ca²⁺-mediated neurotoxicity [63]. Mechanistically, these protective effects are mediated by a direct interaction with GluA1/GluA2 subunits, which inhibits AMPAR-mediated currents and subsequent Ca²⁺ influx [63].

Following intravenous administration (25 mg/kg), KF is rapidly metabolized in the blood and efficiently crosses the BBB, reaching a peak hippocampal concentration of 0.11 μg/mL within 30 min [81]. Beyond its favorable distribution, KF has been shown to protect BBB integrity and ameliorate focal cerebral ischemia [82], [83], [84]. Importantly, a 28-day sub-acute oral toxicity study in mice revealed no adverse effects on clinical signs, body weight, organ weights, hematological or biochemical parameters, oxidative stress markers, or histopathology [85].

Alkaloids

Rhynchophylline (RIN)

RIN, derived from the plant Uncaria rhynchophylla (UR), has been demonstrated to possess antiepileptic properties. Previous research has demonstrated that intracerebroventricular injection (i.c.v.) pretreatment with 100 μM RIN reduces acute pilocarpine-induced seizures in a rat model of temporal lobe epilepsy, achieving a 50 % reduction in the incidence of SE and a concomitant attenuation of its symptom severity [64]. Following RIN pretreatment, electroencephalogram (EEG) recordings in the temporal lobe epilepsy rat model exhibited lower amplitudes and frequencies [64]. RIN’s antiepileptic effect is mediated through its inhibition on NMDAR-mediated currents and I NaP. This action also effectively prevents the upregulation of GluN2B protein expression induced by SE [64].

RIN has been confirmed to cross the BBB. However, due to its poor water solubility and low bioavailability, its delivery to the brain is restricted, resulting in inefficient cerebral targeting [86], 87].

Huperzine A (Hup A)

Hup A, an active lycopodium alkaloid derived from the traditional Chinese medicinal herb Huperzia serrata (also known as “thousand-layered tower”), is an acetylcholinesterase (AChE) inhibitor, and has been extensively applied in the treatment of AD [88], 89].

Recent studies have revealed the antiepileptic potential of Hup A. For instance, pretreatment with Hup A mitigates acute epileptic seizures in rats by inhibiting NMDA-induced excitotoxicity and exerts neuroprotective effects during SE [65]. Notably, these therapeutic benefits occur without significantly affecting electroencephalographic activity, heart rate, body temperature, or behavior [65]. At the cellular level, Hup A antagonizes the excitotoxic effects of NMDA and glutamate on guinea pig neurons via direct binding to the NMDAR and subsequent blockade of Ca²⁺ influx [66]. This indicates that Hup A holds therapeutic potential for epilepsy by targeting NMDAR.

Stachydrine (STA)

STA, the principal alkaloid of Leonurus japonicus (Lamiaceae), has been demonstrated to exhibit a broad spectrum of biological activities, including anti-inflammatory, antioxidant, anticoagulant, anti-apoptotic, and vasodilatory effects [90]. Recent evidence demonstrates that STA exerts potent antiepileptic effects. In the PTZ-kindling model, a 25-day oral administration of STA markedly reduced seizure scores, global EEG power, and discharge amplitude. Furthermore, STA treatment prevented epilepsy-associated cognitive deficits, attenuated neuronal loss, and suppressed the activation of astrocytes and microglia. These protective effects were mediated by the marked down-regulation of NMDAR subunits (GluN1, GluN2A, and GluN2B), as well as CAMK2 and caspase-3 [67].

Although STA exhibits favorable bioavailability [91], [92], [93], its pharmacokinetic profile in the central nervous system remains poorly understood. Specifically, there is a lack of data regarding its distribution into the brain and its ability to permeate the BBB [94].

Palmatine (PALM)

PALM is an isoquinoline alkaloid widely distributed across several plant families, including Ranunculaceae, Berberidaceae, Papaveraceae, Rutaceae, Annonaceae [95]. One study reported that PALM, the principal active constituent of Fibraurea recisa Pierre, exhibits significant antiepileptic properties [96]. PALM suppressed epileptiform behaviors and local field potential (LFP) discharges in zebrafish larvae (induced by 2-ketopent-4-enoate and PTZ), elevated the seizure threshold in the mouse 6-Hz model, and demonstrated efficacy in the timed-infusion PTZ test [68]. Mechanistic insights from molecular docking indicate that PALM forms hydrogen bonds with Thr501, Arg506, and Tyr723 within the AMPA receptor’s ligand-binding domain, suggesting a non-competitive antagonism similar to that of perampanel. Additionally, PALM is further predicted to engage in π-cation interactions with His458 of both GAD65 chains A and B, alongside hydrogen-bond interactions with Gly252 of GAD67 chain A [68].

Although PALM crosses the BBB, its effective brain targeting requires prolonged administration at high doses [97], 98]. Accordingly, PALM has been engineered into transferrin-decorated extracellular vesicles that co-deliver berberine and PALM [99]. These vesicles traverse the BBB and precisely target microglia, efficiently eradicating amyloid-β (Aβ) aggregates and markedly improving cognition and learning in AD mouse models [99]. Given the shared pathophysiological role of neuroinflammation and microglial activation in both AD and epilepsy, future work is expected to enhance the antiepileptic efficacy of PALM by applying this analogous delivery strategy.

Terpenoids

Andrographolide (AGPL)

AGPL, extracted from the plant Andrographis paniculata of the Acanthaceae family, is a diterpenoid lactone compound. It is one of the principal active constituents of the herb A. paniculata. A recent study found that the combination of AGPL and guaiphenesin exerts a synergistic effect on NMDARs [69]. This combination mitigated NMDA-induced cytotoxicity and consequently reduced seizures in both maximal electroshock (MES) and subcutaneous PTZ (sc-PTZ) models [69]. As a newly identified drug combination, its therapeutic potential warrants further investigation. Safety evaluation revealed that mild and reversible elevations in ALT/AST occurred in approximately 30 % of subjects [100].

6-Gingerol (6-GIN)

6-GIN, a main component of ginger rhizome extract, is associated with the irritant taste of ginger. This compound has been demonstrated to penetrate the BBB and exert neuroprotective effects [101]. Latest research shows that 6-GIN suppresses PTZ-induced seizures and epileptiform discharges in zebrafish. It also reduces glutamate levels and the GLU/GABA ratio. Furthermore, 6-GIN downregulates the expression of GRIN2B mRNA in PTZ epileptic model. Molecular docking studies indicate that 6-GIN potentially interacts with multiple NMDAR sites, such as the ATD, glutamate-binding site, and the ion channel pore [70].

Clinical trials have demonstrated that 6-GIN is rapidly absorbed after oral administration and exhibits a favorable safety profile despite achieving extremely low plasma concentrations of the parent compound [102], 103].

Edaravone Dexborneol (EDB)

EDB, a combination of Edaravone and Dexborneol in 4:1, confers robust neuroprotection [104], 105]. Edaravone is a well-established free-radical scavenger, whereas dexborneol – the dextrorotatory isomer of borneol – promotes BBB permeability and exerts antioxidant effects [106], 107]. Recent evidence demonstrates that the combination of edaravone (5 mg/kg) and dexborneol (1.25 mg/kg) effectively suppresses KA–induced seizures and memory deficits, whereas edaravone (3 mg/kg) plus dexborneol (0.75 mg/kg) markedly attenuates pilocarpine-triggered seizures and cognitive impairment [71]. In both temporal-lobe-epilepsy models, the EDB combination outperforms either agent administered alone. Furthermore, EDB prevents post-seizure neuronal damage, most likely through NMDAR-mediated attenuation of Ca²⁺ influx and synergistic modulation of lipid-metabolism and oxidative-stress pathways [71].

EDB is rapidly absorbed via the buccal mucosa, exhibiting a Tmax comparable to that of injectable formulations [108]. Approved in China in 2020, it has emerged as a first-line neuroprotective agent for acute ischemic stroke. Its safety profile is favorable, with adverse events limited to transient dizziness, lingual numbness, and mild gastrointestinal discomfort. Additionally, no excess bleeding or hepatorenal toxicity was observed [109]. Given its neuroprotective properties and favorable safety profile, EDB has been hypothesized to offer prophylactic benefits against post-stroke epileptic seizures. However, direct clinical evidence for this specific indication is still awaited.

CBD

CBD, a non-psychoactive part of the cannabis plant, holds substantial therapeutic potential for diseases of the central nervous system. CBD have multiple targets including GPR55, TRPV1, GABA receptor, AMPAR [110]. A recent study found that CBD possibly functions as a sigma one receptor (σ1R) antagonist. Mechanistic study indicates that CBD binds to σ1R in vitro, disrupting the σ1R-GluN1 complex and mitigating Ca²⁺ influx through NMDARs [72]. Consistent with this mechanism, in an NMDA-induced epilepsy mouse model, CBD treatment reduced the occurrence of clonic and tonic seizures, decreased mortality, significantly prolonged seizure latency, and shortened seizure duration [72].

Furthermore, CBD may play a therapeutic role in febrile seizures by regulating AMPAR kinetics. Evidence from studies using an LPS-induced mouse model has shown that CBD alleviates seizure severity and reduces convulsion incidence [73]. Mechanistic insights from patch-clamp recordings further demonstrated that CBD acts on the AMPAR NTD, where it accelerates GluA1/GluA2 deactivation and slows GluA1 recovery from desensitization, ultimately inhibiting AMPAR-mediated excitatory transmission in hippocampal CA1 neurons [73].

Route of administration critically shapes CBD pharmacokinetics: oral dosing is subject to extensive first-pass metabolism, yielding an absolute bioavailability of merely 6 %, whereas inhalation achieves 11 %–45 % [111]. CBD exhibits pronounced lipophilicity and is rapidly distributed to the brain, adipose tissue, and other organs [112]. In clinical practice, CBD administration is commonly associated with the following adverse reactions: somnolence, fatigue, diarrhea, decreased appetite, and elevated hepatic transaminases [113]. Although high-dose CBD is generally safe and well tolerated, its co-administration with CYP inhibitors entails risks of hepatotoxicity and clinically significant drug–drug interactions [114], 115].

Monoterpene glycosides

Paeoniflorin (PF)

PF, a paeonolide monoterpene glucoside, is extracted from the root of the herb Paeonia lactiflora Pall. A study showed that PF suppresses morphine-induced clonic seizures in mice [74]. When co-administered with MK-801, PF increased seizure latency and reduced episode frequency [74]. The efficacy of PF was enhanced by antisense oligodeoxynucleotides of GluN1, GluN2A, and GluN2B, without significant adverse effects. Molecular docking revealed that PF binds to GluN2A, GluN2B, and GluN2C, with a higher affinity for GluN2A and GluN2B. This finding suggested that PF suppressed epileptic seizures by modulating NMDAR subunits [74].

Following oral administration, PF is rapidly absorbed in the upper small intestine via passive diffusion [116]. However, its absolute oral bioavailability is low, primarily due to extensive first-pass hydrolysis by intestinal flora and hepato-enteric metabolism [117]. Although PF is widely distributed to tissues such as the liver, kidneys, and spleen, its poor membrane permeability limits efficient penetration of the BBB [118], [119], [120]. Additionally, both acute and long-term toxicity studies indicate that PF has a low toxicity profile [121], [122], [123].

Lignans

(−)-Arctigenin (ATG)

ATG is a lignan and the primary bioactive constituent of the dried mature fruits of Arctium lappa L. X-ray crystallography and molecular docking have shown that ATG and its derivatives share a similar binding patterns to the non-competitive AMPAR antagonists GYKI53655 and perampanel [75]. Consistently, ATG antagonizes the human homomeric GluA1 subunit expressed in HEK293 cells and reduces Ca²⁺ influx. Together, these findings highlight the potential of ATG and its derivatives to be developed as antiepileptic drugs targeting AMPARs [75].

ATG has an absolute oral bioavailability of merely 3%–5%, as it undergoes rapid first-pass glucuronidation and consequent systemic clearance [124]. Following absorption, it exhibits extensive plasma protein binding (99.8 %–100 %) and readily crosses the BBB [125]. Regarding its safety profile, a toxicological study indicated that daily subcutaneous administration of 60 mg/kg elicited only mild local irritation, whereas repeated high-dose injections induced hepatic and biliary tract injury [126].

Simple aromatics and phenolic acids

α-Asarone

α-Asarone (trans-2,4,5-trimethoxyphenylpropene) is a natural compound extracted from the dried rhizomes of Acorus gramineus Soland (AGS). α-Asarone effectively extends the latency of PTZ-induced seizures and reduces seizure severity in rat pups [76]. It significantly inhibits NMDAR activity and downregulates the expression of NMDAR subunits (both protein and mRNA) in the hippocampal CA1 and CA3 regions. These actions collectively increase the seizure threshold and mitigate NMDAR-mediated excitotoxicity [76].

Although α-asarone is rapidly absorbed and crosses the BBB in rats [127], its safety profile remains inadequately characterized. It lacks comprehensive toxicokinetic data across species, and no human data exist. Critically, studies in mice suggest it may be carcinogenic in rodents [128]. Thus, a thorough evaluation of its potential cardiotoxic, hepatotoxic, reproductive, and carcinogenic effects is essential.

Ellagic Acid (EA)

EA is a naturally occurring polyphenolic compound with antioxidant properties. It presents in a number of fruits including raspberries, pomegranates, and several other berries. EA has been shown to be beneficial for a range of neurological disorders. For instance, it ameliorates depressive symptoms in patients with multiple sclerosis [129] and improves cognitive function in middle-aged overweight individuals [130]. More importantly, EA elevated the seizure threshold in the PTZ model, regardless of whether it was administered alone or alongside the NMDAR antagonist ketamine. This effect is mediated through EA’s ability to downregulate the expression of frontal cortical NMDAR subunits GluN2A and GluN2B [77].

EA is poorly absorbed in its native form. It is instead predominantly metabolized by the gut microbiota to urolithins, primarily urolithin A and B [131], 132]. No study has reported significant toxic effects related to its administration thus far.

Sinapinic Acid (SA)

SA, a principal constituent of the TCM “Jiezi”, is predominantly isolated from the seeds of cruciferous plants, particularly Sinapis alba L. and Brassica juncea L. Accumulating evidence indicates that SA exerts therapeutic efficacy in AD, Parkinson’s disease, ischemic stroke, and other neurological disorders [133], 134]. A study showed that SA (3 or 10 mg/kg) exerted antiepileptic effects by significantly prolonging the latency to PTZ-induced seizures. Furthermore, it was found to block NMDAR activity and reduce the expression levels of the GluN2A and GluN2B subunits in the prefrontal cortex [78].

The metabolism of SA predominantly occurs within the enterocytes of the small intestine [135]. Although its precise cerebral distribution remains undefined, SA’s documented BBB permeability has warranted its inclusion in central nervous system research. For example, it has emerged as a highly efficient therapeutic agent in glioma therapy [136]. To date, no definitive toxicity data for SA has been reported.

Sodium Houttuyfonate (SH)

SH, a compound isolated from the traditional Chinese medicinal herb Houttuynia cordata Thunb. (H. cordata), exhibits potent antibacterial, anti-inflammatory, and cardioprotective activities [137], [138], [139]. Recent evidence demonstrates that pretreatment with SH (100 mg/kg) confers robust protection against KA-induced excitotoxicity. It markedly prolongs seizure latency, attenuates severity, and prevents hippocampal neuronal death [79]. Mechanistically, SH upregulates glutamate-reuptake proteins (EAAT1-3) and GS, while downregulating glutaminase, thereby reducing hippocampal glutamate levels [79]. Furthermore, SH modulated AMPAR and NMDAR subunit expression, increasing GluA1, GluA2, and GluN2A levels while decreasing GluN2B level. This receptor rebalancing prevents Ca²⁺ overload and excitotoxic injury, underpinning the anticonvulsant efficacy of SH [79].

While SH rapidly distributes to the circulation, intestine, and other organs after oral dosing in mice [140], a critical gap remains in understanding its penetration across the BBB and its distribution profile in the brain.

Herbal extracts targeting NMDARs/AMPARs in epilepsy

Six herbal extracts have been reported to target NMDARs/AMPARs and suppress seizure activity in models of epilepsy, including both in vitro and in vivo studies (Table 2).

Table 2:

The functions and mechanisms of traditional Chinese herbal medicine and extracts in treating NMDARs/AMPARs-mediated epilepsy.

Herb extract	Cell or animal model	Receptor	Mechanism of action	References
GTS	Mg2+-free-induced hippocampal neurons	NMDARs	Channel currents↓ Ca2+ influx↓	[51], 52]
AGS	PTZ-induced rats	NMDARs	GRIN1 mRNA expression↓	[141]
TEN	PTZ-induced rats	NMDARs	GluN2B expression↑	[142]
BM	Pilocarpine-induced rats	NMDARs	Activity of glutamate dehydrogenase↓ Binding affinity of NMDARs for glutamate↓ GluN1 expression↓	[143]
UR	Febrile seizure pups rats, acute brain slices	NMDARs	GluN2A and GluN2B expression↓ Synaptic transmission↓	[144]
SBC	PTZ-induced rats	AMPARs	GluA1 expression↓ Excessive activation of GluA1↓	[145]

GTS, Ginseng Total Saponins; AGS, Acorus gramimeus Soland; 10, Tenuigenin; BM, Bacopa monnieri; UR, Uncaria rhynchophylla; SBC, Scutellaria baicalensis Ceorgi; NMDARs, N-methyl-D-aspartate receptors; PTZ, pentylenetetrazol; AMPARs, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors.

Pannx ginseng

GTS are concentrated from the aqueous extract of the dried roots and rhizomes of Panax ginseng (Araliaceae). In a model of SREDs and SE induced by Mg²⁺-free culture in rat hippocampal neurons, GTS (100 μg/mL) modulated glutamate signaling, reduced Ca²⁺ influx by 62.0 % ± 2.1 %, and suppressed NMDAR-mediated epileptiform discharges. Importantly, in contrast to Rg3, GTS’s mechanism was unrelated to the glycine-binding site and did not antagonize glycine binding to the GluN1 subunit [51], 52].

Although ginsenosides Rg3, Rb1, Rc, Rh1, and Rh2 individually inhibit NMDA-induced Ca²⁺ influx by more than 20 %, they account for only a modest proportion of the activity of the GTS fraction [146]. Thus, the potent effect of GTS is likely mediated by synergistic interactions between these and other constituents, or by more potent unidentified components.

GTS show robust efficacy in preclinical models of various diseases. Yet, their clinical translation has been limited. So far, it has only been approved for marketing for a few diseases [147], 148]. After a single 5 g oral dose of red ginseng, the intact ginsenosides Rb1, Rg3, Rd, and Compound K were detected in circulation [56]. Despite a favorable safety profile, their therapeutic potential is limited by the low systemic concentrations, slow elimination process, and, most notably, poor BBB permeability (an issue particularly evident with Rg3) [56].

Acorus Gramimeus Soland (AGS)

The medicinal plant AGS is a rich source of volatile oils and flavonoids. It has a history of use in TCM for cognitive disorders, which has prompted modern scientific investigation into its neuropharmacological potential. Studies have shown that the water extracts of AGS have anticonvulsant effects similar to of those α-asarone [141]. In the PTZ-kindled model, AGS treatment prolonged the latency to seizures and reduced their incidence and severity. This anticonvulsant effect was correlated with the downregulation of GRIN1 mRNA and a reduction in surface NMDAR density in hippocampal CA1 and CA3 neurons [141].

The principal antiepileptic constituents of AGS extract are α-asarone and β-asarone [149], 150]. Among these, the pharmacokinetics of β-asarone have been more extensively characterized. In rats, β-asarone is rapidly absorbed, distributed, and metabolized. It has been demonstrated to cross the BBB efficiently, with the brain being identified as a significant distribution site [151], 152]. Acute toxicity studies indicate that doses up to 2,500 mg/kg are well-tolerated and did not induce overt toxicity. However, the potential for cumulative nephrotoxicity following prolonged high-dose administration warrants further investigation [153].

Polygala Tenuifolia willd

Tenuigenin (TEN), the principal component extracted from the dried roots of the P. tenuifolia plant of the Polygalaceae family, exhibits exceptional neuroprotective efficacy [154], 155]. In epileptic rat models, TEN treatment elevated the expression of NMDARs in the hippocampal CA1 region. This upregulation suppressed epileptic seizures and ameliorated associated learning and cognitive deficits [142]. However, these findings contrast with the prevailing consensus that reducing NMDAR expression is therapeutic for epilepsy. Therefore, the precise mechanisms underlying TEN’s anticonvulsant effects require further investigation [142].

Pharmacokinetically, TEN exhibits poor membrane permeability [156]. The oral bioavailability of TEN is 8.7 %, with a minor fraction crossing the BBB and infiltrating the cerebral tissue [157], 158]. To date, no stand-alone clinical trials of TEN have been reported. In several studies involving patients with AD, a 12-week combination regimen of TEN (10–20 mg/d) with β-asarone (10–20 mg/d) and memantine significantly improved cognitive performance. The adverse events associated with this combination were mild and transient, including hallucinations, headaches, nausea, and somnolence [159], [160], [161].

Bacopa Monnieri (BM)

BM, a member of the Scrophulariaceae family, is a prostrate herbaceous plant widely distributed in coastal areas of China. Within the Ayurvedic tradition, BM is used to treat AD. Its standardized extract has been incorporated into clinical practice in India and has demonstrated robust efficacy in enhancing cognitive function [162], [163], [164]. Research has demonstrated that the aqueous extract of BM can effectively treat temporal lobe epilepsy in rats, ameliorate learning and cognitive deficits, and reduce stress. After BM treatment, the SE-induced enhancement of glutamate dehydrogenase activity in the hippocampus was diminished, the binding affinity of NMDARs to glutamate was reduced, and the expression of GluN1 was significantly downregulated [143]. Despite substantial preclinical evidence supporting the antiepileptic potential of BM, its therapeutic efficacy and safety in humans remain unestablished due to the lack of clinical trials. Therefore, evidence for its antiseizure effects is currently limited to preclinical models [165], [166], [167].

Clinical studies indicate that the most common adverse events associated with BM extract are gastrointestinal disorders, including nausea, abdominal cramping, and increased bowel movements, which were reported in a long-term study on its cognitive-enhancing effects in elderly participants [168]. While these effects were noted, they were generally mild. More importantly, a six-month trial involving children treated with 225 mg/day of BM extract found this regimen to be effective in improving attention-deficit/hyperactivity symptoms and safe [169]. Taken together, these results support the favorable safety profile of BM extract, indicating the absence of serious adverse or toxic effects in the studied populations.

UR

UR has been investigated for its anticonvulsant potential, particularly in pediatric febrile seizures, mechanistically linked to its sedative and heat-clearing properties. Aqueous extracts of the herb contain approximately 40 constituents, spanning alkaloids, organic acids, terpenoids, and flavonoids. Pharmacokinetic studies have identified 26 parent compounds in the serum, including RIN, isorhynchophylline, hirsutine, hyperoside, RT, quinic acid, chlorogenic acid, and neochlorogenic acid. These compounds are considered to be putative bioactive commpounds. Notably, RIN and related alkaloids have been shown to cross the BBB [86], 170].

Administration of UR aqueous extract (10 g/kg) in a rat-pup febrile seizure model was associated with a reduction in hyperthermia-induced convulsions, likely mediated through the down-regulation of hippocampal GluN2A and GluN2B expression. Additionally, the extract (2 mg/mL) suppressed NMDAR-mediated excitatory synaptic transmission, which may further contribute to its anti-seizure effects [144].

Although studies indicate that ultra-high acute doses of Uncaria total alkaloids induce virtually no overt short-term toxicity in mice [171], the pharmacokinetics and toxicology of the aqueous extract of UR are not well-established.

Scutellaria Baicalensis Ceorgi (SBC)

SBC is known for its effects in clearing heat, drying dampness, purging fire, and detoxification. The medicinal part of the plant is the dried root, and its primary active constituents are flavonoids, such as baicalin and scutellarein. Studies have shown that oral administration of SBC extracts reduces seizure grade and prolongs seizure latency in an epileptic rat model [145]. Following high-dose treatment (1.0 g/kg), SBC extract downregulated GluA1 expression in AMPARs within the hippocampal CA1 and CA3 regions, thereby suppressing excessive activation and mitigating glutamate-induced excitotoxicity. Additionally, SBC extracts ameliorated learning and memory deficits associated with recurrent seizures [145].

Aqueous extracts of SBC stems and leaves have been reported to be non-toxic, non-teratogenic, and non-mutagenic [172]. The maximum tolerated dose was established at 15.0 g/kg in an acute murine model. Furthermore, no appreciable toxicity was observed in rats following oral administration of 1,000 mg/kg/day for 90 days [173]. Clinical trials have shown that the SBC constituent, baicalein, is rapidly absorbed (peaking in plasma within 2 h) and metabolized after oral dosing [174], 175]. It crosses the BBB, and SBC extract doubles the brain flavonoid levels [176]. In addition, UP326, a supplement containing SBC extract, significantly improved cognition [177]. Based on these findings, SBC extract and its derivatives are promising candidates for the development of new antiepileptic agents.

Herbal complexes targeting NMDARs/AMPARs in epilepsy

Seven herbal complexes have been reported to target NMDARs and suppress seizures in cellular and animal models of epilepsy. All these compounds have shown promising therapeutic effects. Furthermore, their efficacy is supported by favorable outcomes in clinical practice (Table 3).

Table 3:

The functions and mechanisms of herbal complex in treating NMDARs/AMPARs-mediated epilepsy.

Herbal complex	Cell or animal model	Receptor	Mechanism of action	References
KC	Mg2+-free--induced hippocampal neurons	NMDARs	Channels decay↓ Channel currents↓ Ca2+ influx↓ GluN2A and GluN2B expression↑	[178]
CD	PTZ-induced rats	NMDARs	GRIN1 mRNA expression↓ The amount of NMDARs↓ Binding affinity of NMDARs for glutamate↓	[179]
CHSGD	Lithium chloride-pilocarpine-induced rats	NMDARs	GluN2B and CaMKII expression↓	[180]
DG	PTZ-induced rats	NMDARs	GluN2B and c-fos expression↓	[181]
TC	PTX-induced rats	NMDARs	GRIN1 mRNA expression↑ Phosphorylated GluN1 expression↑	[182]
XC	Mg2+-free--induced hippocampal neurons	NMDARs	Channel currents↓ Intracellular Ca2+↓	[183]
RC	Mg2+-free--induced hippocampal neurons	NMDARs	Channel currents↓ Intracellular Ca2+↓	[183]

KC, Kangxian Capsules; CD, Caoguozhimu Decoction; CHSGD, Chai-Hu Shu-Gan Decoction; DG, Dianxianqing Granule; TC, Tianbingtiaodu capsule; XC, Xifeng Capsules; RC, Rongchang Capsules; NMDARs, N-methyl-D-aspartate receptors.

Kangxian Capsules (KC)

KC is a formulation based on the “Ditan Decoction” from TCM [184], which consists of nine medicinal herbs, including Acorus tatarinowii, Arisaema amurense, Gastrodia elata, Pseudostellaria heterophylla, Poria cocos, Pinellia ternata, Citrus reticulata, Aquilaria sinensis, and Citrus aurantium [185]. A study demonstrated that application of rabbit cerebrospinal fluid containing KC to a hippocampal neuronal cell model exhibiting epileptiform discharges accelerated NMDAR decay, thereby reducing Ca²⁺ influx. This consequently diminishes the post-epileptiform intracellular Ca²⁺ concentration, mitigating excitotoxicity [178].

Furthermore, KC serves as a complementary therapy to conventional antiepileptic drugs in drug-resistant epilepsy. Its efficacy is attributed to the reduction in seizure frequency and duration, as well as the modulation of pro-inflammatory pathways [186]. Notably, a clinical study in pediatric patients reported that co-administration of KC and levetiracetam provided effective seizure control and cognitive improvement, demonstrating a promising safety profile [187]. Nevertheless, the pharmacokinetic profile of KC has not been fully elucidated, and the specific constituents that reach the brain remain unidentified. Although no overt adverse effects have been observed clinically, even when co-administered with standard antiepileptic drugs, comprehensive toxicological studies are still necessary to confirm its long-term safety and therapeutic value [188].

Caoguozhimu Decoction (CD)

CD originates from the classic TCM text “Detailed Analysis of Epidemic Warm Diseases” and contains a combination of nine medicinal herbs, including Amomum tsao-ko, Anemarrhena asphodeloides, S. baicalensis, Magnolia officinalis, P. ternata, A. tatarinowii, P. lactiflora, Prunus mume, and Glycyrrhiza uralensis. Previuos studies have demonstrated that CD suppresses seizure development in PTZ-kindled rats. Its primary mechanism involves downregulating the mRNA expression of GRIN1 in the hippocampal CA1, CA2, and CA3 subfields and the cortex, as well as reducing neuronal expression of NMDARs [179]. Consequently, this interrupts the transmission of excitatory signals and prevents kindling. Moreover, unlike MK-801, CD does not induce significant side effects [179].

Although the pharmacokinetic profile of CD has not been fully elucidated, its clinical efficacy has been well-documented. In pediatric patients with epilepsy, CD administration resulted in a 66.7 % normalization rate of epileptiform EEG discharges [189]. Notably, no adverse events, such as sedation, somnolence, impaired attention, ataxia, or skin rashes, were observed in patients receiving CD granules [189]. Studies in acute mouse models have shown that i.p. injection of CD granules at 10 g/kg causes transient hypoactivity within 10 min, with no other abnormal behaviors detected. However, the potential toxicity associated with chronic CD administration remains unknown [189].

Chai-Hu Shu-Gan Decoction (CHSGD)

CHSGD, a proprietary formula, consists of 14 medicinal herbs including B. chinense, P. ternata, S. baicalensis, Codonopsis pilosula, Cinnamomum cassia, P. lactiflora, G. uralensis, Ligusticum chuanxiong, Z. jujuba, Angelica sinensis, Draconis ossifragus, Ostrea gigas, Rehmannia glutinosa, and UR. CHSGD treatment significantly reduced seizure frequency, SE duration, and overall severity in a rat model of chronic temporal lobe epilepsy [180]. Mechanistic studies revealed that these effects were accompanied by a marked downregulation of GluN2B and CaMKII expression in the hippocampal CA1 and CA3 regions, as well as the temporal lobe [180].

Despite the lack of pharmacokinetic data for CHSGD, its clinical efficacy as an adjunctive therapy for epilepsy has been well-documented. It has been shown to reduce pro-inflammatory cytokines, improve cognitive function, and alleviate symptoms in children with epilepsy [190]. Notably, CHSGD significantly enhanced the effectiveness of standard antiepileptic drugs. For refractory epilepsy, combination therapy achieved an 88.33 % response rate, reducing seizure frequency and EEG abnormalities [191]. Other regimens has also proven highly effective: CHSGD plus oxcarbazepine yielded a 95.15 % response rate (with 44.66 % EEG normalization), and plus levetiracetam reached 91.11 %, while also improving immune markers, cognition, and oxidative stress [192]. Moreover, CHSGD with lamotrigine benefits patients with focal epilepsy and depression, improving their quality of life [193]. Although no severe toxic or adverse effects have been well-documented in the clinical application of CHSGD, further toxicological studies are necessary to fully evaluate its long-term safety.

Dianxianqing Granule (DG)

DG is a clinical formula consisting of 11 herbs, including Curcuma zedoaria, A. tatarinowii, B. chinense, and Hirudo. It is known for its multiple pharmacological actions, including: resolving phlegm, extinguishing wind, promoting blood circulation, unblocking meridians, nourishing the kidneys, soothing the liver, opening orifices, and enhancing intelligence [194]. One study demonstrated that DG dose-dependently extended seizure latency, shortened SE duration, and improved behavioral outcomes in a rat model of epilepsy. These effects may be mediated through the downregulation of GluN2B and c-fos expression in the brain [181].

However, current research on DG remains confined to animal studies and lacks systematic investigations into its pharmacokinetics, toxicology, and clinical efficacy.

Tianbingtiaodu Capsule (TC)

TC is a TCM formula with B. chinense, C. cassia, G. elata, Buthus martensii, artificial calculus bovis, Coptis chinensis, and Gynostemma pentaphyllum as its primary constituents, along with other auxiliary ingredients. According to a study, TC improved learning and memory deficits in picrotoxin (PTX)-kindled chronic epileptic rats, despite not directly targeting epilepsy [182]. After TC treatment, the expressions of GRIN1 mRNA and phosphorylated GluN1 levels were upregulated in the rat hippocampus (CA3 and DG). Both high and low doses of TC showed varying degrees of efficacy in achieving these effects [182].

Currently, pharmacological studies on TC remain confined to animal models, necessitating further elucidation of its pharmacokinetics, toxicology, and clinical efficacy.

Xifeng Capsules (XC)

XC effectively diminishes NMDAR-mediated currents and reduces the frequency of recurrent high-frequency abnormal neuronal discharges in the hippocampus. This is accompanied by a decrease in intra-neuronal Ca²⁺ concentration. By alleviating excitotoxicity induced by calcium overload, XC ultimately exerts a neuroprotective effect [178], 183].

Clinical evidence indicates that the combination of XC and acupuncture yields significant therapeutic benefits in pediatric epilepsy, with an overall response rate of 96.88 %, contributing to improved quality of life [195]. Moreover, XC monotherapy provides seizure control comparable to carbamazepine in children with benign childhood epilepsy with centrotemporal spikes and is superior in reducing the frequency of epileptiform discharges on EEG [196]. Additionally, as an adjunctive therapy for tonic-clonic seizures, XC achieves satisfactory efficacy without increasing adverse effects [197].

Rongchang Capsules (RC)

The herbal formula RC, which contains Deer Antler, Acorus Tatarinowii, Dodder Seed, Gallbladder Star, Gastrodia Elata, Scorpion, Silkworm, Qingbanxia (Pinellia), Chenpi (Citrus Peel), Poria Cocos, Borneol, and Roasted Licorice, has been proven to possess significant antiepileptic effects [198]. Similar to KC and XC, RC confers neuroprotection by mitigating excitotoxicity through multiple mechanisms: reducing NMDAR-mediated currents, suppressing recurrent high-frequency discharges in hippocampal neurons, and lowering intracellular Ca²⁺ concentration. The inhibitory potency on NMDAR currents was ranked as KC>RC > XC. Conversely, the effectiveness in suppressing abnormal discharges is XC˜RC > KC, whereas the capability to reduce intracellular Ca²⁺ follows the order XC>KC > RC [178], 183].

In the control of tonic–clonic seizures in pediatric epilepsy, RC demonstrated an overall response rate of 77.42 %, an efficacy comparable to that of carbamazepine. Moreover, RC ameliorated cognitive impairment in children with epilepsy. Notably, no adverse events were reported after one year of continuous administration, indicating that RC is both safe and effective [199].

Conclusion and future perspectives

In summary, over the past 25 years, researchers have identified a considerable number of Chinese herbal medicines and natural molecules that act on NMDARs and AMPARs, and investigated their diverse anti-epileptic mechanisms (Figure 4).

Figure 4:

The “TCM–subunit–Mechanisml–symptom relief” network.

The development of TCM for epilepsy continues to face critical methodological challenges (Figure 5). First, there is a pronounced gap between in vitro and in vivo efficacy. Additionally, the absence of definitive plasma concentration–response relationships precludes the establishment of rigorous exposure–effect models for these drugs. Furthermore, the field relies heavily on MES and PTZ screening paradigms, which are inadequate models of human focal epileptogenesis. Finally, the persistent scarcity of randomized controlled trials diminishes the clinical relevance of the findings. Together, these issues significantly hinder the development of TCM-derived antiseizure drugs.

Figure 5:

Future research directions and strategic frameworks for antiepileptic drug development targeting NMDARs and AMPARs.

iGluRs dysfunction can contribute to epileptic seizures through multiple mechanisms. Current research indicates that most TCM compounds or monomers intervene in epilepsy by modulating receptor or subunit expression, Ca²⁺ influx, and receptor-mediated currents. Although NMDARs are more potent than AMPARs in neuroprotection against excitotoxicity and in regulating seizures by controlling extracellular Ca²⁺ entry, AMPARs, as the primary fast excitatory glutamate receptors in the brain, play a crucial role in synaptic plasticity and neuronal firing regulation. Most studies reviewed in this paper focused on TCM applications in NMDAR-mediated epilepsy, with only a minority addressing AMPARs. However, AMPAR activation-induced depolarization and paroxysmal depolarizing shifts (PDS) under pathological conditions are also key mechanisms of seizure generation. Nevertheless, no studies have investigated regarding TCM direct modulation of AMPAR function. Furthermore, the regulation of AMPAR subunits trafficking within neurons through nutrient intake and energy metabolism represents a current research hotspot [200], 201]. Therefore, a promising direction for TCM may involve influencing AMPAR transport via nutrient and metabolic regulation to intervene in epileptic seizures.

The abundant resources within TCM represent a promising frontier for anti-epileptic drug discovery. The successful clinical translation of these traditional herbal treatments is anticipated to offer significant benefits to patients with epilepsy.