Effects of some GABAergic agents on quinine-induced seizures in mice (original) (raw)
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Journal of Young Pharmacists, 2014
Background: Presently available anti-seizure drugs cannot control seizures in 20-40% epilepsy patients who develop refractory epilepsy. None of the currently available anti-seizure drugs targets hypersynchronization of epileptogenic impulses. Process of hypersynchronization involves gap junction (GJ) activity. Quinine blocks GJs, and prevents seizures in animal models. Since comparative studies were lacking, this animal study compared anticonvulsant activity of quinine with that of valproate and phenytoin. Materials and Methods: Seizures were induced in adult albino Sprague/Dawley rats (n = 72) using pentylenetetrazole (PTZ) and maximum electroshock (MES) methods, comparator drugs being valproate (90 mg/kg) and phenytoin (27 mg/kg), respectively. Quinine was given in three doses (28, 35 and 42 mg/kg). Results: Higher doses of quinine (35 and 42 mg/kg) controlled PTZ seizures; efficacy was similar to valproate. MES seizures were not suppressed. Conclusion: Quinine has in-vivo anticonvulsant activity in rats in PTZ model at higher doses, but not in MES model in the doses tested.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2008
Quinine specifically blocks connexin 36 (Cx36), one of the proteins that form gap junction channels. Quinine suppressed ictal epileptiform activity in in vitro and in vivo studies without decreasing neuronal excitability. In this study, we considered the possible mechanism of anticonvulsant effects of quinine (1, 250, 500, 1000 and 2000 μM, i.c.v.) in the pentylenetetrazole (PTZ) model of seizure. Thus, we used trimethylamine (TMA) (0.05 μM, 5 μM, 50 μM), a gap junction channel opener, to examine whether it could reverse the effects of quinine in rats. Intracerebroventricular (i.c.v.) injection of quinine affected generalized tonic-clonic seizure (GTCS) induced by PTZ by increments in seizure onset and reducing seizure duration. Additionally, pretreatment with different doses of TMA (i.c.v.) attenuated the anticonvulsant effects of quinine on the latency and duration of GTCS. It can be concluded that quinine possesses anticonvulsant effects via modulation of gap junction channels, which could contribute to the control of GTCS.
Neuroscience, 2002
öThe e¡ect of quinine on pyramidal cell intrinsic properties, extracellular potassium transients, and epileptiform activity was studied in vitro using the rat hippocampal slice preparation. Quinine enhanced excitatory post-synaptic potentials and decreased fast-and slow-inhibitory post-synaptic potentials. Quinine reduced the peak potassium rise following tetanic stimulation but did not a¡ect the potassium clearance rate. Epileptiform activity induced by either low-Ca 2þ or high-K þ arti¢cial cerebrospinal £uid (ACSF) was suppressed by quinine. The frequency of spontaneous interictal bursting induced by picrotoxin, high-K þ , or 4-aminopyridine was signi¢cantly increased. In normal ACSF, quinine did not a¡ect CA1 pyramidal cell resting membrane potential, input resistance, threshold for action potentials triggered by intracellular or extracellular stimulation, or the orthodromic and antidromic evoked population spike amplitude. The main e¡ects of quinine on intrinsic cell properties were to increase action potential duration and to reduce ¢ring frequency during sustained membrane depolarizations, but not at normal resting membrane potentials. This attenuation was enhanced at increasingly depolarized membrane potentials. These results suggest that quinine suppresses extracellular potassium transients and ictal activity and modulates interictal activity by limiting the ¢ring rate of cells in a voltage-dependent manner. Because quinine does not a¡ect 'normal' neuronal function, it may merit consideration as an anticonvulsant.
Guanosine and GMP prevent seizures induced by quinolinic acid in mice
Brain Research, 2000
In the mammalian CNS, glutamate and GABA are the principal neurotransmitters mediating excitatory and inhibitory synaptic events, respectively, and have been implicated in the neurobiology of seizures. Guanine-based purines, including the nucleoside guanosine and the nucleotide GMP, have been shown to antagonize glutamatergic activity at the receptor level and the other purine nucleoside adenosine is a well-known modulator of seizure threshold. In the present study we investigated the anticonvulsant effect of i.p. guanosine and GMP against seizures induced by the glutamate agonist quinolinic acid (QA) or the GABA antagonist picrotoxin in mice. Animals were A pretreated with an i.p. injection of saline, guanosine or GMP 30 min before either an i.c.v. injection of 4 ml QA (36.8 nmol) or a subcutaneous injection of picrotoxin (3.2 mg / kg). All animals pretreated with vehicle followed by QA or picrotoxin presented seizures, which were completely prevented by the NMDA antagonist MK-801 and the GABA agonist phenobarbital, respectively. Guanosine and GMP dose-dependently protected against QA-induced seizures, up to 70 and 80% at 7.5 mg / kg, with ED 52.660.4 and 1.760.6 50 mg / kg, respectively. Conversely, neither guanosine, GMP nor MK-801 affected picrotoxin-induced seizures, indicating some degree of specificity towards the glutamatergic system. This study suggests anticonvulsant properties of i.p. guanosine and GMP, which may be related with antagonism of glutamate receptors.
Pharmacology Biochemistry and Behavior, 2004
The anticonvulsant activity of competitive 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F)-quinoxaline (NBQX) and noncompetitive 2,3benzodiazepines and tetrahydroisoquinolines (THIQs) AMPA/kainate receptor antagonists, was tested in different experimental seizure models and compared with diazepam, a conventional antiepileptic drug acting on GABAergic neurotransmission. In particular, the compounds were evaluated against audiogenic and maximal electroshock seizures (MES) test and pentetrazol (PTZ) seizures model, and all of them showed protective action.
Excitatory amino acid antagonists protect mice against seizures induced by bicuculline
Brain Research, 1990
The effects of excitatory amino acid antagonists on convulsions induced by intracerebroventricular (i.c.v.) or systemic (s.c.) administration of the ),-aminobutyric acid A (GABAA) antagonist bicucuUine (BIC) were tested in mice. 3-((+)-2-Carboxypiperazin-4-yl)-propyl-1-phosphonate (CPP), 2-amino-7-phosphonoheptanoate (AP7) and (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate (MK-801) were used as representatives of N-methyl-D-aspartate (NMDA) antagonists, y-D-Glutamylaminomethylsulphonate (~,-D-GAMS) typified a preferential kainate (KA) antagonist, 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) represented a preferential quisqualate (QA) antagonist, and kynurenic acid (KYNA) was used as a mixed NMDA/KA antagonist. Bicuculline methiodide (BMI) induced clonic convulsions following i.c.v, administration with a CDso of 0.183 nmol (range 0.164-0.204). The excitatory amino acid antagonists blocked clonic seizures induced by BMI in the dose of 0.224 nmol (approximately CD97) when coinjected into the lateral ventricle. CPP (EDs0 0.0075 nmol) was the most potent anticonvulsant and was followed by AP7 (0.182 nmol), MK-801 (0.22 nmol), ?'-o-GAMS (0.4 nmol), KYNA (1.7 nmol) and CNQX (5.17 nmol). Muscimol (MSC), the GABA A agonist, blocked BMI-induced seizures with an EDso of 0.25 nmol. Systemic (s.c.) administration of BIC induced in mice generalized seizures with a CDso of 2.2 mg/kg (range 1.9-2.5) for clonus and CDso of 2.4 mg/kg (range 2.2-2.7) for tonus. The seizures induced by s.c. injection of BIC in the dose of 3.2 mg/kg (approximately CD97 ) were blocked by pretreatment (i.p.) with the NMDA antagonists MK-801 (EDso 0.075 mg/kg for clonus and 0.044 mg/kg for tonus), CPP (7.743 mg/kg for clonus and 0.032 mg/kg for tonus) and CGS 19755 (> 10 mg/kg for clonus and 3.01 mg/kg for tonus). The GABA A agonist MSC had no effect on clonus (> 2.5 mg/kg) and prevented mice from tonus with an EDso of 1.77 mg/kg. These results suggest an important role of excitation mediated by dicarboxylic amino acids in the pathogenesis of seizures triggered by bicucuiline in mice.
Neurochemical Research, 2008
Glutamate uptake into synaptic vesicles is a vital step for glutamatergic neurotransmission. Quinolinic acid (QA) is an endogenous glutamate analog that may be involved in the etiology of epilepsy and is related to disturbances on glutamate release and uptake. Guanine-based purines (GBPs) guanosine 5¢-monophosphate (GMP and guanosine) have been shown to exert anticonvulsant effects against QA-induced seizures. The aims of this study were to investigate the effects of in vivo administration of several convulsant agents on glutamate uptake into synaptic vesicles and investigate the role of MK-801, guanosine or GMP (anticonvulsants) on glutamate uptake into synaptic vesicles from rats presenting QA-induced seizures. Animals were treated with vehicle (saline 0.9%), QA 239.2 nmoles, kainate 30 mg/kg, picrotoxin 6 mg/kg, PTZ (pentylenetetrazole) 60 mg/kg, caffeine 150 mg/kg or MES (maximal transcorneal electroshock) 80 mA. All convulsant agents induced seizures in 80-100% of animals, but only QA stimulated glutamate uptake into synaptic vesicle. Guanosine or GMP prevented seizures induced by QA (up to 52% of protection), an effect similar to the NMDA antagonist MK-801 (60% of protection). Both GBPs and MK-801 prevented QA-induced glutamate uptake stimulation. This study provided additional evidence on the role of QA and GBPs on glutamatergic system in rat brain, and point to new perspectives on seizures treatment.