Treating Epilepsy with Natural Products

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Milan Malaník	--	3072	2023-08-07 12:57:54	\|
2	format correct	Conner Chen	Meta information modification	3072	2023-08-08 08:27:11	\| \|
3	format correct	Conner Chen	Meta information modification	3072	2023-08-10 05:39:53	\|

This entry is adapted from the peer-reviewed paper 10.3390/ph16081061

Epilepsy is a neurological disease characterized by recurrent seizures that can lead to uncontrollable muscle twitching, changes in sensitivity to sensory perceptions, and disorders of consciousness. Although modern medicine has effective antiepileptic drugs, the need for accessible and cost-effective medication is urgent, and products derived from plants could offer a solution.

epilepsy anticonvulsant natural products

1. Natural Products That Affect Voltage-Gated Na⁺ and Ca²⁺ Channels

Voltage-gated sodium channels (VGSCs) initiate and conduct action potentials in excitable cells such as neurons or muscle cells, whereas voltage-gated calcium channels (VGCCs) are activated during action potentials, and they conduct the influx of Ca²⁺ into cells to initiate physiological processes, such as neurotransmission and muscle contraction ^[1]. Both channels represent molecular targets for drugs used in the treatment of epilepsy (see above).

Not many plant-derived compounds that affect VGSCs and VGCCs have been reported (Table 1). The effects of monoterpenes on various ion channels have been reviewed recently by Oz et al. ^[2], but most of the compounds mentioned exerted anticonvulsant effects only at doses too high to be implemented in clinical practice. Therefore, alkaloids and coumarins seem to have better prospects than monoterpenoids.

Several Aconitum alkaloids have been proven to interact with Na⁺ channels ^[3]^[4]^[5]^[6]^[7]^[8]. Unfortunately, these alkaloids have been isolated only from Aconitum species endemic to some regions of China. Furthermore, the isolation of these compounds is very tricky, with small yields. Because the total synthesis of aconitine-type alkaloids remains elusive, the prospects for Aconitum alkaloids are vague.

On the other hand, piperine, the major bioactive component in black pepper (Piper nigrum), significantly inhibited Na⁺ channel activity in mice ^[9]. Moreover, co-administration with carbamazepine (CBZ) or phenytoin decreased the elimination of these AEDs and enhanced their bioavailability ^[10]. The metabolism of piperine in the liver is limited, and its high blood–brain barrier permeability has been demonstrated in the Caco-2 monolayer model ^[11]. Its only limiting factor is poor solubility in water, and this can be improved, e.g., by a nanoprecipitation method leading to enhanced oral bioavailability and brain delivery of piperine after oral administration ^[12]. Altogether, piperine represents a very promising candidate for further evaluation in clinical trials, albeit with the caveat that increased attention must be paid to piperine-mediated drug interactions ^[13].

Similarly, the co-administration of coumarins significantly reduced the ED₅₀ values of AEDs in the MES test in mice, as observed for imperatorin (40 mg/kg, i.p.) in combination with CBZ, phenobarbital, or phenytoin ^[14], and for xanthotoxin (50 and 100 mg/kg, i.p.) in combination with CBZ and valproate (VPA), respectively ^[15]. Additionally, xanthotoxin increased the total brain concentration of CBZ and VPA by about 84% and 46%, respectively, probably by inhibiting P-glycoprotein ^[15]. Therefore, co-administering natural compounds with conventional AEDs could be a way to increase the anticonvulsant activity of AEDs and thus improve the comfort of patients suffering from epilepsy.

Table 1. Natural products that affect VGSCs, VGCCs, or VGPCs.

Compound	Effective Dose	Animal Model	Seizure-Inducing Agent	Mechanism	Source
Paeoniflorin (monoterpene)	100 mg/kg/day, p.o. (for 10 days)	Male immature Lewis rats	Hyperthermia	Suppression of [Ca²⁺]_i elevation via mGluR5	^[16]
Thymol (monoterpene)	50 and 100 mg/kg, i.p.	Male Swiss mice Male Wistar rats	PTZ, MES, Strychnine, 4-AP	Possibly via positive modulation of GABA_A and voltage-dependent Na⁺ channel blockade	^[17]
Iritectol G (triterpene)	10 μM	Neocortical neurons of C57BL/6 mice	4-AP	Interaction with inactivated state of VGSC	^[18]
Imperatorin (coumarin)	30–50 µM	NG108-15 cells	Voltage-clamp assay	Inhibition of VGSC	^[19]
Xanthotoxin (coumarin)	50 and 100 mg/kg, i.p. + CBZ 100 mg/kg, i.p. + VPA	Male Swiss mice	MES	Inhibition of P-glycoprotein Inhibition of VGPC Modulation of calcium-dependent potassium channels	^[20]
Acacetin (flavonoid)	10 and 50 mg/kg, i.p.	Male Sprague Dawley rats	KA	Inhibition of glutamate release by decrease in voltage-dependent Ca²⁺ entry	^[21]
Aconitine (alkaloid)	1 μM	Hippocampal slices of male Wistar rats	Low Mg²⁺-ACSF	Modulation of Na⁺ channels	^[3]
3-Acetylaconitine (alkaloid)	0.01–1 μM	Hippocampal slices of male Wistar rats	Mg²⁺-free ACSF Bicuculline	Inactivation of Na⁺ channels	^[5]
Lappaconitine (alkaloid)	1–100 μM	Hippocampal slices of male Wistar rats	Low Mg²⁺-ACSF Bicuculline	Blockade of Na⁺ channels	^[6]
N-desacetyl lappaconitine (alkaloid)	1–100 μM	Hippocampal slices of male Wistar rats	Low Mg²⁺-ACSF Bicuculline	Blockade of Na⁺ channels	^[6]
1-Benzoylnapelline (alkaloid)	1–100 μM	Hippocampal slices of male Wistar rats	Low Mg²⁺-ACSF Bicuculline	Modulation of Na⁺ channels	^[7]
6-Benzoylheteratisine (alkaloid)	0.01–10 μM	Hippocampal slices of male Wistar rats	Bicuculline	Blockade of Na⁺ channels	^[8]
Nantenine (alkaloid)	20–50 mg/kg, i.p.	Male albino mice	PTZ MES	Decrease in Ca²⁺-influx into the cell	^[22]
Piperine (alkaloid)	5, 10, and 20 mg/kg, i.p.	Male Swiss mice	PTZ, MES, NMDA, PTX, Bicuculline, BAYK-8644, Strychnine	Na⁺ channel antagonist activity	^[9]
Veratridine (alkaloid)	1 μM	Hippocampal slices of male Wistar rats	Low Ca²⁺/high Mg²⁺-ACSF	Block of inactivation of Na⁺ channels	^[4]

2. Natural Products That Affect the Gabaergic Transmission

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system (CNS). It is synthesized from glutamate by glutamic acid decarboxylase (GAD). GABA receptors can be divided into the ionotropic GABA_A receptors and the metabotropic GABA_B receptors. GABA_A receptors are ligand-gated ion channels that increase the flow of chloride ions into the cell and thus promote inhibitory effects in the brain ^[23]. The potentiation of GABAergic transmission is one of the main targets of the AEDs currently used in clinical practice (see above).

Whereas only a few natural products interact with VGSCs and VGCCs, phytoconstituents most often affect the modulation of GABA_A receptors (Table 2). The most significant anticonvulsant effects mediated by GABAergic transmission have been observed for terpenoids. Manayi et al. ^[24] have reviewed the ability of natural terpenoids to modulate the GABAergic system, but most of the compounds identified exerted anticonvulsant effects only at doses too high to be implemented in clinical practice.

Monoterpenes and sesquiterpenes are constituents of essential oils, and they have properties plausible for a potential application. Their low molecular weight and high lipophilicity allow them to penetrate membranes and interact with epilepsy-related proteins ^[25]. Thymoquinone, the dominant compound in black seed oil (Nigella sativa), has shown the most notable activity of all the monoterpenes found in this search, inhibiting convulsions in male BALB/c mice at the relatively low dose of 40 mg/kg ^[26]. Preclinical findings led to a pilot study in children with refractory epilepsy. The results demonstrated that thymoquinone was effective and well-tolerated ^[27]. Moreover, thymoquinone potentiated the antiepileptic properties of VPA ^[24] and phenytoin ^[28]. It also displayed a neuroprotective effect in Sprague Dawley rats by phosphorylating cAMP response element-binding protein (CREB) ^[29] and downregulating TNF-α and COX-2 ^[30]. Unfortunately, thymoquinone inhibits the activity of cytochrome P450 2C9 (CYP2C9), and this must be taken into account when thymoquinone is co-administered with phenytoin ^[31]. To sum up, its anticonvulsant and neuroprotective properties make thymoquinone a very promising substance that deserves further investigation with emphasis on an in-depth exploration of its pharmacokinetics and potential interactions.

Iridoids seem to be effective in the inhibition of convulsions as well, and especially the reports of the anticonvulsant activity of the extracts of Valeriana species are increasingly frequent. Pretreatment with valepotriate (5, 10, 20 mg/kg/day, i.p.) protected mice against MES and PTZ-induced convulsions, but it was far less effective than diazepam (4 mg/kg/day, i.p.) ^[32]. Significant anticonvulsant activity has also been reported for paederosidic acid, a rare sulfur-containing iridoid ^[33], but such compounds are, unfortunately, very unstable under acidic conditions, which makes their peroral administration difficult ^[34].

Bilobalide, the main sesquiterpene trilactone found in the leaves of Ginkgo biloba, must be included. Bilobalide (30 mg/kg, p.o., once a day for 4 days) elevated GABA levels in the hippocampus, cerebral cortex, and striatum of male ddY mice, possibly through the potentiation of the activity of GAD ^[35]. Also considering its neuroprotective effect ^[36], makes bilobalide seems very promising, although Ng et al. point out that bilobalide negatively modulated the action of GABA at α₁β₂γ_2L GABA_A receptors ^[37].

An even more promising natural product affecting GABA transmission has been found in huperzine A (HupA), a dietary supplement used in the USA as a memory enhancer. HupA is an acetylcholinesterase inhibitor isolated from the Chinese club moss Huperzia serrata. It also exerts anti-inflammatory and neuroprotective effects by activating nicotinic cholinergic receptors ^[38]. In addition, HupA has delivered seizure relief in a 6 Hz model, with an ED₅₀ value of 0.34 mg/kg in the 32 mA paradigm, being 57 times more potent than levetiracetam and 301 times more potent than VPA ^[39]. It also suppressed PTZ-induced seizures in rats by activating the cortical transmission of GABA ^[40]. These findings, together with the favorable pharmacokinetic properties of HupA in humans ^[41], have led to clinical testing.

Recently, several coumarins have been reported to effectively inhibit PTZ-induced seizures in the zebrafish larvae model of epilepsy at doses lower than those of the positive controls diazepam (10 mM) and VPA (1 mM), respectively ^[42]^[43]. Based on the seizure-inducing agent used (PTZ), it was postulated that the test coumarins interfered with the GABA transmission. Coumarins have previously been shown to inhibit the activity of GABA transaminase (GABA-T), the main degradative enzyme of GABA ^[44]. This hypothesis was supported by a molecular docking study of oxypeucedanin hydrate, the most active furanocoumarin, to the structural model of GABA-T. The results indicated that a bulky substituent at the C5 position is crucial for antiseizure activity, whereas an analogous bulky moiety substituted at the C8 position diminishes the activity ^[43]. Similar results have been reported by Singhuber et al. ^[45] in a study dealing with the modulation of GABA-induced chloride currents by selected coumarin derivatives on recombinant α₁β₂γ_2S GABA_A receptors expressed in Xenopus laevis oocytes ^[45]. On the other hand, exactly the opposite results were found for the mice MES test. C5-substituted furanocoumarins were inactive, whereas C8-substituted furanocoumarins exerted strong anticonvulsant activity ^[46]. Hence, more studies are needed to clarify the structure–activity relationship with respect to the model of epilepsy used as well as to find out more about bioavailability. However, as coumarins are simple molecules, they are ideal for chemical synthesis and modifications to improve their pharmacodynamic and pharmacokinetic properties.

Table 2. Natural products with influence on GABAergic transmission.

Compound	Effective Dose	Animal Model	Seizure-Inducing Agent	Mechanism	Source
Thymol (monoterpene)	50 and 100 mg/kg, i.p.	Male Swiss mice Male Wistar rats	PTZ, MES, Strychnine, 4-AP	Possibly via positive modulation of GABA_A and voltage-dependent Na⁺ channel blockade	^[17]
Thymoquinone (monoterpene)	40 mg/kg/day, p.o. (for 7 days)	Sprague Dawley rats	PTZ	Activation of GABA_B1R/CaMKII/_pCREB pathway	^[29]
Paederosidic acid (iridoid)	5–40 mg/kg, i.p.	Male ICR mice Sprague Dawley rats	MES PTZ	Upregulation of GAD65	^[33]
Valepotriate (iridoid)	5–20 mg/kg/day, i.p. (for 3 weeks)	Male ICR mice Sprague Dawley rats	MES PTZ	Upregulation of GABA_A, GAD65, and Bcl-2 and downregulation of caspase-3	^[32]
Bilobalide (sesquiterpene)	30 mg/kg/day, p.o. (for 4 days)	Hippocampus, cortex, and striatum of male ddY mice	INH	Elevation of GABA levels Potentiation of GAD activity	^[35]
Curcumol (sesquiterpene)	100 mg/kg/day, i.p. (for 3 days)	Male C57BL/6J mice	PTZ KA	Facilitation of GABAergic inhibition	^[47]
(+)-Dehydrofukinone (sesquiterpene)	10, 30, and 100 mg/kg, i.p.	Female Swiss mice	PTZ	Modulation of GABA_A receptors	^[48]
Betulin (triterpene)	50 and 100 mg/kg, i.p.	Male ICR mice	Bicuculline	Binding to the GABA_A receptor	^[49]
Ginsenoside Rg₃ (triterpene)	100 μM	Xenopus laevis oocytes	Electrode voltage-clamp technique	GABA_A receptor activation via interaction with the γ₂ subunit	^[50]
Ursolic acid stearoyl glucoside (triterpene)	50 mg/kg, i.p.	Wistar albino rats	MES INH	Possibly via GABA receptor stimulation	^[51]
Embelin (benzoquinone)	0.156–0.625 mg/kg, i.p.	Adult zebrafish	PTZ	Affinity toward GABA_A receptor	^[52]
Cnidilin (coumarin)	300 µM	Xenopus oocytes	Two-microelectrode voltage clamp assay	Modulation of GABA_A receptors of the subunit combination α₁β₂γ_2S	^[53]
Osthole (coumarin)	300 µM	Xenopus oocytes	Two-microelectrode voltage clamp assay	Modulation of GABA_A receptors of the subunit combination α₁β₂γ_2S	^[53]
Lucidafuranocouma-rin A (coumarin)	10–16 μM	Zebrafish larvae	PTZ	Possibly via interaction with the GABA_A receptor	^[42]
Oxypeucedanin (coumarin)	10–40 μM	Zebrafish larvae	PTZ	Possibly via interaction with the GABA_A receptor	^[43]
Oxypeucedanin hydrate (coumarin)	20–50 μM	Zebrafish larvae	PTZ	Possibly via interaction with the GABA_A receptor	^[43]
Notopterol (coumarin)	0.25–2 μM	Zebrafish larvae	PTZ	Possibly via interaction with the GABA_A receptor	^[43]
Pimpinellin (coumarin)	20–80 μM	Zebrafish larvae	PTZ	Possibly via interaction with the GABA_A receptor	^[43]
Hyuganin C (coumarin)	2.5–20 μM	Zebrafish larvae	PTZ	Possibly via interaction with the GABA_A receptor	^[43]
Rosmarinic acid (phenolic)	30 mg/kg, i.p.	Female C57BL/6 mice	PTZ Pilocarpine	Probably activation of the GABAergic system	^[54]
Chlorogenic acid (phenolic)	5 mg/kg/day, p.o. (for 15 days)	Male Swiss albino mice	Pilocarpine	Suppressing glutamate receptors, neuroprotective effect	^[55]
Gastrodin (phenolic)	60 mg/kg/day, p.o. (for 7 days)	Mongolian gerbils	Genetic seizure model (seizure-sensitive gerbils)	Decrease in GABA degradation Decrease in GABA-T, SSADH, and SSAR immunoreactivities	^[56]
Rutin (flavonoid)	50 and 150 nM, i.c.v.	Male Wistar rats	PTZ	Positive allosteric modulation of the GABA_A receptor complex via interaction at the benzodiazepine site	^[57]
Wogonin (flavonoid)	5 and 10 mg/kg, i.p.	Male Sprague Dawley rats	MES PTZ	Potentiation of the activity of GABA	^[58]
Vitexin (flavonoid)	100 and 200 µM, i.c.v.	Male Wistar rats	PTZ	Interaction with GABA_A benzodiazepine receptor complex	^[59]
Vitexin (flavonoid)	10 mg/kg/day, p.o. (for 15 days)	Male Swiss albino mice	Pilocarpine	Suppressing glutamate receptors, neuroprotective effect	^[55]
Nobiletin (flavonoid)	12.5, 25, and 50 mg/kg/day, o.g. (for 6 days)	C57BL/6 mice	PTZ	Modulation GAD65/GABA_A expression, BDNF-TrkB, PI3K/Akt	^[60]
(+)-Erythravine (alkaloid)	0.25–3 μg/μL, i.c.v.	Male Wistar rats	Bicuculline, NMDA, KA, PTZ	Probably modifying GABA neurotransmission	^[61]
(+)-11-α-Hydroxy-erythravine (alkaloid)	0.25–3 μg/μL, i.c.v.	Male Wistar rats	Bicuculline, NMDA, KA, PTZ	Probably modifying GABA neurotransmission	^[61]
Huperzine A (alkaloid)	0.6 mg/kg, i.p.	Male Sprague Dawley rats	PTZ	Activation of cortical GABA transmission	^[40]
Lobeline (alkaloid)	10, 20, 30 mg/kg, i.p.	Male Swiss mice	PTZ Strychnine	Enhancing the GABA release	^[62]
Montanine (alkaloid)	30 and 60 mg/kg, i.p.	Swiss mice and Wistar rats of either sex	PTZ	Modulation of several neurotransmitter receptor systems including GABA_A receptors	^[63]
Piperine (alkaloid)	2.5, 5, 10, and 20 mg/kg, i.p.	Male Swiss mice	Pilocarpine	Multiple anticonvulsant mechanisms, modulation of the GABA system, antioxidant, and anti-inflammatory activity	^[64]

3. Natural Products That Reduce Postsynaptic Excitability by Affecting AMPA or NMDA Receptors

Glutamate is the principal excitatory neurotransmitter in the brain, and therefore, glutamate receptor agonists, such as α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), N-methyl-D-aspartate (NMDA), and kainate, act as elicitors of seizures. Glutamate receptors can be divided into ionotropic glutamate receptors (ligand-gated ion channels) and metabotropic glutamate receptors (G-protein-coupled receptors) ^[65]. Among the ionotropic glutamate receptors, the AMPA-type and NMDA-type glutamate receptors are the most important, as certain AEDs affect these ionotropic receptors (e.g., perampanel and topiramate).

Interestingly, no reports of natural products interacting with AMPA receptors have been found during some searches, except for one recent study describing the potent anticonvulsant activity of magnolol and honokiol in a model of therapy-resistant epilepsy. However, the authors postulate the involvement of not only AMPA receptors but also GABA_A and cannabinoid receptors ^[66]. Magnolol and honokiol, the main bioactive substances in the bark of Magnolia officinalis, are known for antioxidant, anti-inflammatory, and neuroprotective properties that make them promising for further research in the field of epilepsy, especially at a time when knowledge of their toxicity and bioavailability is accumulating ^[67].

Panax ginseng is well-known for its neuroprotective properties with ginsenosides as the main active constituents. Among the test ginsenosides, 20(S)-Rg₃ and 20(S)-Rh₂ inhibited NMDA receptors. However, 20(S)-Rg₃ interacted with the glycine site, while 20(S)-Rh₂ likely did so with the polyamine-binding site of NMDA receptors. (R)-isomers were inactive and the mono-glycosylated moiety at C-3 was found to be essential for binding to polyamine sites ^[68]. Further assays showed that 20(S)-Rg₃ regulated GABA_A receptor activity by interacting with the γ₂ subunit ^[50], demonstrating its multitarget mechanism of action. Nevertheless, the bioavailability of ginsenosides after oral administration is relatively poor. Low water solubility and easy degradation by gastric acid and gut microbiota are the crucial disadvantages. Therefore, their absorption needs to be enhanced by sophisticated formulation strategies ^[69].

4. Natural Products with Multiple Mechanisms of Action: Cannabinoids

Cannabis sativa contains more than 100 compounds (lipophilic phytocannabinoids) with different therapeutic potentials and because phytocannabinoids affect diverse epilepsy-related targets ^[70], they have been given a separate section. Medicinal marijuana is applicable as a treatment option mainly for patients with chronic, autoimmune, inflammatory, degenerative, or oncological illnesses, and also for palliative care ^[71]. Multiple in vitro and in vivo preclinical trials have reported antiepileptic effects for several constituents of medical marijuana. Compounds of interest include psychoactive ∆⁹-tetrahydrocannabinol (∆⁹-THC) and structurally similar cannabidiol (CBD), along with non-psychoactive ∆⁹-tetrahydrocannabivarin (∆⁹-THCV), cannabidivarin (CBDV), and ∆⁹-tetrahydrocannabinolic acid (Δ⁹-THCA). ∆⁹-THC acts as a potent partial agonist on endocannabinoid receptor CB₁, influencing both GABAergic and glutamatergic synaptic transmission. The clinical use of medical marijuana is limited because the anticonvulsant effect of ∆⁹-THC is relatively unpredictable. It acts simultaneously on several receptor targets, such as the transient receptor potential (TRP) cation channels TRPA1, TRPV2, and TRPM8; the orphan G-coupled protein receptor GPR55; the 5-HT_3A receptor; the peroxisome proliferator-activated receptor gamma (PPARγ); the μ- and δ-opioid receptors, the β-adrenoreceptors; and some subtypes of Ca²⁺, K⁺, and Na⁺ channels. Interestingly, some experiments have shown medical marijuana to have no or even a pro-convulsant effect ^[70]. Δ⁹-THCA is used to prevent seizures, e.g., in the USA. This metabolic precursor of Δ⁹-THC is more affordable and should have only minor psychoactive properties ^[72]. Experimental observations have demonstrated that it has anticonvulsant effects via the modulation of ion channels and enzymes crucial for the biosynthesis of the endocannabinoid 2-arachidonoylglycerol ^[70]. The mechanisms of anticonvulsant activity of Δ⁹-THCV and CBDV are not well understood. Both compounds probably exert their anticonvulsant effects via non-CB₁/CB₂ mechanisms. TRPV1, TRPV2, TRPA1, and TRPM8 channels are the likely molecular targets of Δ⁹-THCV and CBDV ^[73].

CBD is the most promising of these agents, with effects proved by several clinical trials, especially for the treatment of drug-resistant epilepsies. Recent studies have proposed that its anticonvulsant effect may involve agonistic activity at the TRPV1 channel, the blockade of human T-type VGCCs, the modulation of various receptors such as 5-HT_1A, 5-HT_2A, GPR55, adenosine A1 and A2, voltage-dependent anion-selective channel protein 1 (VDAC1), or an influence on the release of TNF-α ^[70].

Smoked, inhaled, or vaporized Δ⁹-THC has a bioavailability in the range from ~10–35% in contrast to (~6%) by oral administration. CBD and CBDV are hardly soluble in water, and their bioavailability after oral administration is poor, but many trials have evaluated cannabinoids suspended in sesame oil or mixed with glycocholate to increase their bioavailability, and intranasal, sublingual, and transdermal applications are common. Unfortunately, because of their lipophilic properties, large amounts of cannabinoids accumulate in adipose and other tissues, especially with repeated administration. Negative interactions with other drugs metabolized by the cytochrome P450 system or isoenzymes CYP3A4, CYP2C19, CYP2C9, and CYP2D6 should be taken into account, especially in Europe, where the co-administration of CBD and clobazam has been approved as adjunctive treatment of Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS). The strong inhibition of CYP2C19 by CBD leads to a remarkable rise in clobazam concentration, which may contribute to side effects, including somnolence and sedation. Finally, potenti

References

Catterall, W.A.; Lenaeus, M.J.; Gamal El-Din, T.M. Structure and Pharmacology of Voltage-Gated Sodium and Calcium Channels. Annu. Rev. Pharmacol. Toxicol. 2020, 60, 133–154.
Oz, M.; Lozon, Y.; Sultan, A.; Yang, K.-H.S.; Galadari, S. Effects of Monoterpenes on Ion Channels of Excitable Cells. Pharmacol. Ther. 2015, 152, 83–97.
Ameri, A.; Gleitz, J.; Peters, T. Inhibition of Neuronal Activity in Rat Hippocampal Slices by Aconitum Alkaloids. Brain Res. 1996, 738, 154–157.
Ameri, A.; Shi, Q.; Aschoff, J.; Peters, T. Electrophysiological Effects of Aconitine in Rat Hippocampal Slices. Neuropharmacology 1996, 35, 13–22.
Ameri, A. Inhibition of Rat Hippocampal Excitability by the Plant Alkaloid 3-Acetylaconitine Mediated by Interaction with Voltage-Dependent Sodium Channels. Naunyn-Schmiedebergs Arch. Pharmacol. 1997, 355, 273–280.
Ameri, A. Structure-Dependent Differences in the Effects of the Aconitum Alkaloids Lappaconitine, N-Desacetyllappaconitine and Lappaconidine in Rat Hippocampal Slices. Brain Res. 1997, 769, 36–43.
Ameri, A. Inhibition of Rat Hippocampal Excitability by the Aconitum Alkaloid, 1-Benzoylnapelline, but Not by Napelline. Eur. J. Pharmacol. 1997, 335, 145–152.
Ameri, A. Effects of the Alkaloids 6-Benzoylheteratisine and Heteratisine on Neuronal Activity in Rat Hippocampal Slices. Neuropharmacology 1997, 36, 1039–1046.
Mishra, A.; Punia, J.K.; Bladen, C.; Zamponi, G.W.; Goel, R.K. Anticonvulsant Mechanisms of Piperine, a Piperidine Alkaloid. Channels 2015, 9, 317–323.
Tiwari, A.; Mahadik, K.R.; Gabhe, S.Y. Piperine: A Comprehensive Review of Methods of Isolation, Purification, and Biological Properties. Med. Drug Discov. 2020, 7, 100027.
Ren, T.; Wang, Q.; Li, C.; Yang, M.; Zuo, Z. Efficient Brain Uptake of Piperine and Its Pharmacokinetics Characterization after Oral Administration. Xenobiotica 2018, 48, 1249–1257.
Ren, T.; Hu, M.; Cheng, Y.; Shek, T.L.; Xiao, M.; Ho, N.J.; Zhang, C.; Leung, S.S.Y.; Zuo, Z. Piperine-Loaded Nanoparticles with Enhanced Dissolution and Oral Bioavailability for Epilepsy Control. Eur. J. Pharm. Sci. 2019, 137, 104988.
Lee, S.H.; Kim, H.Y.; Back, S.Y.; Han, H.-K. Piperine-Mediated Drug Interactions and Formulation Strategy for Piperine: Recent Advances and Future Perspectives. Expert Opin. Drug Metab. Toxicol. 2018, 14, 43–57.
Luszczki, J.J.; Glowniak, K.; Czuczwar, S.J. Imperatorin Enhances the Protective Activity of Conventional Antiepileptic Drugs against Maximal Electroshock-Induced Seizures in Mice. Eur. J. Pharmacol. 2007, 574, 133–139.
Zagaja, M.; Pyrka, D.; Skalicka-Wozniak, K.; Glowniak, K.; Florek-Luszczki, M.; Glensk, M.; Luszczki, J.J. Effect of Xanthotoxin (8-Methoxypsoralen) on the Anticonvulsant Activity of Classical Antiepileptic Drugs against Maximal Electroshock-Induced Seizures in Mice. Fitoterapia 2015, 105, 1–6.
Hino, H.; Takahashi, H.; Suzuki, Y.; Tanaka, J.; Ishii, E.; Fukuda, M. Anticonvulsive Effect of Paeoniflorin on Experimental Febrile Seizures in Immature Rats: Possible Application for Febrile Seizures in Children. PLoS ONE 2012, 7, e42920.
Sancheti, J.; Shaikh, M.F.; Chaudhari, R.; Somani, G.; Patil, S.; Jain, P.; Sathaye, S. Characterization of Anticonvulsant and Antiepileptogenic Potential of Thymol in Various Experimental Models. Naunyn-Schmiedebergs Arch. Pharmacol. 2014, 387, 59–66.
Zhang, C.; Chen, J.; Zhao, F.; Chen, R.; Yu, D.; Cao, Z. Iritectol G, a Novel Iridal-Type Triterpenoid from Iris Tectorum Displays Anti-Epileptic Activity in Vitro through Inhibition of Sodium Channels. Fitoterapia 2017, 122, 20–25.
Wu, K.-C.; Chen, Y.-H.; Cheng, K.-S.; Kuo, Y.-H.; Yang, C.-T.; Wong, K.-L.; Tu, Y.-K.; Chan, P.; Leung, Y.-M. Suppression of Voltage-Gated Na+ Channels and Neuronal Excitability by Imperatorin. Eur. J. Pharmacol. 2013, 721, 49–55.
Skalicka-Woźniak, K.; Orhan, I.E.; Cordell, G.A.; Nabavi, S.M.; Budzyńska, B. Implication of Coumarins towards Central Nervous System Disorders. Pharmacol. Res. 2016, 103, 188–203.
Lin, T.-Y.; Huang, W.-J.; Wu, C.-C.; Lu, C.-W.; Wang, S.-J. Acacetin Inhibits Glutamate Release and Prevents Kainic Acid-Induced Neurotoxicity in Rats. PLoS ONE 2014, 9, e88644.
Ribeiro, R.A.; Leite, J.R. Nantenine Alkaloid Presents Anticonvulsant Effect on Two Classical Animal Models. Phytomedicine 2003, 10, 563–568.
Akyuz, E.; Polat, A.K.; Eroglu, E.; Kullu, I.; Angelopoulou, E.; Paudel, Y.N. Revisiting the Role of Neurotransmitters in Epilepsy: An Updated Review. Life Sci. 2021, 265, 118826.
Manayi, A.; Nabavi, S.M.; Daglia, M.; Jafari, S. Natural Terpenoids as a Promising Source for Modulation of GABAergic System and Treatment of Neurological Diseases. Pharmacol. Rep. 2016, 68, 671–679.
De Alvarenga, J.F.R.; Genaro, B.; Costa, B.L.; Purgatto, E.; Manach, C.; Fiamoncini, J. Monoterpenes: Current Knowledge on Food Source, Metabolism, and Health Effects. Crit. Rev. Food Sci. Nutr. 2023, 63, 1352–1389.
Hosseinzadeh, H.; Parvardeh, S. Anticonvulsant Effects of Thymoquinone, the Major Constituent of Nigella Sativa Seeds, in Mice. Phytomedicine 2004, 11, 56–64.
Akhondian, J.; Kianifar, H.; Raoofziaee, M.; Moayedpour, A.; Toosi, M.B.; Khajedaluee, M. The Effect of Thymoquinone on Intractable Pediatric Seizures (Pilot Study). Epilepsy Res. 2011, 93, 39–43.
Pottoo, F.H.; Salahuddin, M.; Khan, F.A.; Alomar, F.; Al Dhamen, M.A.; Alhashim, A.F.; Alqattan, H.H.; Gomaa, M.S.; Alomary, M.N. Thymoquinone Potentiates the Effect of Phenytoin against Electroshock-Induced Convulsions in Rats by Reducing the Hyperactivation of m-TOR Pathway and Neuroinflammation: Evidence from In Vivo, In Vitro and Computational Studies. Pharmaceuticals 2021, 14, 1132.
Ullah, I.; Badshah, H.; Naseer, M.I.; Lee, H.Y.; Kim, M.O. Thymoquinone and Vitamin C Attenuates Pentylenetetrazole-Induced Seizures Via Activation of GABAB1 Receptor in Adult Rats Cortex and Hippocampus. Neuromol. Med. 2015, 17, 35–46.
Shao, Y.; Feng, Y.; Xie, Y.; Luo, Q.; Chen, L.; Li, B.; Chen, Y. Protective Effects of Thymoquinone Against Convulsant Activity Induced by Lithium-Pilocarpine in a Model of Status Epilepticus. Neurochem. Res. 2016, 41, 3399–3406.
Wang, Z.; Wang, X.; Wang, Z.; Lv, X.; Yin, H.; Li, W.; Li, W.; Jiang, L.; Liu, Y. Potential Herb-Drug Interaction Risk of Thymoquinone and Phenytoin. Chem. Biol. Interact. 2022, 353, 109801.
Wu, A.; Ye, X.; Huang, Q.; Dai, W.-M.; Zhang, J.-M. Anti-Epileptic Effects of Valepotriate Isolated from Valeriana Jatamansi Jones and Its Possible Mechanisms. Phcog. Mag. 2017, 13, 512.
Yang, T.; Kong, B.; Gu, J.-W.; Kuang, Y.-Q.; Cheng, L.; Yang, W.-T.; Cheng, J.-M.; Ma, Y.; Yang, X.-K. Anticonvulsant and Sedative Effects of Paederosidic Acid Isolated from Paederia Scandens (Lour.) Merrill. in Mice and Rats. Pharmacol. Biochem. Behav. 2013, 111, 97–101.
Ling, S.-K.; Tanaka, T.; Kouno, I. Effects of Iridoids on Lipoxygenase and Hyaluronidase Activities and Their Activation by β-Glucosidase in the Presence of Amino Acids. Biol. Pharm. Bull. 2003, 26, 352–356.
Sasaki, K.; Hatta, S.; Haga, M.; Ohshika, H. Effects of Bilobalide on γ-Aminobutyric Acid Levels and Glutamic Acid Decarboxylase in Mouse Brain. Eur. J. Pharmacol. 1999, 367, 165–173.
Jiang, M.; Li, J.; Peng, Q.; Liu, Y.; Liu, W.; Luo, C.; Peng, J.; Li, J.; Yung, K.K.L.; Mo, Z. Neuroprotective Effects of Bilobalide on Cerebral Ischemia and Reperfusion Injury Are Associated with Inhibition of Pro-Inflammatory Mediator Production and down-Regulation of JNK1/2 and P38 MAPK Activation. J. Neuroinflammation 2014, 11, 167.
Ng, C.C.; Duke, R.K.; Hinton, T.; Johnston, G.A.R. Effects of Bilobalide, Ginkgolide B and Picrotoxinin on GABAA Receptor Modulation by Structurally Diverse Positive Modulators. Eur. J. Pharmacol. 2017, 806, 83–90.
Damar, U.; Gersner, R.; Johnstone, J.T.; Schachter, S.; Rotenberg, A. Huperzine A as a Neuroprotective and Antiepileptic Drug: A Review of Preclinical Research. Expert Rev. Neurother. 2016, 16, 671–680.
Bialer, M.; Johannessen, S.I.; Levy, R.H.; Perucca, E.; Tomson, T.; White, H.S. Progress Report on New Antiepileptic Drugs: A Summary of the Twelfth Eilat Conference (EILAT XII). Epilepsy Res. 2015, 111, 85–141.
Gersner, R.; Ekstein, D.; Dhamne, S.C.; Schachter, S.C.; Rotenberg, A. Huperzine A Prophylaxis against Pentylenetetrazole-Induced Seizures in Rats Is Associated with Increased Cortical Inhibition. Epilepsy Res. 2015, 117, 97–103.
Li, Y.X.; Zhang, R.Q.; Li, C.R.; Jiang, X.H. Pharmacokinetics of Huperzine a Following Oral Administration to Human Volunteers. Eur. J. Drug Metabol. Pharmacokinet. 2007, 32, 183–187.
Kozioł, E.; Deniz, F.S.S.; Orhan, I.E.; Marcourt, L.; Budzyńska, B.; Wolfender, J.-L.; Crawford, A.D.; Skalicka-Woźniak, K. High-Performance Counter-Current Chromatography Isolation and Initial Neuroactivity Characterization of Furanocoumarin Derivatives from Peucedanum Alsaticum L (Apiaceae). Phytomedicine 2019, 54, 259–264.
Kozioł, E.; Jóźwiak, K.; Budzyńska, B.; De Witte, P.A.M.; Copmans, D.; Skalicka-Woźniak, K. Comparative Antiseizure Analysis of Diverse Natural Coumarin Derivatives in Zebrafish. Int. J. Mol. Sci. 2021, 22, 11420.
Choi, S.Y.; Ahn, E.-M.; Song, M.-C.; Kim, D.W.; Kang, J.H.; Kwon, O.-S.; Kang, T.-C.; Baek, N.-I. In Vitro GABA-Transaminase Inhibitory Compounds from the Root OfAngelica Dahurica. Phytother. Res. 2005, 19, 839–845.
Singhuber, J.; Baburin, I.; Ecker, G.F.; Kopp, B.; Hering, S. Insights into Structure–Activity Relationship of GABAA Receptor Modulating Coumarins and Furanocoumarins. Eur. J. Pharmacol. 2011, 668, 57–64.
Luszczki, J.J.; Wojda, E.; Andres-Mach, M.; Cisowski, W.; Glensk, M.; Glowniak, K.; Czuczwar, S.J. Anticonvulsant and Acute Neurotoxic Effects of Imperatorin, Osthole and Valproate in the Maximal Electroshock Seizure and Chimney Tests in Mice: A Comparative Study. Epilepsy Res. 2009, 85, 293–299.
Ding, J.; Wang, J.-J.; Huang, C.; Wang, L.; Deng, S.; Xu, T.-L.; Ge, W.-H.; Li, W.-G.; Li, F. Curcumol from Rhizoma Curcumae Suppresses Epileptic Seizure by Facilitation of GABA(A) Receptors. Neuropharmacology 2014, 81, 244–255.
Garlet, Q.I.; Pires, L.D.C.; Milanesi, L.H.; Marafiga, J.R.; Baldisserotto, B.; Mello, C.F.; Heinzmann, B.M. (+)-Dehydrofukinone Modulates Membrane Potential and Delays Seizure Onset by GABAa Receptor-Mediated Mechanism in Mice. Toxicol. Appl. Pharmacol. 2017, 332, 52–63.
Muceniece, R.; Saleniece, K.; Rumaks, J.; Krigere, L.; Dzirkale, Z.; Mezhapuke, R.; Zharkova, O.; Klusa, V. Betulin Binds to γ-Aminobutyric Acid Receptors and Exerts Anticonvulsant Action in Mice. Pharmacol. Biochem. Behav. 2008, 90, 712–716.
Lee, B.-H.; Kim, H.-J.; Chung, L.; Nah, S.-Y. Ginsenoside Rg3 Regulates GABAA Receptor Channel Activity: Involvement of Interaction with the γ2 Subunit. Eur. J. Pharmacol. 2013, 705, 119–125.
Kazmi, I.; Afzal, M.; Gupta, G.; Anwar, F. Antiepileptic Potential of Ursolic Acid Stearoyl Glucoside by GABA Receptor Stimulation. CNS Neurosci. Ther. 2012, 18, 799–800.
Kundap, U.P.; Choo, B.K.M.; Kumari, Y.; Ahmed, N.; Othman, I.B.; Shaikh, M.F. Embelin Protects Against Acute Pentylenetetrazole-Induced Seizures and Positively Modulates Cognitive Function in Adult Zebrafish. Front. Pharmacol. 2019, 10, 1249.
Zaugg, J.; Eickmeier, E.; Rueda, D.C.; Hering, S.; Hamburger, M. HPLC-Based Activity Profiling of Angelica Pubescens Roots for New Positive GABAA Receptor Modulators in Xenopus Oocytes. Fitoterapia 2011, 82, 434–440.
Grigoletto, J.; Oliveira, C.V.D.; Grauncke, A.C.B.; Souza, T.L.D.; Souto, N.S.; Freitas, M.L.D.; Furian, A.F.; Santos, A.R.S.; Oliveira, M.S. Rosmarinic Acid Is Anticonvulsant against Seizures Induced by Pentylenetetrazol and Pilocarpine in Mice. Epilepsy Behav. 2016, 62, 27–34.
Aseervatham, G.S.B.; Suryakala, U.; Doulethunisha; Sundaram, S.; Bose, P.C.; Sivasudha, T. Expression Pattern of NMDA Receptors Reveals Antiepileptic Potential of Apigenin 8-C-Glucoside and Chlorogenic Acid in Pilocarpine Induced Epileptic Mice. Biomed. Pharmacother. 2016, 82, 54–64.
An, S.-J.; Park, S.-K.; Hwang, I.K.; Choi, S.Y.; Kim, S.K.; Kwon, O.-S.; Jung, S.J.; Baek, N.-I.; Lee, H.Y.; Won, M.H.; et al. Gastrodin Decreases Immunoreactivities of Gamma-Aminobutyric Acid Shunt Enzymes in the Hippocampus of Seizure-Sensitive Gerbils. J. Neurosci. Res. 2003, 71, 534–543.
Nassiri-Asl, M.; Shariati-Rad, S.; Zamansoltani, F. Anticonvulsive Effects of Intracerebroventricular Administration of Rutin in Rats. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2008, 32, 989–993.
Park, H.G.; Yoon, S.Y.; Choi, J.Y.; Lee, G.S.; Choi, J.H.; Shin, C.Y.; Son, K.H.; Lee, Y.S.; Kim, W.K.; Ryu, J.H.; et al. Anticonvulsant Effect of Wogonin Isolated from Scutellaria Baicalensis. Eur. J. Pharmacol. 2007, 574, 112–119.
Abbasi, E.; Nassiri-Asl, M.; Shafeei, M.; Sheikhi, M. Neuroprotective Effects of Vitexin, a Flavonoid, on Pentylenetetrazole-Induced Seizure in Rats: Neuroprotective Effects of Vitexin. Chem. Biol. Drug Des. 2012, 80, 274–278.
Yang, B.; Wang, J.; Zhang, N. Effect of Nobiletin on Experimental Model of Epilepsy. Transl. Neurosci. 2018, 9, 211–219.
Faggion, S.A.; Cunha, A.O.S.; Fachim, H.A.; Gavin, A.S.; Dos Santos, W.F.; Pereira, A.M.S.; Beleboni, R.O. Anticonvulsant Profile of the Alkaloids (+)-Erythravine and (+)-11-α-Hydroxy-Erythravine Isolated from the Flowers of Erythrina Mulungu Mart Ex Benth (Leguminosae–Papilionaceae). Epilepsy Behav. 2011, 20, 441–446.
Tamboli, A.M.; Rub, R.A.; Ghosh, P.; Bodhankar, S. Antiepileptic Activity of Lobeline Isolated from the Leaf of Lobelia Nicotianaefolia and Its Effect on Brain GABA Level in Mice. Asian Pac. J. Trop. Biomed. 2012, 2, 537–542.
Da Silva, A.; De Andrade, J.; Bevilaqua, L.; Desouza, M.; Izquierdo, I.; Henriques, A.; Zuanazzi, J. Anxiolytic-, Antidepressant- and Anticonvulsant-like Effects of the Alkaloid Montanine Isolated from Hippeastrum Vittatum. Pharmacol. Biochem. Behav. 2006, 85, 148–154.
Da Cruz, G.M.P.; Felipe, C.F.B.; Scorza, F.A.; Da Costa, M.A.C.; Tavares, A.F.; Menezes, M.L.F.; De Andrade, G.M.; Leal, L.K.A.M.; Brito, G.A.C.; Da Graça Naffah-Mazzacoratti, M.; et al. Piperine Decreases Pilocarpine-Induced Convulsions by GABAergic Mechanisms. Pharmacol. Biochem. Behav. 2013, 104, 144–153.
Hanada, T. Ionotropic Glutamate Receptors in Epilepsy: A Review Focusing on AMPA and NMDA Receptors. Biomolecules 2020, 10, 464.
Li, J.; Copmans, D.; Partoens, M.; Hunyadi, B.; Luyten, W.; De Witte, P. Zebrafish-Based Screening of Antiseizure Plants Used in Traditional Chinese Medicine: Magnolia Officinalis Extract and Its Constituents Magnolol and Honokiol Exhibit Potent Anticonvulsant Activity in a Therapy-Resistant Epilepsy Model. ACS Chem. Neurosci. 2020, 11, 730–742.
Lin, Y.; Li, Y.; Zeng, Y.; Tian, B.; Qu, X.; Yuan, Q.; Song, Y. Pharmacology, Toxicity, Bioavailability, and Formulation of Magnolol: An Update. Front. Pharmacol. 2021, 12, 632767.
Lee, E.; Kim, S.; Chul Chung, K.; Choo, M.-K.; Kim, D.-H.; Nam, G.; Rhim, H. 20(S)-Ginsenoside Rh2, a Newly Identified Active Ingredient of Ginseng, Inhibits NMDA Receptors in Cultured Rat Hippocampal Neurons. Eur. J. Pharmacol. 2006, 536, 69–77.
Pan, W.; Xue, B.; Yang, C.; Miao, L.; Zhou, L.; Chen, Q.; Cai, Q.; Liu, Y.; Liu, D.; He, H.; et al. Biopharmaceutical Characters and Bioavailability Improving Strategies of Ginsenosides. Fitoterapia 2018, 129, 272–282.
Gaston, T.E.; Friedman, D. Pharmacology of Cannabinoids in the Treatment of Epilepsy. Epilepsy Behav. 2017, 70, 313–318.
Mouhamed, Y.; Vishnyakov, A.; Qorri, B.; Sambi, M.; Frank, S.S.; Nowierski, C.; Lamba, A.; Bhatti, U.; Szewczuk, M.R. Therapeutic potential of medicinal marijuana: An educational primer for health care professionals. Drug Healthc. Patient Saf. 2018, 10, 45–66.
Perucca, E. Cannabinoids in the Treatment of Epilepsy: Hard Evidence at Last? J. Epilepsy Res. 2017, 7, 61–76.
Devinsky, O.; Cilio, M.R.; Cross, H.; Fernandez-Ruiz, J.; French, J.; Hill, C.; Katz, R.; Di Marzo, V.; Jutras-Aswad, D.; Notcutt, W.G.; et al. Cannabidiol: Pharmacology and Potential Therapeutic Role in Epilepsy and Other Neuropsychiatric Disorders. Epilepsia 2014, 55, 791–802.

© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.

Upload a video for this entry

Information

Subjects: Pharmacology & Pharmacy

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Milan Malaník

Marie Čulenová

Alice Sychrová

Adrianna Skiba

Krystyna Skalicka-Woźniak

Karel Šmejkal

View Times: 228

Update Date: 10 Aug 2023

Table of Contents

Video Upload Options

Confirm

1. Natural Products That Affect Voltage-Gated Na⁺ and Ca²⁺ Channels

2. Natural Products That Affect the Gabaergic Transmission

3. Natural Products That Reduce Postsynaptic Excitability by Affecting AMPA or NMDA Receptors

4. Natural Products with Multiple Mechanisms of Action: Cannabinoids

References

Video Upload Options

Confirm

1. Natural Products That Affect Voltage-Gated Na+ and Ca2+ Channels

2. Natural Products That Affect the Gabaergic Transmission

3. Natural Products That Reduce Postsynaptic Excitability by Affecting AMPA or NMDA Receptors

4. Natural Products with Multiple Mechanisms of Action: Cannabinoids

References

1. Natural Products That Affect Voltage-Gated Na⁺ and Ca²⁺ Channels