Date of Award
Doctor of Philosophy (PhD)
Curcumin is a polyphenolic compound isolated from the rhizomes of Curcuma longa. Curcumin has been demonstrated to have antioxidant, anti-inflammatory, and anticancer properties. Moreover, it has been shown to exhibit beneficial effects in the treatment of several neurodegenerative diseases including Alzheimer’s and Parkinson’s diseases. However, the molecular and cellular targets mediating the pharmacological actions of curcumin remain largely unknown. In this study, the effects of curcumin application on the functional properties of the nicotinic acetylcholine receptor, a prototype for ligand-gated ion channels were investigated. Using the two-electrode voltage clamp technique, the results showed that curcumin co-application caused a significant potentiation of the action of human α7-nicotinic acetylcholine receptors (α7-nAChR) expressed in Xenopus oocytes. Importantly, curcumin was found less effective on other nicotinic receptor subunit combinations and other members of ligand-gated ion channels. Curcumin significantly decreased desensitization of α7-nAChR suggesting that it acts as a type II PAM. High affinity-binding site for curcumin on α7-nAChR was also verified by molecular docking study.
In the second part of this study, the neuroprotective effects of curcumin in an animal model of Parkinson’s disease were investigated. Stereotaxic micro-neurosurgery was successfully established (for the first time in our university) and used to induce the toxin based (6-hydroxydopamine; 6-OHDA) animal model of Parkinson’s disease. This was followed by testing the behavior of the animals, tissue collection, immunohistochemistry, striatal fiber density measurement, and stereological data analysis. Systemic administration of curcumin alleviated 6-OHDA-induced motor abnormalities and protected against substantia nigra pars compacta dopaminergic neuronal loss, through an α7-nAChRs-mediated mechanism. The protective effects of curcumin were completely reversed by the administration of the α7-nAChR-selective antagonist methyllycaconitine (MLA).
In summary, the results of this study suggest that α7-nAChR-mediated activation is an important mechanism for the neuroprotective effects of curcumin in toxin-based (6-hydroxydopamine; 6-OHDA) animal model of Parkinson’s disease.
Gaber ElNebrisi, Eslam Mohammed, "The Role of Human α7-Nicotinic Acetylcholine Receptors in Mediating Neuroprotective Action of Curcumin" (2018). Medical Education Dissertations. 3.