Repositioning of a nutraceutical, scoparone, in the management of MK-801-induced schizophrenia-like behavior in Mice: An insight into SIRT1/PGC-1α/TFAM pathway.

Schizophrenia is a prevalent neurodevelopmental psychiatric disorder that remains inadequately managed by current treatments, highlighting the urgent need for new pharmacotherapeutic approaches. Nutraceuticals have gained attention due to their favorable safety and multifaceted pharmacological benefits. Among these, scoparone exhibits a well-documented neuropsychopharmacological profile; however, its potential therapeutic effects on schizophrenia remain unclear and warrant further investigation. Consequently, this study aimed to evaluate the influence of scoparone treatment on MK-801-induced schizophrenia-like behaviors in C57BL/6 mice. C57BL/6 mice were injected with MK-801 (0.6 mg/kg/day, i.p.) for 7 consecutive days to induce schizophrenia. Mice were treated with scoparone (25 mg/kg/day, i.p.) 2 h after the MK-801 administration. Interestingly, scoparone attenuated MK-801-induced positive, negative, and cognitive symptoms of schizophrenia, as demonstrated in behavioral tests. Furthermore, it hindered MK-801-induced histopathological changes in the hippocampus. Importantly, the biochemical analysis shed light on the ability of scoparone to activate the neuroprotective silent mating type information regulation 2 homolog 1/peroxisome proliferator-activated receptor-γ coactivator-1-α/mitochondrial transcription factor A (SIRT1/PGC-1α/TFAM) signaling pathway, thereby regulating mitochondrial homeostasis. Concisely, PGC-1α activation hinders dynamin-related protein 1 (Drp1) levels, restricting mitochondrial fission. Conversely, it augments the fusion of adjacent mitochondria by boosting Mitofusin 2 (MFN2) and protein optic atrophy 1 (OPA1) levels. Moreover, it enhanced mitophagy for selective removal of damaged mitochondria. In conclusion, this study underscores scoparone's beneficial effect in MK-801-induced schizophrenia-like behaviors via SIRT1 activation, which manipulates multiple axes involved in the pathophysiology of schizophrenia.