Melatonin protects hippocampal neurons in vivo against kainic acid-induced damage in mice

Abstract

In this investigation, 40 mg/kg of the excitatory neurotoxin kainic acid (KA) was subcutaneously administered to CD2-F1 mice. In this mouse strain morphological damage induced by KA in the hippocampus was markedly concentrated in the CA3 pyramidal neurons. Neuronal injury was accompanied by several pathological neurobehavioral activities including arching of tail, tremors and seizures, and by certain biochemical changes, i.e., increased lipid peroxidation products (LPO) in the brain. When melatonin was injected intraperitoneally at a single dose of 5 mg/kg 10 min before KA administration, it significantly reduced these pathological neurobehavioral changes and almost completely attenuated the increase in LPO and morphological damage induced by KA. The neuroprotective effect of melatonin against KA-induced brain damage in mice is believed to be in part related to its oxygen radical scavenging properties as well as its antiepileptic and GABA receptor regulatory actions. Considering melatonin's relative lack of toxicity and ability to enter the brain, these results along with previous evidence suggest that melatonin, which is a natural substance, may be useful in combating free radical-induced neuronal injury in acute situations such as stroke and brain trauma as well as neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease that have free radicals as causative factors.

Melatonin, mitochondria, and cellular bioenergetics

“…Both experimental and clinical anticonvulsant activity of melatonin was reported [Molina-Carballo et al, 1997;Lapin et al, 1998]. Reduced melatonin levels are related to increased brain damage after stroke or excitotoxic seizures in rats [Manev et al, 1996], whereas melatonin protected the brain against kainic acid or quinolinic acid oxidative damage Tan et al, 1998;Cabrera et al, 2000]. Electrophysiological experiments further demonstrated the antagonism of melatonin against the NMDA-induced excitotoxicity, an effect involving the inhibition of the nNOS [Escames et al, 1996;Leó n et al, 1998Leó n et al, , 2000.…”

Protective Mechanism of Melatonin on Kainic Acid Induced Immune Modulatory Effect on Lymphocytes Derived from Mouse Spleen

“…In this study the authors documented that melatonin did not directly inhibit the action of kainic acid on lymphoctes but had an anti-inflammatory and antioxidant mechanism which was evident by the expression mRNA of MAPK 14, iNOS and other inflammatory cytokine levels, However attenuation of free radical species and proinflammatory cytokines was resulted by MLT treatment in a concentration dependent manner. In vivo as well, melatonin reduced the ability of kainic acid to kill neurons in both the cerebellum and in the hippocampus [29,30]. Moreover, melatonin reduced the associated neural lipid peroxidation as well as preventing the death of the majority of the rats that received kainic acid [31].…”

“…Briefly, single cell suspension of splenic lymphocytes was divided in to several groups; each group contained 1 ml of the splenic lymphocytes single cell suspension in triplicate. The concentration of kainic acid and melatonin were fixed according to the authors earlier studies [20][21][22][23][24][25][26][27][28][29][30][31][32][33]. First group I was kept as normal control 9 without any treatment); group II was treated with 1 mM of kainic acid alone (KA); group III was treated with 1 mM melatonin alone (MLT); group IV was treated with KA (1 mM)+MLT (0.25 mM) in combination; groups V was treated with KA (1 mM)+MLT (0.5 mM) in combination, groups VI was treated with KA (1 mM)+MLT (1 mM) in combination.…”

“…First group I was kept as normal control 9 without any treatment); group II was treated with 1 mM of kainic acid alone (KA); group III was treated with 1 mM melatonin alone (MLT); group IV was treated with KA (1 mM)+MLT (0.25 mM) in combination; groups V was treated with KA (1 mM)+MLT (0.5 mM) in combination, groups VI was treated with KA (1 mM)+MLT (1 mM) in combination. In all the combination groups of KA and MLT, MLT was added simultaneously together with the KA [20][21][22][23][24][25][26][27][28][29][30][31][32][33].…”

The Cross-Talk Between Mitochondria and the Nucleus in the Response to Oxidative Stress Associated with Mitochondrial Dysfunction in Mitochondrial Encephalomyopathies

“…On the other hand, to interfere with increased ROS during the onset of epilepsy appears to be another possible strategy for therapy. Natural antioxidant compounds such as vitamin C and E, melatonin and catalase have been shown to decrease oxidative stress and alleviate the seizure-induced brain injury (MacGrego et al, 1996;Tan et al, 1998). It has been reported that clinical trial of vitamin E as a therapy for epilepsy is controversial because it failed to improve seizure activity in pediatric patients.…”