Upadhayay Shubham, Soni Divya
Department of Pharmacology, Central University of Punjab, Ghudda, Bhatinda, Punjab, India.
J Biochem Mol Toxicol. 2025 Aug;39(8):e70413. doi: 10.1002/jbt.70413.
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.
迟发性运动障碍（TD）是一种主要由于多巴胺能D2受体超敏反应引起的病理状态，通常由长期服用抗精神病药物导致，会引发不自主的运动亢进。到目前为止，尚无永久性治疗方法可治愈TD。本研究旨在探讨雷洛昔芬和氟维司群（一种选择性雌激素受体调节剂（SERM））对氟哌啶醇诱导的大鼠TD的神经保护作用。我们的研究重点是评估雷洛昔芬和氟维司群对TD大鼠行为、生化、凋亡、神经炎症、免疫组织化学及蛋白质印迹分析表达改变的影响。在氟哌啶醇（1mg/kg）处理的大鼠中，给予雷洛昔芬（5和10mg/kg）和氟维司群（5和10mg/kg）剂量依赖性地改善了运动活性、运动协调性、神经肌肉力量，并减少了空嚼运动（VCMs）、伸舌（TP）、面部抽搐（FJ）。而雷洛昔芬和氟维司群与GPER1的非选择性拮抗剂来曲唑一起给药则降低了雷洛昔芬和氟维司群的作用。因此，雷洛昔芬和氟维司群降低了注射氟哌啶醇大鼠的氧化损伤（丙二醛和谷胱甘肽）、半胱天冬酶水平（半胱天冬酶3和9）以及炎症标志物（肿瘤坏死因子-α、白细胞介素-1β和白细胞介素-6）。此外，雷洛昔芬和氟维司群治疗上调了TD大鼠中GPER1/PI3k/Akt/Nrf2/HO-1信号通路的表达；这些通路可能是氧化应激、神经炎症和凋亡减少的原因。同时，来曲唑与雷洛昔芬和氟维司群一起处理显著下调了这些蛋白质的表达，表明雷洛昔芬和氟维司群通过GPER1信号通路发挥作用。该研究得出结论，雷洛昔芬和氟维司群具有抗氧化、抗炎、抗凋亡和神经保护特性，表明它们可用于治疗包括TD在内的神经系统疾病。
