Possible involvement of CREB/BDNF signaling pathway in neuroprotective effects of topiramate against methylphenidate induced apoptosis, oxidative stress and inflammation in isolated hippocampus of rats: Molecular, biochemical and histological evidences.

Chronic abuse of methylphenidate (MPH) can cause serious neurotoxicity. The neuroprotective effects of topiramate (TPM) were approved, but its putative mechanism remains unclear. In current study the role of CREB/BDNF signaling pathway in TPM protection against methylphenidate-induced neurotoxicity in rat hippocampus was evaluated. 60 adult male rats were divided randomly into six groups. Groups received MPH (10mg/kg) only and concurrently with TPM (50mg/kg and 100mg/kg) and TPM (50 and 100mg/kg) only for 14 days. Open field test (OFT) was used to investigate motor activity. Some biomarkers of apoptotic, anti-apoptotic, oxidative, antioxidant and inflammatory factors were also measured in hippocampus. Expression of total (inactive) and phosphorylated (active) CREB and BDNF were also measured in gene and protein levels in dentate gyrus (DG) and CA1 areas of hippocampus. MPH caused significant decreases in motor activity in OFT while TPM (50 and 100mg/kg) inhibited MPH-induced decreases in motor activity. On the other hand, MPH caused remarkable increases in Bax protein level, lipid peroxidation, catalase activity, IL-1β and TNF-α levels in hippocampal tissue. MPH also caused significant decreases of superoxide dismutase, activity and also decreased CREB, in both forms, BDNF and Bcl-2 protein levels. TPM, by the mentioned doses, attenuated these effects and increased superoxide dismutase, glutathione peroxidase and glutathione reductase activities and also increased CREB, in both forms, BDNF and Bcl-2 protein levels and inhibited MPH induced increase in Bax protein level, lipid peroxidation, catalase activity, IL-1β and TNF-α levels. TPM also inhibited MPH induced decreases in cell number and changes in cell shapes in DG and CA1 areas. TPM can probably act as a neuroprotective agent against MPH induced neurotoxicity and this might have been mediated by CREB/BDNF signaling pathway.
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