Changes in brain amino acids and nitric oxide after melatonin administration in rats with pentylenetetrazole‐induced seizures

Abstract

We examined the effect of melatonin on brain levels of amino acids and nitric oxide (NO) after pentylenetetrazole (PTZ)-induced seizures in rats. Animals were treated with melatonin (10-160 mg/kg, i.p.) 30 min before PTZ administration (100 mg/kg, s.c.), and were killed 3 hr later. At the dose of 80 mg/kg, melatonin significantly increased the latency (5.7-12.7 min) and decreased the duration (31.2-18.4 s) of the first seizure, reducing PTZ induced mortality from 87.5 to 25%. After kill, brains were removed and neurotransmitters and nitrite levels measured in prefrontal cortex (PF), parieto-temporal cortex (PF), striatum (ST), hippocampus (HP) and brain stem (BS) by high performance liquid chromatography. PTZ treatment increased glutamine levels in all brain areas studied, without changes in glutamate, gamma-amino butyric acid (GABA) and glycine. Aspartate and taurine increased in PF and PT and in HS and PT, respectively. Melatonin administration displayed a dose-dependent effect. At doses of 10-40 mg/kg, melatonin counteracted the PTZ-induced glutamine increase and reduced both glutamate and aspartate levels in the studied areas, with minor changes in GABA and glycine content. At doses of 80 and 160 mg/kg, the levels of glutamine, and glutamate, and to a lesser extent aspartate increased, whereas serine levels did not change. These two doses of melatonin also increased taurine, GABA and glycine in most brain areas studied. Treatment with melatonin (40-160 mg/kg) significantly decreased nitrite content in PT cortex, ST and BS areas of epileptic rats, without changes in the other brain regions. The results suggest that the anticonvulsant property of melatonin involves a modulation of both brain amino acids and NO production.

The role of the melatoninergic system in epilepsy and comorbid psychiatric disorders

“…Moreover, the anticonvulsant efficacy of agomelatine against i.v.-injected PTZ in mice was reported to involve iNOS or nNOS induction, because selective iNOS and nNOS inhibitors attenuated the effect of agomelatine (Dastgheib and Moezi, 2014). These results concurred with previous findings that the NO/L-arginine pathway was involved in the anticonvulsant effect of melatonin against clonic seizures induced by i.v.-infused PTZ (Bikjdaouene et al, 2003;YahyaviFirouz-Abadi et al, 2006). …”

“…Similarly with previously reported results on the anticonvulsant effects of melatonin at doses ranging from 40 to 80 mg/kg in PTZinduced seizures in a variety of species (Bikjdaouene et al, 2003;Moezi et al, 2011;Solmaz et al, 2009;Yahyavi-Firouz-Abadi et al, 2007), the authors showed that agomelatine was active at doses of 25 and 50 mg/kg. Agomelatine was also effective against pilocarpineinduced SE at a dose of 75 mg/kg (Aguiar et al, 2012), while melatonin had an anticonvulsant effect only after repeated injections in this model of epilepsy (Costa-Lotufo et al, 2002;De Lima et al, 2011).…”

“…In addition to the MT receptor-mediated effects of melatonin in seizure models, a number of studies have demonstrated the participation also of GABAergic, 5-HT-ergic, and NO/Larginine pathways (Bikjdaouene et al, 2003;Dastgheib and Moezi, 2014;Golombek et al, 1992;Ray et al, 2004;Yahyavi-Firouz-Abadi et al, 2007). Melatonin potentiates the effect of several AEDs, such as carbamazepine and phenobarbital (Borowicz et al, 1999;Forcelli et al, 2013), but fails to protect neonatal rats against PTZ-induced seizures, even at the high dose of 80 mg/kg (Forcelli et al, 2013).…”

Effects of melatonin and theanine administration on pentylenetetrazole-inducedseizures and brain tissue oxidative damage in ovariectomized rats

“…Previously, several in vivo and in vitro studies demonstrated the potential effects of theanine and melatonin in reducing oxidative stress (16,50,51). Theanine increases the production of GABA and dopamine, while it protects the cells of the hippocampus, the major center of learning and memory, from oxidative damage (17).…”

Progress in neuroprotective strategies for preventing epilepsy

“…Fourth, melatonin modulates the electrical activity of the neurons by acting on plasma membrane receptors (Acuna-Castroviejo et al, 1995) and facilitating the GABA-ergic function (Wan et al, 1999), both of which likely contribute to anticonvulsive effects (Dawson and Encel, 1993;Golombek et al, 1996). Fifth, melatonin has been shown to inhibit brain glutamate receptors and NO production (Bikjdaouene et al, 2003;Yahyavi-Firouz-Abadi et al, 2006). The GABA-ergic effect of melatonin possibly occurs through changes in membrane ion permeability with increased chloride ion influx through GABA A -dependent chloride channels (Rosenstein et al, 1990).…”