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Obstructive sleep apnea (OSA) patients suffer from intermittent hypoxia (IH) and neuropsychologic impairments. Oxidative stress is involved in the pathogenesis of OSA, so the application of an antioxidant may be useful. We evaluated the hypothesis that melatonin would reduce IH-induced hippocampal injury via an increased expression of antioxidant enzymes. Adult Sprague–Dawley rats that had received a daily injection of melatonin or vehicle were exposed to IH for 8 hr/day for 7 or 14 days. The serum and hippocampus were harvested for the measurement of malondialdehyde (MDA). Apoptotic cell death was studied histologically in hippocampal sections. The mRNA expression of inflammatory mediators including tumor necrosis factor-alpha, inducible nitric oxide synthase, cyclooxygenase-2 and antioxidant enzymes including glutathione peroxidase, catalase and copper/zinc superoxide dismutase were examined in the hippocampus by RT-PCR. The results show significant increases in levels of serum and hippocampal MDA, apoptotic cell death and mRNA levels of inflammatory mediators in hypoxic rats when compared with the normoxic controls. Also, mRNA levels of the antioxidant enzymes were decreased in hypoxic animals. In the melatonin-treated hypoxic rats, serum MDA levels were comparable with those in normoxic control rats. Also, melatonin treatment significantly reduced hippocampal MDA levels and totally prevented apoptosis. Moreover, there were a decreased expression of the inflammatory mediators and an elevated expression of antioxidant enzymes in the melatonin injected rats when compared with vehicle-treated animals. These results indicate that melatonin mitigates oxidative stress and the pathogenesis of IH-induced hippocampal injury via its antioxidant and anti-inflammatory properties which includes stimulation of transcriptional regulation of antioxidant enzymes.