Melatonin attenuates kainic acid-induced hippocampal neurodegeneration and oxidative stress through microglial inhibition.
The antioxidant and anti-inflammatory effects of melatonin on kainic acid (KA)-induced neurodegeneration in the hippocampus were evaluated in vivo. It has been suggested that the pineal secretory product, melatonin, protects neurons in vitro from excitotoxicity mediated by kainate-sensitive glutamate receptors, and from oxidative stress-induced DNA damage and apoptosis. In this study, we injected 10 mg/kg kainate intraperitoneally (i.p.) into adult male Sprague-Dawley rats. This results in selective neuronal degeneration accompanied by intense microglial activation and triggers DNA damage in the hippocampus. We tested the in vivo efficacy of melatonin in preventing KA-induced neurodegeneration, oxidative stress and neuroinflammation in the hippocampus. Melatonin (2.5 mg/kg, i.p.) was given 20 min before, immediately after, and 1 and 2 hr after KA administration. Rats were killed 72 hr later and their hippocampi were examined for evidence of DNA damage (in situ dUTP end-labeling, i.e. TUNEL staining), cell viability (hematoxylin and eosin staining), and microglial (isolectin-B4 histochemistry) and astroglial responses (glial fibrillary acidic protein immunohistochemistry), as well as lipid peroxidation (4-hydroxynonenal immunohistochemistry). A cumulative dose of 10 mg/kg melatonin attenuates KA-induced neuronal death, lipid peroxidation, and microglial activation, and reduces the number of DNA breaks. A possible mechanism for melatonin-mediated neuroprotection involves its antioxidant and anti-inflammatory actions. The present data suggest that melatonin is potentially useful in the treatment of acute brain pathologies associated with oxidative stress-induced neuronal damage such as epilepsy, stroke, and traumatic brain injury.
Chung
Seung-Yun
SY
Department of Pediatrics, Our Lady of Mercy Hospital, Catholic University Medical College, Inchon, Korea.
Han
Seol-Heui
SH
D000818:Animals; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D017628:Microglia / Q000187:drug effects*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley
D008550:Melatonin; D007608:Kainic Acid