Glycyrrhizic Acid Mitigates Haloperidol-Induced Neurotoxicity in SHSY-5Y Cells and Rats Via Activation of PI3k/Akt/Nrf2 Pathways

Antipsychotic medications are used to treat a psychological condition called ‘Schizophrenia’. However, its long-term administration causes irregular involuntary motor movements, targeting the orofacial regions. Glycyrrhizic acid (GA) is a naturally occurring triterpene saponin glycoside obtained from the roots of the Glycyrrhiza glabra (liquorice) plant and well known for its antioxidant, antiapoptotic and neuroprotective abilities. The present study investigated the neuroprotective potential of GA against haloperidol (Halo) induced neurotoxicity in SHSY-5Y cells and Wistar rats. Schrodinger software was utilized to estimate the target binding affinity of GA with various targets. To assess cell viability, SHSY-5Y cells were pretreated with GA (25, 50, and 100 µM) 1 h before halo (100 µM) treatment. In an in-vivo study, Wistar rats were divided into five groups: control (saline), halo (1 mg/kg), GA (25 mg/kg), and GA (50 mg/kg). The GA was injected for 21 days, 1 h before halo. All behavior changes were recorded on the 14th and 21st days. Results indicate that pretreatment with GA improves cell viability and reduces ROS formation in halo-treated SHSY-5Y cells, showing its antioxidant ability. Furthermore, GA administration reduced vacuous chewing movements, tongue protrusion, facial jerking, and locomotor abnormalities in halo-treated rats. Moreover, GA treatment improves antioxidant levels, including GSH, and SOD, in halo-injected rats. Additionally, GA treatment upregulates the striatal expression of p-PI3k, p-Akt, and Nrf2 in rats injected with halo. Findings indicate that GA can be a therapeutic agent for tardive dyskinesia and other neurological disorders.

Graphical Abstract