Efficacy and safety of prophylactic use of benzhexol after risperidone treatment in MK-801-induced mouse model of schizophrenia.

Rationale: There is a debate about whether doctors should prophylactically use benzhexol in schizophrenic patients to reduce the occurrence of extrapyramidal side effects (EPS) after risperidone treatment.

Objectives: We conducted a prospective animal model to explore the efficacy and safety of the prophylactic use of benzhexol after risperidone treatment and the mechanism of the process.

Methods: C57/BL mice were injected with MK-801 (0.5 mg/kg, i.p.) once a day for two weeks. The open field test (OFT) and the novel object recognition test (NORT) assessed the schizophrenia-like behavior of mice. After four weeks of treatment with benzhexol (10 mg/kg, i.g.) and risperidone (3 mg/kg, i.g.), the inclined screen test (IST), rotarod test (RT), open field test (OFT), novel object recognition test (NORT) and the Morris water maze test (MWM) were conducted successively. The expression of BDNF, p-Tau, and Tau in the hippocampus was detected by Western blot assay.

Results: We showed that benzhexol can significantly attenuate risperidone-induced motor coordination impairments and catalepsy and did not affect the efficacy of risperidone in reducing spontaneous activity. Notably, the prophylactic use of benzhexol reduced the recognition memory and spatial memory in MK-801-induced model mice after risperidone. In addition, benzhexol increased the ratio of p-Tau/Tau and decreased BDNF expression levels in the hippocampus.

Conclusions: We found that the prophylactic use of benzhexol can reduce the occurrence of EPS and does not affect the efficacy of risperidone in the treatment of positive symptoms. Benzhexol may impair cognitive function but did not cause further deterioration of cognitive function in MK-801 mice.