Geraniin Ameliorates Haloperidol-Induced Orofacial Dyskinesia in Rats Through Mitigating Neuronal Oxidative Stress, Neuroinflammation, and Apoptosis via Modulation of the Nrf2 Signaling Pathway

Geraniin (GRN), an ellagitannin from Phyllanthus urinaria, shows antioxidant, anti-inflammatory, and neuroprotective effects. This study evaluated GRN's potential against haloperidol (HPD)-induced orofacial dyskinesia (OD). Rats treated with HPD (1 mg/kg i.p.) for 21 days exhibited dopamine D2 receptor blockade, neurotoxicity, and OD, characterized by vacuous chewing movements (VCM) and tongue protrusion (TP). Then, 60 min post-HPD, GRN was administered i.p. daily for 21 days. OD behaviors were assessed, and on Day 21, striatal tissues were analyzed for oxidative stress, mitochondrial function, inflammation, and apoptosis. GRN alone did not cause OD but significantly reduced HPD-induced VCM and TP. It also reduced oxidative stress, improved antioxidant defense, preserved mitochondrial function, and decreased neuroinflammation and apoptosis. These effects were blocked by ML385, a nuclear factor erythroid-2-related factor 2 (Nrf2) pathway inhibitor. GRN protects against HPD-induced OD, likely via Nrf2 activation. It may be a promising candidate for TD therapy, pending further clinical investigation.