Quercetin Exerts Anti-convulsant Effects in Animal Model of Grand Mal Epilepsy: Modulation of GABA and Glycinergic Pathways
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Abstract:
Quercetin is low molecular weight flavonoid having multiple neuropharmacological actions. Recently, its anticonvulsant effect was reported in rats using electrical kindling models. However, earlier cell culture studies have documented antagonistic action of quercetin on GABAA, GABAC and Glycine channels, which is contrary to recent findings. Hence, the present study aimed at characterizing the effects of quercetin administration in various experimental models of epilepsy. Dose-dependent effects of quercetin on maximal-electroshock seizure (MES) were determined. Further, the effective dose was tested in pentylenetetrazol-induced seizures (PTZ), and strychnine-induced seizures to study the involvement of GABA and Glycinergic receptors. The results revealed a potent anticonvulsant effect of quercetin in MES induced seizures at a dose of 5 and 10 mg/kg. This effect was found to be retained in case of PTZ-induced convulsions and strychnine-induced convulsions (quercetin 10 mg/kg). The present finding warrants further substantiation along with their correlation to molecular mechanism of action.Keywords:
Pentylenetetrazol
GABA receptor antagonist
Flumazenil
Picrotoxin
Convulsion
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Picrotoxin
Mechanism of Action
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GABA receptor antagonist
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Terpinen-4-ol (4TRP) is a monoterpenoid alcoholic component of essential oils obtained from several aromatic plants. We investigated the psychopharmacological and electrophysiological activities of 4TRP in male Swiss mice and Wistar rats. 4TRP was administered intraperitoneally (i.p.) at doses of 25 to 200 mg/kg and intracerebroventricularly (i.c.v.) at concentrations of 10, 20, and 40 ng/2 μ L. For in vitro experiments, 4TRP concentrations were 0.1 mM and 1.0 mM. 4TRP (i.p.) inhibited pentylenetetrazol- (PTZ-) induced seizures, indicating anticonvulsant effects. Electroencephalographic recordings showed that 4TRP (i.c.v.) protected against PTZ-induced seizures, corroborating the behavioural results. To determine whether 4TRP exerts anticonvulsant effects via regulation of GABAergic neurotransmission, we measured convulsions induced by 3-mercapto-propionic acid (3-MP). The obtained results showed involvement of the GABAergic system in the anticonvulsant action exerted by 4TRP, but flumazenil, a selective antagonist of the benzodiazepine site of theG A B A A
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Intravenous injection of N-methyl-D,L-aspartic acid (NMDLA) into mice produces characteristic convulsions followed by death. The present study was designed to determine the degree of blockade of these seizures/mortality by compounds acting at various subsites on the N-methyl-D-aspartic acid (NMDA) receptor complex (competitive and noncompetitive antagonists, as well as inhibitors of the strychnine-insensitive glycine subsite, and Zn++ subsite agonists), and also calcium channel blockers, clinically used anticonvulsants, plus selected compounds with activities or structures similar to specific agents chosen. Activity among compounds was correlated to in vitro potency regarding inhibition of binding of MK801 to the ionic channel subsite associated with the NMDA receptor. Furthermore, all compounds were examined for antiseizure properties with respect to tonic hindlimb extension elicited by maximal electroshock (MES) and clonus induced by pentylenetetrazol (PTZ). Drugs were subsequently classified according to their spectra of efficacy in these tests. The following characteristics emerged: 1) agents active at all 3 NMDA mechanisms (convulsions/mortality/MK801 binding) plus MES and PTZ, were MK801 and CPP [3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid]; 2) active at all the NMDA mechanisms and MES were ketamine and dextromethorphan; 3) active against NMDLA-induced convulsions/mortality, MES and PTZ, but not MK801 binding, were doxepin, desipramine and diazepam; 4) active against NMDLA-induced convulsions/mortality and MES were des-Me-doxepin, flunarizine and remacemide; 5) active against NMDLA-induced convulsions/mortality and PTZ was nisoldipine; 6) active against only NMDLA-induced convulsions/mortality were chlorpheniramine and iproniazid; 7) active in the MES and PTZ tests were phenobarbital, pentobarbital and valproate; 8) active in the MES test alone were phenytoin and carbamazepine; 9) active against PTZ only was ethosuximide; 10) active only in the in vitro MK801 binding assay were HA966, 7-Cl-kynurenate and AP7 (2-amino-7-phosphonoheptanoic acid); and 11) no demonstrable actions had AP4 (2-amino-4-phosphonobutyric acid) and mianserin. In conclusion, inhibition of NMDLA-induced convulsions/mortality in vivo is not necessarily correlated to a noncompetitive displacement of MK801 binding to NMDA receptor sites in vitro, nor is inhibition of NMDA-elicited convulsions/mortality correlated with a specific ability of a compound to inhibit either MES or PTZ seizures.
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This study was performed to examine the anticonvulsant effects of the extracts of JeongGan-Tang and explanation of its action mechanism. Method: 1) The inhibitory effect on convulsions induced by pentylenetetrazole, picrotoxin and strychnine was investigated in vivo 2) The inhibitory effect on GABA transaminase activity was evaluated in vivo and in vitro. 3) The brain GABA level and glutamate level in pentylenetetrazole-induced convulsion model were analyzed by HPLC, Results: 1) JeongGan-Tang showed the significant effect on the pentylenetetrazole-induced convulsion, which may mean that its anticonvulsant effect would be resulted from the activation of GABA receptor and chloride channel rather than the presynaptic- or postsynaptic inhibition. 2) JeongGan-Tang exhibited proper inhibitory activity on GABA transaminase in vitro and in vivo. 3) JeongGan-Tang increased the brain GABA level but did not affect the brain glutamate content, which may suggest that this drug supresses the convulsion by increase of GABA, an inhibitory neurotransmitter. Conclusion : JeongGan-Tang can be used as an anticonvulsant prescription by the modulation of GABAergic neurotramission.
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The anticonvulsant activity of diazepam given alone or in combination with diphenylhydantoin (DPH) or di-n propylacetate (DPA) was evaluated in pentylenetetrazol (PTZ) and bicuculline-induced convulsions in male mice. DPH did not influence the seizures induced by either convulsants, but potentiated the anticonvulsant activity of diazepam against PTZ induced convulsions. However, the anticonvulsant activity of diazepam against bicuculline- induced convulsions was not influenced by pretreatment with DPH. On the other hand, pretreatment with DPA caused potentiation of the anticonvulsant activity of diazepam against both PTZ and bicuculline-induced seizures. These data suggest that the enhancement of the anti PTZ activity of diazepam by DPH might be related to an increase in the total number of specific benzodiazepine binding sites, while the anti-bicuculline effect of diazepam does not seem to involve in interaction with benzodiazepine receptor sites. Furthermore, the data also propose that gamma-aminobutyric acid (GABA)-ergic mechanisms may mediate the DPA potentiation of diazepam anticonvulsant activity against PTZ and bicuculline-induced convulsions.
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Convulsion
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Indazole
Pargyline
Tranylcypromine
NBQX
Nomifensine
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Pentylenetetrazol
Picrotoxin
Flumazenil
Convulsion
Convulsants
GABA receptor antagonist
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Objective:To investigate the anticonvulsant activity of the lobeline isolated from the Lobelia nicotianaefolia in chemoconvulsant-induced seizures and its biochemical mechanism by investigating relationship between seizure activities and altered gamma amino butyric acid(GABA)in brain of mice in Pentylenetetrazol(PTZ) seizure models.Methods:The anticonvulsant activity of the isolated lobelinc(5,10,20 and 30 mg/kg.i.p.) was investigated in PTZ and strychnine induced seizures in mice and the effect of isolated lolieline on brain GABA level in seizures induced by PTZ.Diazepam was used as reference anticonvulsant drugs for comparison.Results:Isolated lobeliue(10,20 and 30 nig/kg.up.) significautly delayed and antagonized(P < 0.050-0.001)the onset of PTZ-induced seizures.It also antagonized strychnine induced seizures.The mortality was also prevented in the test group of animals.In biochemical evaluation,isolated lolieline(5,10and 20 mg/kg,i.p.) significantly increased the brain GABA level.And at dose of 30 mg/kg GABA level showed slight decrease in PTZ model.Conclusions:In our findings,isolated lolieline(20mg/kg) exhibited potent anticonvulsant activity against PTZ induced seizures.Also a biochemical evaluation suggested significant increase in harain GABA level at 20 nig/kg up.of isolated lolieline.Hence,we may propose that lolieline reduces epileptic seizures by enhancing the GABA release supporting the GABAergic mechanism.
Pentylenetetrazol
Convulsion
Seizure threshold
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AIM: In the present study we verified the anticonvulsant properties of the new tryptamine analogue, N-salicyloyltryptamine (NST), in rodents. METHODS AND RESULTS: In the evaluation of the anticonvulsant activity, NST protected the animals from the incidence of seizures induced by pentylenetetrazole (PTZ) and picrotoxin (PIC), in doses of 100 and 200 mg/kg. NST (100 and 200 mg/kg, i.p.) significantly eliminated the extensor reflex of maximal electric-induced seizure tests in 40% of the experimental animals. However, in the PTZ model FLU (10 mg/kg, i.p.), an antagonist of the benzodiazepine (BZD) site in the GABA A-BZD receptor complex, inhibited the prolongation of seizure latency induced by NST. CONCLUSION: Our results demonstrated an anticonvulsant activity of the new analogue that could be, at least in part, associated to the involvement of the GABAergic mechanism.
Picrotoxin
Tiagabine
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