alpha-asarone and Seizures

In mammals, peroxisome proliferators activated receptors (PPARs), the nuclear hormone receptors, have been reported to be involved in seizure control. Selective agonists and antagonists of PPARs raise seizure thresholds and suppress seizures, respectively. In this study, we evaluated the anticonvulsant effects of α-asaronol, a metabolic product of α-asarone, on pentylenetetrazole (PTZ)-induced seizures in zebrafish and investigated the underlying mechanisms. As a result, α-asaronol ameliorated seizures with increase of seizure latency, as well as decrease of seizure-like behavior, c-fos expression, and abnormal neuronal discharge in a concentration dependent manner. By comparing gene expression profiles of zebrafish undergoing seizures and α-asaronol pretreated zebrafish, we found that α-asaronol attenuate seizures through increase of PPAR γ expression, while PPAR γ antagonist GW9662 inhibit the anti-seizures actions of α-asaronol. Moreover, molecular docking simulation implied the physical interaction between α-asaronol and PPAR γ. The overall results indicated that the anticonvulsant effects of α-asaronol are regulated through PPAR γ-mediated pathway, which shed light on development of α-asaronol as a potential antiepileptic drug. In addition, it is for first time to report that PPAR γ is associated with seizures in zebrafish, supporting previous evidence that zebrafish is a suitable alternative for studying seizures.

Topics: Allylbenzene Derivatives; Anilides; Animals; Anisoles; Anticonvulsants; Behavior, Animal; Convulsants; Hydroxides; Locomotion; Molecular Docking Simulation; Pentylenetetrazole; PPAR gamma; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA-Seq; Seizures; Transcriptome; Zebrafish

Alpha-asarone is one of the bioactive phytochemicals present in the rhizomes of Acorus species and demonstrated its anticonvulsant activity in rodents. Alpha-asarone protected mice from the gamma-aminobutyric acid (GABA) type A receptor antagonist or N-methyl-d-aspartate (NMDA) receptor agonist-induced seizures. In our recent study, α-asarone attenuated the nicotine withdrawal-induced depression-like behavior in mice. The seizures induced by nicotine is mediated through the activation of nicotinic acetylcholine receptors (nAChRs) and stimulation of NMDA receptors. Therefore, we hypothesized that α-asarone might be effective against nicotine-induced seizures. Also, the interaction of α-asarone with nAChRs is unknown. In this study, we investigated the effect of α-asarone on the locomotor activity and body temperature in mice. In addition, we studied the effect of α-asarone on nicotine-induced seizures in mice. Finally, we assessed in vivo pharmacodynamic interaction of α-asarone with nAChRs using nicotine-induced hypomotility and hypothermia tests in mice. The results of this study showed that the α-asarone (50-200 mg/kg, i.p.) and diazepam (5 mg/kg, i.p.) treatment significantly decreased the locomotor activity and body temperature in mice. Furthermore, α-asarone (50-200 mg/kg, i.p.) and diazepam (5 mg/kg, i.p.) pretreatment significantly prolonged the onset time of nicotine-induced seizures in mice. However, α-asarone (30 and 50 mg/kg, i.p.) pretreatment did not inhibit the nicotine-induced hypomotility or hypothermia in mice. Conversely, mecamylamine (1 mg/kg, s.c.) pretreatment completely blocked the nicotine-induced seizures and significantly prevents the nicotine-induced hypomotility and hypothermia in mice. Overall, these results suggest that the protective effect of α-asarone against nicotine-induced seizures did not mediate through the antagonism of nAChRs. We also postulated that the GABAergic and glutamatergic activities of α-asarone could be involved in its protective effect against nicotine-induced seizures and based on this aspect further studies are required.

Topics: Allylbenzene Derivatives; Animals; Anisoles; Anticonvulsants; Dose-Response Relationship, Drug; Locomotion; Male; Mice; Mice, Inbred ICR; Neuroprotective Agents; Nicotine; Nicotinic Antagonists; Receptors, Nicotinic; Seizures

For centuries, extracts of Acorus gramineus have been used extensively in traditional Chinese medicine for the treatment, management, and/or control of human ailments, including central nervous system disorders such as convulsions and epilepsy. In the present study, we investigated the anticonvulsant activity of chronic treatment with the plant's major essential oil component (a-asarone, 50-200 mg/kg, per os (p.o.)) against maximal electroshock seizure (MES), pentylenetetrazole (PTZ)-induced seizures in mice, lithium-pilocarpine (LI-PILO)-induced status epilepticus (SE), and spontaneous recurrent seizures (SRSs) in rats and determined whether a single acute administration of a-asarone at various doses could produce anticonvulsant activity. As the standard antiepileptic drugs used, chronically administered a-asarone (50-200 mg/kg, p.o.) significantly delayed (p<0.05) the onset of, and antagonized maximal electroshock seizure and PTZ-induced seizures. Chronically administered a-asarone (50-200 mg/kg) also profoundly antagonized LI-PILO-induced seizures. The SE incidence, SE latency and seizure severity as well as mortality were significantly reduced after treatment with a-asarone at different doses. Higher doses of a-asarone (100-200 mg/kg) significantly reduced spontaneous recurrent seizure incidence, severity, and seizure frequency during treatment in LI-PILO-induced SRSs rats. On the other hand, a single acute administration of a-asarone (50-200 mg/kg) produced weak anticonvulsant activity in MES and PTZ-induced seizures. The results of this laboratory animal study indicate that chronically administered a-asarone possesses anticonvulsant activity in the mammalian experimental model used, and thus suggest that a-asarone may be used as a natural supplementary remedy in the management of convulsions and epilepsy.

Topics: Acorus; Allylbenzene Derivatives; Animals; Anisoles; Anticonvulsants; Disease Models, Animal; Lethal Dose 50; Mice; Phytotherapy; Rats; Rats, Wistar; Seizures

Anticonvulsant properties of α-asarone were studied in mice at three doses with different toxicity. The 100mg/kg dose decreased both treadmill performance and locomotor activity, caused hypothermia, and potentiated pentobarbital-induced sleep. The last two effects and no toxicity were observed at 60 and 22mg/kg, respectively. In chemical (pentylenetetrazole, picrotoxin, N-methyl-D-aspartate, pilocarpine) and electrical (maximal electroshock) seizure tests, neither seizures nor death were prevented by 60 mg/kg α-asarone which, however, exhibited protective-like effects (delay in the onset of clonic and/or tonic seizures and/or in the death of mice). Magnesium deficiency-dependent audiogenic seizures responded to non-toxic doses of α-asarone (60 mg/kg and less): 22 mg/kg protecting 50% of tested animals. Because these seizures respond to both anti-seizure and antioxidant compounds, antioxidant properties of α-asarone were studied, indicating 5 Units of superoxide dismutase-like activity per mg α-asarone. Treatment of mice by α-asarone (daily dose of 100mg/kg during 7 days) induced brain antioxidant enzymes (superoxide dismutase, glutathione peroxidase and reductase) in striatum and hippocampus and to a lesser extent in cortex. In view of recent findings about deleterious roles of chronic inflammatory/oxidant stresses in human epilepsy outcome, antioxidant and inductive properties of α-asarone are proposed to be coherent bases for traditional clinical efficacy.

Topics: Allylbenzene Derivatives; Animals; Anisoles; Anticonvulsants; Antioxidants; Brain; Disease Models, Animal; Female; Glutathione Peroxidase; Glutathione Reductase; Mice; Motor Activity; Seizures; Superoxide Dismutase

In the Ayurvedic system of medicine, the roots and rhizomes of an indigenous Indian plant Acorus calamus are used together with the roots of Rauwolfia serpentina for treating many mental ailments. The influence of asarone and beta-asarone (the trans and cis forms of 2,4,5-trimethoxy-1-propenyl benzene), two active principles of Acorus calamus, when given alone and together with either reserpine or chlorpromazine, has been studied on the conditioned avoidance response of trained rats, on the fighting behaviour of paired mice subjected to mild foot shock and on electro-convulsions. Except for electro-convulsions, asarone in small doses potentiates the effects of reserpine and of chlorpromazine; beta-asarone has no such effect. Estimation of the 5-hydroxytryptamine content of rat brain showed that neither acorus oil nor its active principles increase the concentration of 5-hydroxytryptamine; nor do these compounds cause an additional decrease in the 5-hydroxytryptamine content of the brains of animals treated with reserpine. It is concluded that the potentiating effect of these principles is unrelated to 5-hydroxytryptamine concentration. In experiments using electro-convulsions, asarone increased the percentage mortality of animals treated with chlorpromazine but not of those treated with reserpine.

Topics: Acorus; Allylbenzene Derivatives; Animals; Anisoles; Avoidance Learning; Behavior; Chlorpromazine; Conditioning, Classical; Conditioning, Psychological; Mice; Oils, Volatile; Plants; Rats; Reserpine; Rhizome; Seizures; Serotonin