Date of Award

11-2018

Document Type

Dissertation

Department

Medical Education

First Advisor

Murat Oz

Second Advisor

Safa Shehab

Third Advisor

Shreesh Ojha

Abstract

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.

Comments

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. The prevalence increases with advancing age. PD is a slowly progressive multisystem disorder rather than just a disease involving massive neuropathological alterations in the brain, characterized by selective a degeneration of dopaminergic nigrostriatal neurons. Recently, it was suggested that activation of the cholinergic system has neuroprotective effects on dopaminergic neurons, and human α7-nicotinic acetylcholine receptors (α7-nAChR) stimulation may be a potential therapeutic target in Parkinson’s disease management.

Curcumin is a polyphenolic compound isolated from the rhizomes of Curcuma longa. Curcumin 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, we investigated the effect of curcumin on the functional properties of α7-nAChR using the two-electrode voltage clamp technique. Curcumin caused a significant potentiation of the action of α7-nAChR expressed in Xenopus oocytes. Moreover, 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 positive allosteric modulator type II. Also, we have tested the neuroprotective effect of curcumin in-vivo in toxin-based (6-hydroxydopamine; 6-OHDA) animal model of Parkinson’s disease. 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. Administration of the α7-nAChR-selective antagonist methyllycaconitine, reversed completely the neuroprotective effects of curcumin.

To our knowledge, this is the first study demonstrating that curcumin acts as type II positive allosteric modulator of α7-nAChR and has a neuroprotective effect in 6-OHDA animal model of Parkinson’s disease. Importantly, recent studies indicate that potentiation of α7-nAChR by specific agonists causes beneficial effects in psychosis and autistic disorders. Therefore, the results of our findings have the potential to develop novel agents such as curcumin in the treatment of not only neurodegenerative diseases but also for psychosis and autistic disorders.

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