Abstract
Background Valproic acid (anticonvulsant medication) has been found to inhibit histone deacetylase activity and suppress hippocampal neurogenesis, which causes memory impairment in both humans and rodents. The neurohormone melatonin, which regulates mammalian seasonal and circadian physiology, has recently been shown to have neuroprotective properties, counteracting memory impairment associated with VPA-caused hippocampal neurogenesis reduction. This study is aimed at investigating the molecular mechanisms of melatonin associated with VPA-induced hippocampal neurogenesis and memory impairment. Methods Male Spraque-Dawley rats received VPA (300 mg/kg) twice daily or melatonin (8 mg/kg/day) or some rats were given melatonin for 14 days during VPA administration. Results The VPA-treated rats showed a significant increase in malondialdehyde (MDA) levels in the hippocampus and p21-positive cells in the subgranular zone (SGZ) of the dentate gyrus (DG) but decreased superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) activities. Moreover, VPA significantly decreased levels of nestin, Notchl, nuclear factor erythroid 2-related factor 2 (Nrf2), doublecortin (DCX), sex determining region Y-box 2 (SOX2), and brain-derived neurotrophic factor (BDNF). Conclusions We found that melatonin was able to counteract these neurotoxic effects, acting as a neuroprotectant in VPA-induced memory hippocampal neurogenesis impairment by preventing intracellular oxidative stress and increasing antioxidant activity.
Highlights
Valproic acid has been found to inhibit histone deacetylase activity and suppress hippocampal neurogenesis, which causes memory impairment in both humans and rodents
Animals that underwent valproic acid (VPA) treatment had significantly lower brain-derived neurotrophic factor (BDNF) levels than those in the control (p < 0:0001, Figure 3(f)) and preventive groups. These results demonstrate that melatonin coadministration can protect against BDNF protein deficiency caused by VPA
We found that oxidative stress triggered by VPA leads to stimulation of p21 expression, resulting in the suppression of hippocampal neurogenesis
Summary
Valproic acid (anticonvulsant medication) has been found to inhibit histone deacetylase activity and suppress hippocampal neurogenesis, which causes memory impairment in both humans and rodents. We found that melatonin was able to counteract these neurotoxic effects, acting as a neuroprotectant in VPA-induced memory hippocampal neurogenesis impairment by preventing intracellular oxidative stress and increasing antioxidant activity. Oxidative stress is a result of an imbalance between ROS and antioxidant systems, which is an important cause of neuronal cell death and memory loss in neurodegenerative disorders [2, 3]. The oxidative damage underlying neuronal cell death, which results from increased oxidative stress and decreases in antioxidative agents in the hippocampus and prefrontal cortex, contributes to memory impairment [6, 7]. Exposure to valproic acid (VPA), an anticonvulsant drug, causes memory impairment associated with aberrations in hippocampal neurogenesis, lower hippocampal cell proliferation, cell survival, and immature neuron numbers [8]. The adverse effects of VPA treatment in both patients [9] and animal models [10] are Oxidative Medicine and Cellular Longevity
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