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NEUROPROTECTIVE EFFECTS OF HISTAMINE H3 RECEPTOR LIGANDS CIPROXIFAN AND CLOBENPROPIT THROUGH ANTIAPOPTOTIC AND ANTIOXIDANT MECHANISMS: EVIDENCE FROM IN VIVO AND COMPUTATIONAL STUDIES

VASUDEVAN MANI 1*, MINHAJUL ARFEEN 2, MAI B. ALWESMI ³

¹ Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah 51452, Saudi Arabia
2 Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Buraydah 51452, Saudi Arabia
3 Department of Medical-Surgical Nursing, College of Nursing, Princess Nourah bint Abdulrahman University, Riyadh 11564, Saudi Arabia

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Histamine H3 receptors (H3Rs) located on presynaptic neurons function as both autoreceptors and heteroreceptors, regulating neurotransmitter release. This dual role makes them compelling targets for drug discovery, particularly for the treatment of neurodegenerative conditions. Therefore, in this work, two structurally distinct H3R antagonists, ciproxifan (CIP) and clobenpropit (CLO), were evaluated for neuroprotection using a lipopolysaccharide (LPS) treated animal model. CIP and CLO were assessed at doses of 1 and 3 mg/kg, respectively (oral, 30 days). Neuroinflammation and neurotoxicity were induced by intraperitoneal LPS administration (1 mg/kg) during the final four days of the protocol (days 27 - 30). To capture the mechanistic breadth of any neuroprotective response, brain tissue analyses included apoptotic signalling proteins and oxidative stress markers. It includes B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), Caspase-3, malondialdehyde (MDA), reduced glutathione (GSH) and catalase activity. The treatment with CIP and CLO resulted in reduced Bax, Caspase-3 and MDA levels, accompanied by increased Bcl-2, GSH and catalase levels. Molecular docking studies revealed favourable binding of CIP and CLO with Bcl-2, Bax and Caspase-3. Collectively, the combined in vivo and computational findings suggest that CIP and CLO may exert neuroprotective effects against LPS-induced neuronal injury.