Objective: Objective:

1. To investigate the neuroprotective effect of FDA-approved compounds (Raloxifene and Fulvestrant) against haloperidol-induced neurotoxicity in SHSY-5Y cells and adult zebrafish

2. To explore the molecular mechanism of both compounds via analysis of GPR30/Nrf2/HO-1/CREB by RTpcr and WB

Background: Background: Tardive dyskinesia (TD) is a severe neurological condition, that occurs after long-term use of typical antipsychotic drugs, characterized by irregular involuntary movements, targeting the orofacial region. The raloxifene and fulvestrant have similar pharmacological properties as identified in 17β-estradiol a well-known estrogen receptor modulator and G-Protein-Coupled Estrogen Receptor 30 (GPR30) activator showing anti-oxidant, anti-inflammatory, and antiapoptotic properties against neurological disorders.

Method: Material and Methods: In this study, SHSY-5Y cell lines were treated with raloxifene (0.001 and 0.01µM), fulvestrant (0.001 and 0.01µM), with haloperidol (100 µM) as well as with GPR30 antagonist G-15 (1µM) and agonist G-1 (2 µM). For the in-vivo study, a total of 48 adult zebrafish were divided into four groups (n=12):

Results: Haloperidol (100 µM) treatment reduced 50% cell viability than the control groups, whereas, treatment of raloxifene and fulvestrant significantly increased the cell viability of haloperidol-treated cells. Moreover, G-1 agonists increase cell viability then haloperidol-treated cells. In addition, raloxifene and fulvestrant reduced ROS generation, and apoptosis and enhanced the RT-PCR expression of Bcl2/Nrf2/HO-1/CREB in SHSY-5Y-cells as compared to haloperidol-treated cells. In an in-vivo study, raloxifene (10 ug/kg, i.p.) and fulvestrant (10 ug/kg, i.p.) enhance the total distance travelled, mean speed, and decrease in catalepsy behaviour in an adult zebrafish as compare to alone haloperidol (10 ug/mL) group. Similarly, raloxifene (10 ug/kg, i.p.) and fulvestrant (10 ug/kg, i.p.) significantly decreased the number of entries in the bottom zone and increased entries in top zone in novel diving tank as compared to haloperidol group. Additionally, treatment with raloxifene and fulvestrant significantly increased antioxidants in zebrafish brains than the toxin group.

Conclusion: Findings suggest that raloxifene and fulvestrant can activate the Bcl2/Nrf2/HO-1/CREB signaling pathways showing a neuroprotective effect against haloperidol-mediated toxicity.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gpr30-agonists-attenuate-haloperidol-induced-neurotoxicity-in-sh-sy5y-cells-and-adult-zebrafish/