Raloxifene and Fulvestrant Exert Antioxidant, Anti-Inflammatory, and Antiapoptotic Action Against Haloperidol-Induced...

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Tardive dyskinesia (TD) is a movement disorder caused by long-term antipsychotic use, leading to dopamine D2 receptor supersensitivity and involuntary hyperkinetic movements.
• Currently, no permanent cure exists for TD, highlighting the need for novel therapeutic strategies.
• Selective estrogen receptor modulators (SERMs) like raloxifene and fulvestrant are being investigated for their potential neuroprotective properties.

Purpose of the Study:

• To investigate the neuroprotective effects of raloxifene and fulvestrant against haloperidol-induced TD in a rat model.
• To evaluate the impact of these SERMs on behavioral, biochemical, apoptotic, and inflammatory markers associated with TD.
• To elucidate the underlying signaling pathways, specifically the GPER1/PI3k/Akt/Nrf2/HO-1 pathway, involved in the therapeutic action of raloxifene and fulvestrant.

Main Methods:

• Haloperidol was administered to rats to induce TD.
• Rats were treated with varying doses of raloxifene and fulvestrant, with some groups also receiving letrozole (a GPER1 antagonist).
• Evaluations included behavioral assessments (locomotor activity, VCMs, TP, FJ), biochemical assays (oxidative stress markers), apoptosis markers (caspases), inflammatory markers (cytokines), immunohistochemistry, and western blot analysis to assess protein expression and signaling pathways.

Main Results:

• Raloxifene and fulvestrant dose-dependently improved motor coordination and reduced involuntary movements (VCMs, TP, FJ) in haloperidol-treated rats.
• These treatments significantly reduced oxidative stress (MDA, GSH), caspase levels (3 and 9), and inflammatory markers (TNF-α, IL-1β, IL-6).
• Raloxifene and fulvestrant upregulated the GPER1/PI3k/Akt/Nrf2/HO-1 signaling pathway, which was diminished by letrozole co-administration, indicating a GPER1-dependent mechanism.

Conclusions:

• Raloxifene and fulvestrant exhibit significant antioxidant, anti-inflammatory, antiapoptotic, and neuroprotective effects in a rat model of TD.
• The therapeutic benefits are mediated through the GPER1 signaling pathway.
• These findings suggest that raloxifene and fulvestrant hold promise as potential therapeutic agents for managing neurological disorders, including tardive dyskinesia.