Melatonin reverses H-89 induced spatial memory deficit: Involvement of oxidative stress and mitochondrial function.

Oxidative stress and mitochondrial dysfunction play indispensable role in memory and learning impairment. Growing evidences have shed light on anti-oxidative role for melatonin in memory deficit. We have previously reported that inhibition of protein kinase A by H-89 can induce memory impairment. Here, we investigated the effect of melatonin on H-89 induced spatial memory deficit and pursued their interactive consequences on oxidative stress and mitochondrial function in Morris Water Maze model. Rats received melatonin (50 and 100µg/kg/side) and H-89(10µM) intra-hippocampally 30min before each day of training. Animals were trained for 4 consecutive days, each containing one block from four trials. Oxidative stress indices, including thiobarbituric acid (TBARS), reactive oxygen species (ROS), thiol groups, and ferric reducing antioxidant power (FRAP) were assessed using spectrophotometer. Mitochondrial function was evaluated through measuring ROS production, mitochondrial membrane potential (MMP), swelling, outer membrane damage, and cytochrome c release. As expected from our previous report, H-89 remarkably impaired memory by increasing the escape latency and traveled distance. Intriguingly, H-89 significantly augmented TBARS and ROS levels, caused mitochondrial ROS production, swelling, outer membrane damage, and cytochrome c release. Moreover, H-89 lowered thiol, FRAP, and MMP values. Intriguingly, melatonin pre-treatment not only effectively hampered H-89-mediated spatial memory deficit at both doses, but also reversed the H-89 effects on mitochondrial and biochemical indices upon higher dose. Collectively, these findings highlight a protective role for melatonin against H-89-induced memory impairment and indicate that melatonin may play a therapeutic role in the treatment of oxidative- related neurodegenerative disorders.

Inhibition of PKA attenuates memory deficits induced by ß-amyloid (1-42), and decreases oxidative stress and NF-κB transcription factors.

Alzheimer's disease (AD), the most relevant cause of dementia in elderly, is characterized by amyloid ß (Aß) containing plaques and neurofibrillatory tangles, synaptic and neuronal loss, along with progressive cognitive impairment in short-term memory. However, mechanistic links between protein kinase A (PKA), oxidative stress and memory loss in response to Aß remain elusive. In the present study, we examined the effects of post-training bilateral intra-hippocampal infusions of the specific protein kinase AII inhibitor, H-89, on memory deficits induced by Aß (1-42) in Aß-pretreated rats. H-89 and Aß were administered immediately after completion of training. All animals were trained for 4 consecutive days and tested 9 and 19 days after the infusions. Significant differences were observed in the time and distance of finding the hidden platform in Aß treated animals after 19 days. Interestingly, intra-hippocampal infusion of H-89 (5µM/side) significantly prevented the Aß-induced memory impairment. Furthermore, evaluation of NFκB (nuclear factor-κB), and antioxidant enzymes, such as γ-GCS (glutamylcysteine synthetase), HO-1 (hemeoxygenase-1), GSH (glutathione), and SOD (superoxide dismutase) confirmed the protective effect of H-89. Given the possible neuroprotective effects of H-89 on Aß-induced memory impairment, our results may open a new avenue for the prevention of AD by PKAII signaling pathway inhibitor.