Melatonin Protects Against Maximal Electroshock Seizures Induced Cognitive Impairment in Mice

Abstract: Epilepsy is a serious neurological disorder associated with cognition impairment. It has been observed that not only epilepsy but antiepileptic drugs are also associated with memory impairment. In the present study we have evaluated the effect of acute administration of three antiepileptic drugs; lamotrigine (10mg/kg, p.o.), oxcarbazepine (15mg/kg, p.o.) and topiramate (10mg/kg, p.o.) on cognition after delivering maximal electroshock seizure (MES) to mice. Further, effect of melatonin (50mg/kg, p.o.) co-administration with other drugs on memory was also assessed after MES. Two behavioural tests were performed to assess the memory: elevated plus maze (EPM) test for transfer latency and passive avoidance response (PAR) test for step-down latency. The results of present study indicate that acute administration of all the tested drugs did not impair initial and retention transfer latencies in EPM and PAR test in sham mice. In vehicle treated group acquisition latency was significantly increased in EPM test as compared to sham control. All the administered drugs after receiving MES did not alter acquisition and retention latencies in EPM and PAR test in mice. Melatonin administration has significantly decreased the initial transfer latency as compared to vehicle treated mice (p<0.01). Paradoxically melatonin administration with lamotrigine has significantly increased the initial transfer latency (p<0.05). In conclusion, the present study shows that melatonin administration has significantly improved cognition after maximal electroshock seizures in mice

Introduction
Cognitive impairment is frequently encountered in patients of epilepsy. Apart from seizures, deficits in mental functions such as consciousness and specific cognitive functions such as attention, memory and language causes more devastating effects on quality of life (Qol) of epileptic patients. A variety of factors contribute to cognitive impairment during epilepsy. It has been established that antiepileptic drug (AED) treatment is also associated with cognitive impairment. At therapeutic doses, polytherapy with AEDs disturbs memory formation, retention and orientation. In addition, high circulating antiepileptic drug concentrations and high dosages have been found to debilitate intellectual functioning. It has been observed that cognition impairment often requires drug discontinuation, even when the drug is improving seizure frequency. Among the newer AEDs, use of lamotrigine has shown inconclusive result on cognition. However, few reports suggest an impairment of cognition with the use of lamotrigine. Although topiramate in low doses has improved seizure frequency and EEG abnormalities but it has impaired memory in the patients receiving it.4 Scarce data are available regarding the neurobehavioural effect of oxcarbazepine.

Melatonin is a pineal hormone synthesised from the precursor serotonin. It is a potent scavenger of hydroxyl and peroxyl radical. It has been suggested that melatonin crosses the blood-brain barrier and exerts its neurobiologically relevant action by scavenging reactive oxygen species. Further, melatonin has been found to be antiepileptic in various animal studies using different convulsive stimuli. Melatonin was observed to improve learning and memory impairment in various animal models of cognitive impairment. Melatonin was found to improve learning and memory impairment in mice induced by aluminium chloride. Its treatment has improved learning and memory in chronic ethanol-induced learning and memory impairment model. Centrally applied melatonin in mouse brain lead to facilitation of short term memory.

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