The antioxidant melatonin reduces cortical neuronal death after intrastriatal injection of kainate in the rat

The anti-excitotoxic efficacy of the pineal hormone melatonin was investiga ted in kainate-injured brains of rats. Kainate (a glutamate-receptor agonis t, 2.5 nmol in 1 mu l) was directly injected to unilateral striatum. Melato nin (10 mg/kg) was administrated intraperitoneally 1 h before and 1, 3, and 5 h after intrastriatal kainate injection in adult Sprague-Dawley rats. Th ree days after kainate injection, a significant neuronal damage was found, as determined by Nissl staining and the TUNEL method, not only in the injec ted striatum, but also in the ipsilateral neighboring cortex. The kainate-i nduced cortical apoptotic neuronal death was significantly attenuated by tr eatment with melatonin compared with the vehicle control group. However, no detectable changes were observed in the contralateral side of the brain in either vehicle- or melatonin-treated rats. Moreover, the biochemical resul ts indicated that kainate can indeed induce oxidative stress, such as a dec rease in the content of total glutathione (GSH), oxidized glutathione (GSSG ), and an increase in the ratio of GSSG/GSH in the striatum and cortex comp ared with the contralateral brain regions. In the kainate-injected striatum , melatonin did not reduce the oxidative stress, but in the neighborhood of injected area-cortex, kainate-induced oxidative stress was significantly r educed by melatonin. Enhancement of glutathione-peroxidase activity was ind uced by intrastriatal kainate injection, not only in the cortical area of c ontrol and melatonin-treated rats, but also in striatum of control rats. Ho wever, a large elevation was found in the melatonin-treated cortex. Taking the morphological and biochemical data together, the present results sugges t that melatonin functions as an antioxidant by upregulating the glutathion e antioxidative defense system, thereby reducing neuronal death caused by e xcitotoxicity and preventing the kainate-induced damage from spreading to a djacent brain regions.