Tetrahydrocurcumin Has Similar Anti-Amyloid Properties as Curcumin: In Vitro Comparative Structure-Activity Studies

Panchanan Maiti; Jayeeta Manna; Joshua Thammathong; Bobbi Evans; Kshatresh Dutta Dubey; Souvik Banerjee; Gary L Dunbar

doi:10.3390/antiox10101592

Tetrahydrocurcumin Has Similar Anti-Amyloid Properties as Curcumin: In Vitro Comparative Structure-Activity Studies

Antioxidants (Basel). 2021 Oct 11;10(10):1592. doi: 10.3390/antiox10101592.

Authors

Panchanan Maiti^{1

2

3

4

5}, Jayeeta Manna¹, Joshua Thammathong⁶, Bobbi Evans⁶, Kshatresh Dutta Dubey⁷, Souvik Banerjee⁶, Gary L Dunbar^{1

2

3

4}

Affiliations

¹ Field Neurosciences Institute, Ascension St. Mary's Hospital, Saginaw, MI 48604, USA.
² Field Neurosciences Institute Laboratory for Restorative Neurology, Central Michigan University, Mt. Pleasant, MI 48859, USA.
³ Program in Neuroscience, Central Michigan University, Mt. Pleasant, MI 48859, USA.
⁴ Department of Psychology, Central Michigan University, Mt. Pleasant, MI 48859, USA.
⁵ Brain Research Laboratory, College of Health and Human Services, Saginaw Valley State University, Saginaw, MI 48604, USA.
⁶ Department of Physical Sciences, College of Science, Technology, Engineering, and Mathematics, University of Arkansas Fort Smith, Fort Smith, AR 72913, USA.
⁷ Department of Chemistry and Center for Informatics, School of Natural Sciences, Shiv Nadar University, Delhi-NCR, Gautam Buddha Nagar 201314, India.

Abstract

Despite its potent anti-amyloid properties, the utility of curcumin (Cur) for the treatment of Alzheimer's disease (AD) is limited due to its low bioavailability. Tetrahydrocurcumin (THC), a more stable metabolite has been found in Cur-treated tissues. We compared the anti-amyloid and neuroprotective properties of curcumin, bisdemethoxycurcumin (BDMC), demethoxycurcumin (DMC) and THC using molecular docking/dynamics, in-silico and in vitro studies. We measured the binding affinity, H-bonding capabilities of these compounds with amyloid beta protein (Aβ). Dot blot assays, photo-induced cross linking of unmodified protein (PICUP) and transmission electron microscopy (TEM) were performed to monitor the Aβ aggregation inhibition using these compounds. Neuroprotective effects of these derivatives were evaluated in N2a, CHO and SH-SY5Y cells using Aβ42 (10 µM) as a toxin. Finally, Aβ-binding capabilities were compared in the brain tissue derived from the 5× FAD mouse model of AD. We observed that THC had similar binding capability and Aβ aggregation inhibition such as keto/enol Cur and it was greater than BDMC and DMC. All these derivatives showed a similar degree of neuroprotection in vitro and labeled Aβ-plaques ex vivo. Overall, ECur and THC showed greater anti-amyloid properties than other derivatives. Therefore, THC, a more stable and bioavailable metabolite may provide greater therapeutic efficacy in AD than other turmeric derivatives.

Keywords: Alzheimer’s disease; MD simulation; amyloid beta protein; binding energy; curcumin; docking site; molecular docking; neurodegeneration; structure-activity study.