Chronic 5-HT(3) receptor antagonism ameliorates seizures and associated memory deficit in pentylenetetrazole-kindled mice.

Our previous studies have suggested a strong involvement of serotonergic innervations in epileptogenesis and associated memory impairment. Several studies have suggested that the modulation of 5-HT3 receptors could serve as a promising tool for the management of epilepsy and memory deficit. The present study was envisaged to confirm this hypothesis. In this study, kindling was induced in male Swiss Albino mice using a subconvulsive dose of pentylenetetrazole (PTZ) (35mg/kg at 48±2h). Once the animals were kindled, they were treated with a vehicle, ondansetron (0.1, 0.5, 1mg/kg/day; i.p.), m-chlorophenylbiguanide (m-CPBG) (1mg/kg/day; i.p.), and ondansetron+m-CPBG for 20days. On days 5, 10, 15, and 20, they were administered a PTZ challenging dose (35mg/kg) to assess the seizure severity score; thereafter, memory was evaluated. After behavioral assessment on day 20, the animals were sacrificed and their brains were isolated to estimate cortical and hippocampal neurotransmitter levels (glutamate and gamma aminobutyric acid (GABA) by the high-performance liquid chromatography with the fluorescence detection method, and the nitrite level and acetylcholinesterase (AChE) activity by the microplate reader method). Ondansetron treatment significantly reduced the seizure severity and improved the acquisition performance in a dose-dependent manner. Neurochemical analysis suggested that ondansetron treatment significantly reduced the nitrite level and AChE activity in the cortex as well as in the hippocampus. The outcome of this study suggests the reduction in AChE activity and the nitrite level could be considered as protective mechanisms of ondansetron for amelioration of PTZ kindling and associated memory deficit.

Mishra A ，Goel RK 《-》

Fluvoxamine alleviates seizure activity and downregulates hippocampal GAP-43 expression in pentylenetetrazole-kindled mice: role of 5-HT3 receptors.

Alhaj MW ，Zaitone SA ，Moustafa YM 《-》

Exploring the ameliorative role of α7 neuronal nicotinic acetylcholine receptor modulation in epilepsy and associated comorbidities in post-PTZ-kindled mice.

The present study aimed to explore the ameliorative role of alpha7 (α7) neuronal nicotinic acetylcholine receptor (nAChR) modulation in epilepsy and associated comorbidities in postpentylenetetrazole (PTZ)-kindled mice. The subconvulsive dose of PTZ (35 mg/kg, i.p.) was used to induce kindling-associated epileptogenesis in mice. After successful kindling, animals were treated intraperitoneally with saline, phenytoin (35 mg/kg), valproate (300 mg/kg), choline chloride (α7 agonist; 400 mg/kg and 800 mg/kg), and methyllycaconitine citrate (α7 antagonist; 3.5 mg/kg and 7.0 mg/kg) for 10 days. All the groups except naive were exposed to PTZ injections on day 3, 6, and 9 of treatment to assess seizure severity score. Epilepsy-associated comorbid depression was evaluated by tail suspension test, sucrose preference test, and plasma corticosterone levels, whereas epilepsy-associated memory deficit condition was assessed by step-through paradigm, Morris water maze, and nitrite levels. Neurochemical perturbations related to epilepsy and associated depression and memory deficit were measured by high-performance liquid chromatography (HPLC). Post-PTZ-kindled mice displayed significant depressive behavior and memory impairment as compared with naive mice as evidenced by corresponding behavioral and biochemical observations. Methyllycaconitine citrate treatment was unable to produce any ameliorative effect in diseased condition. Choline administration dose dependently ameliorated depression, memory impairment, and seizure severity in post-PTZ-kindled mice. The behavioral findings of the study were concurred with neurochemical and biochemical findings. In conclusion, the present study demonstrated the amelioration of epilepsy, comorbid depression, and memory deficit by α7 nAChR agonist choline chloride in PTZ-kindled mice model.

Sharma NK ，Kaur S ，Goel RK 《-》

Ameliorative effect of Curcumin on seizure severity, depression like behavior, learning and memory deficit in post-pentylenetetrazole-kindled mice.

Epilepsy is a chronic neurological disorder and generally associated with certain psychiatric comorbidities. Among several comorbidities depressive behavior and cognitive impairment has been reported to be most debilitating comorbidity associated with epilepsy. This study was envisaged to evaluate the ameliorative effect of Curcumin on depression like behavior and cognitive impairment observed in pentylenetetrazole kindled animals. Male Swiss Albino mice were kindled with subconvulsive dose of pentylenetetrazole (35 mg/kg, i.p.). Successfully kindled animals were used in the study to observe the effect of different treatments. Treatment groups received phenytoin (30 mg/kg) and Curcumin (50, 100 and 200mg/kg) for 15 days. The animals were challenged with pentylenetetrazole (35 mg/kg, i.p.) on day 5, 10 and 15 and seizure severity score, immobility period, number of mistakes and step down latency were recorded. On 15th day, all the animals were sacrificed after behavioral evaluations and their brain was isolated and homogenized to estimate brain norepinephrine, serotonin, total nitrite level and acetylcholinesterase activity. Phenytoin treatment significantly improved the depressive like behavior along with its anticonvulsant effect, however was unable to improve memory impairment. Curcumin significantly attenuated seizure severity, depression like behavior and memory impairment in kindled animals, in dose dependent manner. These results were supported by the biochemical modulation of brain monoamine, nitrosative stress level and acetylcholinesterase activity. Thus present study concluded that Curcumin has the ameliorative effect on seizure severity, depression like behavior and memory impairment in pentylenetetrazole kindled mice, possibly via central monoaminergic modulation and inhibitory effect on nitrosative stress and acetylcholinesterase activity.

Choudhary KM ，Mishra A ，Poroikov VV ，Goel RK ... -  《-》

Comparative behavioral and neurochemical analysis of phenytoin and valproate treatment on epilepsy induced learning and memory deficit: Search for add on therapy.

Mishra A ，Goel RK 《-》