Raloxifene and Fulvestrant Exert Antioxidant, Anti-Inflammatory, and Antiapoptotic Action Against Haloperidol-Induced Tardive Dyskinesia in Rats via Activation of the GPER1/PI3k/Akt/Nrf2/HO-1 Signaling Pathways.

Tardive Dyskinesia (TD) is a pathological condition mainly arises due to supersensitivity of dopaminergic D2 receptors is often caused by long-term administration of antipsychotic medication that leads to involuntary hyperkinetic movement. Till now, there is no permanent treatment available to cure TD. The present study aimed to investigate the neuroprotective effect of raloxifene and fulvestrant, a selective estrogen receptor modulator (SERM), against haloperidol-induced TD in rats. Our study is focused on evaluating the effect of raloxifene and fulvestrant on alteration in behavior, biochemical, apoptosis, neuroinflammation, Immunohistochemistry, and western blot analysis expression in TD rats. In haloperidol (1 mg/kg) treated rats, administration of raloxifene (5 & 10 mg/kg) and fulvestrant (5 & 10 mg/kg) dose dependently improved the locomotor activity, motor co-ordination, neuromuscular strength and decreased Vacuous Chewing Movements (VCMs), Tongue Protrusion (TP), Facial Jerking (FJ). Whereas administration of raloxifene and fulvestrant along with letrozole a nonselective antagonist of GPER1 reduced the effect of raloxifene and fulvestrant. Consequently, raloxifene and fulvestrant reduced oxidative insults (MDA and GSH), caspases level (Caspase 3 and 9), and inflammatory markers (TNF-α, IL-1β, and IL-6), in rats injected with haloperidol. Furthermore, raloxifene and fulvestrant treatment upregulates the expression of GPER1/PI3k/Akt/Nrf2/HO-1 signaling pathway in TD rats; these pathways may be responsible for the reduction in oxidative stress, neuroinflammation, and apoptosis. Meanwhile, treatment of letrozole with raloxifene and fulvestrant substantially downregulated the expression of these proteins, suggesting that raloxifene and fulvestrant exert its effect via GPER1 signaling pathway. The study concludes that raloxifene and fulvestrant have antioxidant, anti-inflammatory, antiapoptotic, and neuroprotective properties suggesting that they could be used in the management of neurological disorders, including TD.