"RNSP (Rannasangpei)" Rescued MK-801-induced Schizophrenia-like Behaviors in Mice via Oxidative Stress and BDNF-TrkB/Akt Pathway

Schizophrenia (SCZ) is a complex, severe psychotic disorder that is highly persistent. Patients often cannot control their emotions and have delusions of victimization, world-weariness, and even suicide. Therefore, safer and more effective drugs are urgently needed. Rannasangpei (RNSP) from "the four medicine tantras" was used as a neuroprotective agent. The objective of this study was to investigate the effect and mechanism of RNSP on MK-801-induced SCZ in mice. Fifty C57BL/6J mice were randomly divided into a normal group, a model group, an RNSP group, a crocin (CRO) group, and an olanzapine (OLA) group, except for the normal group. The remaining mice were used to establish the MK-801-induced SCZ model. Changes in positive symptoms and cognitive impairment in mice before and after drug intervention were assessed by using the prepulse inhibition (PPI) test, Y-maze test (YMT), and open-field test (OFT). Intragastric administration of RNSP alleviated the symptoms of SCZ in SCZ mice, as demonstrated by the PPI, YMT, and OFT results. Compared with the model group, the first-line antipsychotic olanzapine reversed the anxiety-like phenotypes, hypermotility, and PPI deficits in the SCZ model mice. Further analysis revealed that RNSP reduced oxidative stress in SCZ model mice, as evidenced by increased superoxide dismutase (SOD) levels and decreased malondialdehyde (MDA) levels in the hippocampus, cortex, and blood of SCZ model mice. In our study, RNSP treatment restored the expression of brain-derived neurotrophic factor (BDNF), dopamine D2 receptor, p-Trkb, Akt/p-Akt, and doublecortin and inhibited the expression of IBA1 and Bax in the hippocampus of SCZ model mice. The polymerase chain reaction data indicated that RNSP treatment increased the expression of Bcl-2 and TGF-beta and decreased the expression of Bax, IL-1 beta, and TNF-alpha in the brains of the model mice. Our results are the first to show that RNSP reverses SCZ-like behaviors in rodents (both positive symptoms and cognitive deficits) by reducing oxidative stress and activating the BDNF-TrkB/Akt pathway, suggesting that RNSP is a novel approach for treating SCZ.