(M1430-05-32) Tetrahydrocurcumin, a Metabolic By-Product of Curcumin, Shows Neuroprotection: A Potential Therapeutic Metabolite for Neurodegenerative Pathologies

Purpose: Due to its potent pharmacodynamic properties combined with minimal adverse effects, curcumin (Curcuma longa-Turmeric) is one of the most beneficial natural products used globally. Curcumin has been used as a dietary supplement and nutraceutical prophylactically and therapeutically. Additionally, it has also been used for cosmetic purposes. On the other hand, curcumin's limited bioavailability has long been a barrier to its application in medicine. Therefore, the metabolites of curcumin have become a recent study topic, and extensive studies have been done to enhance curcumin usage. Furthermore, past and current data show that curcumin or curcuminoid metabolites have biological activity comparable to or better than its precursor. However, very few studies have focused on the neuroprotective effect of Tetrahydrocurcumin (a key curcumin metabolite). Hence, the current study focused on establishing the novel neuroprotective action of Tetrahydrocurcumin.

Methods: Both in-silico and in-vitro studies were performed to elucidate and validate the neuroprotective effects and potential neuroprotective mechanisms of Tetrahydrocurcumin. HT-22 (hippocampal neurons) and N27 (dopaminergic neurons) were used to illustrate the impact of Tetrahydrocurcumin on hippocampal and dopaminergic neuronal viability. Moreover, to investigate the neuroprotective mechanisms, markers of oxidative stress, mitochondrial function, inflammation, and apoptosis were studied. With regard to the markers of oxidative stress, reactive oxygen species, nitrite, hydrogen peroxide, and glutathione content was measured spectrophotometrically and spectrofluorimetrically. For the mitochondrial function, Complex-I and IV activities and NADH content were measured spectrophotometrically. Caspase-3 and protease activities were measured spectrofluorimetrically as the markers of apoptosis. Statistical comparisons were made using the GraphPad Prism-5.

Results: Tetrahydrocurcumin demonstrated significant dose and time-dependent neuroprotection on both neurons (hippocampal (p < 0.05), and dopaminergic (p < 0.05)). The neuroprotection was attributed to its antioxidant and anti-apoptotic actions. Tetrahydrocurcumin dose-dependently and significantly reduced the prooxidants and increased the antioxidants as compared to the control. Similarly, the mitochondrial functions were also significantly elevated as compared to the control.

Conclusion: Neuronal dysfunction can be mitigated using natural antioxidants to scavenge free radicals and restore homeostasis. Prior to the development of efficient therapies, there were a number of challenges with their low bioavailability, stability, and safety that need to be rectified. Due to its neuroprotective pharmacodynamic actions, with higher bioavailability and stability than curcumin, Tetrahydrocurcumin can be an impactful therapeutic natural bioactive metabolite for preventing, reducing the rate of progression, and treating neurodegenerative pathologies.

Acknowledgements: We sincerely thank Dr. Muhammed Majeed and Dr. Nagabhushanam kalyanam, Sabinsa Corporation, East Windsor, New Jersey. We thank the Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University.