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Background: In neonatal rats, MK-801 treatments can produce schizophrenia-like symptoms. Crocin is a water soluble carotenoid in Saffron that exerts potent neuroprotective effects. This work aimed to demonstrate the function of crocin in the alleviation of motor and cognitive impairments elicited by MK-801 in a neonatal rodent schizophrenia model, and to illustrate the underlying molecular mechanisms. Methods: Rats were treated with vehicle, MK-801 (1 mg/kg), MK-801 + 25 mg/kg crocin, or MK-801 + 50 mg/kg crocin. Motor learning and coordination, locomotion and exploratory activities, as well as spatial memory were assessed using the rotarod test, pen field test, and the Morris water maze test, respectively. Relative mRNA and protein levels of genes of interest were analyzed using qRT-PCR and Western blot assays, respectively. Results: In the hippocampus of rats with MK-801-elicited schizophrenia, administration of crocin elevated the expression of silent information regulator-1 (SIRT1) and brain derived neurotrophic factor (BDNF), and relieved the oxidative stress. The learning deficits and motor perturbations caused by MK-801 treatments were also alleviated by the crocin administration. Conclusion: Collectively, crocin has exerted neuroprotective effects in the rat model of MK-801-elicited schizophrenia, via regulations of SIRT1 and downstream BDNF expression in the hippocampus.