Activation of bitter taste receptors (TAS2R) protects against rotenone-induced neurotoxicity: Could ghrelin have a role?

• Published in: European journal of pharmacology 2024-09, Vol.978, p.176802, Article 176802
• Main Authors: Hewedy, Wafaa A., Darwish, Inas E.
• Format: Article
• Language: English
• Subjects: Animals; Bitter taste receptors; Dopamine - metabolism; Ghrelin; Ghrelin - pharmacology; Male; Neurodegeneration; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Oxidative Stress - drug effects; Parkinson disease; Quaternary Ammonium Compounds - pharmacology; Quaternary Ammonium Compounds - therapeutic use; Rats; Rats, Wistar; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - metabolism; Rotenone - toxicity; TAS2Rs agonists
• ISSN: 0014-2999; 1879-0712; 1879-0712
• DOI: 10.1016/j.ejphar.2024.176802

Bitter taste receptors (TAS2Rs) and their downstream signaling pathways are expressed not only in the oral tissues but also in extraoral tissues. Emerging data has demonstrated the beneficial effect of ghrelin in neurodegenerative diseases. Gaining more insight into the interaction between TAS2Rs and gut hormones may expand their therapeutic applications. Herein, we aimed to assess the possible effect of TAS2R activation by denatonium benzoate (DB) in modulating functional and neurobiochemical alterations in a model of Parkinson’s disease (PD). PD model was induced by daily injection of rotenone (2 mg/kg). Rats received DB (5 mg/kg), atenolol (10 mg/kg), or both concomitantly with rotenone, daily for 28 days. Evaluation of the motor abnormalities and histological examination of brain tissues were conducted. In addition, striatal dopamine contents, immunohistochemical expression of tyrosine hydroxylase, plasma ghrelin level, and biochemical analysis of markers of inflammation and oxidative stress were assessed. Treatment with DB increased serum levels of ghrelin and striatal dopamine contents with consequent amelioration of oxidative stress and attenuation of inflammatory cytokines. Moreover, DB treatment significantly ameliorated motor disturbance and histological abnormalities compared to untreated rats. Atenolol inhibited ghrelin release and abolished the positive effect of DB suggesting the involvement of ghrelin on such effects. The current study suggests that TAS2Rs agonists are promising candidates for ameliorating rotenone-induced PD pathology in rats, an action that could be linked to the enhancement of ghrelin release with consequent antioxidant and anti-inflammatory activities. •Ghrelin displays neuroprotective effect in neurodegenerative diseases including PD.•Denatonium benzoate, a TAS2Rs agonist, displayed neuroprotective effect in rotenone-induced model of PD.•Activation of TAS2Rs could be a promising target for neurodegenerative diseases.