Methylphenidate (MPH) abuse causes adverse neurobehavioral and neurochemical effects. Some herbal components such as crocin have shown neuroprotective properties. The current study evaluates the potential role of the cyclic AMP response element binding protein (CREB)‑brain‑derived neurotrophic factor (BDNF) signaling pathway in mediating the neuroprotective effects of crocin against MPH‑induced neurotoxicity in rats. Seventy adult male rats were randomly divided into seven groups. Group 1 and 2 received 0.7 ml/rat of normal saline and 10 mg/kg of MPH, respectively. Groups 3, 4, 5, and 6 were treated simultaneously with MPH (10 mg/kg) and crocin (10, 20, 40, and 80 mg/kg, respectively) for 21 days. Group 7 was treated with crocin (80 mg/kg) alone for 21 days. The Morris water maze (MWM) and open field test were used to assess cognitive and locomotor activities. Hippocampal neurotoxicity parameters and levels of BDNF and CREB were evaluated. Simultaneous treatment with various doses of crocin reduced the MPH‑induced cognition disturbances and hyperlocomotion. In addition, lipid peroxidation increased with MPH treatment and levels of the oxidized forms of glutathione (GSSG), interleukin 1 beta (IL‑1β), tumor necrosis factor alpha (TNF‑α), and Bax increased. MPH treatment decreased levels of the reduced form of glutathione (GSH), P‑CREB, Bcl‑2, and BDNF in the hippocampus. MPH also reduced activity of superoxide dismutase, glutathione peroxidase, and glutathione reductase in the hippocampus. In contrast, crocin attenuated MPH‑induced oxidative stress, inflammation, and apoptosis, and increased levels of P‑CREB and BDNF. Thus, crocin – likely via stimulation of the P‑CREB/BDNF signaling pathway – displayed neuroprotection against MPH‑induced neurotoxicity
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