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The Emerging Landscape of Natural Small-molecule Therapeutics for Huntington’s Disease

Huntington’s disease (HD) is a rare and fatal neurodegenerative disorder with no disease-modifying therapeutics. HD is characterized by extensive neuronal loss and is caused by the inherited expansion of the huntingtin (HTT) gene that encodes a toxic mutant HTT (mHTT) protein having expanded polyglu...

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Autores principales: Bhat, Shahnawaz Ali, Ahamad, Shakir, Dar, Nawab John, Siddique, Yasir Hassan, Nazir, Aamir
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Bentham Science Publishers 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10227909/
https://www.ncbi.nlm.nih.gov/pubmed/36797612
http://dx.doi.org/10.2174/1570159X21666230216104621
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author Bhat, Shahnawaz Ali
Ahamad, Shakir
Dar, Nawab John
Siddique, Yasir Hassan
Nazir, Aamir
author_facet Bhat, Shahnawaz Ali
Ahamad, Shakir
Dar, Nawab John
Siddique, Yasir Hassan
Nazir, Aamir
author_sort Bhat, Shahnawaz Ali
collection PubMed
description Huntington’s disease (HD) is a rare and fatal neurodegenerative disorder with no disease-modifying therapeutics. HD is characterized by extensive neuronal loss and is caused by the inherited expansion of the huntingtin (HTT) gene that encodes a toxic mutant HTT (mHTT) protein having expanded polyglutamine (polyQ) residues. Current HD therapeutics only offer symptomatic relief. In fact, Food and Drug Administration (FDA) approved two synthetic small-molecule VMAT2 inhibitors, tetrabenazine (1) and deutetrabenazine (2), for managing HD chorea and various other diseases in clinical trials. Therefore, the landscape of drug discovery programs for HD is evolving to discover disease-modifying HD therapeutics. Likewise, numerous natural products are being evaluated at different stages of clinical development and have shown the potential to ameliorate HD pathology. The inherent anti-inflammatory and antioxidant properties of natural products mitigate the mHTT-induced oxidative stress and neuroinflammation, improve mitochondrial functions, and augment the anti-apoptotic and pro-autophagic mechanisms for increased survival of neurons in HD. In this review, we have discussed HD pathogenesis and summarized the anti-HD clinical and pre-clinical natural products, focusing on their therapeutic effects and neuroprotective mechanism/s.
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spelling pubmed-102279092023-10-11 The Emerging Landscape of Natural Small-molecule Therapeutics for Huntington’s Disease Bhat, Shahnawaz Ali Ahamad, Shakir Dar, Nawab John Siddique, Yasir Hassan Nazir, Aamir Curr Neuropharmacol Medicine, Neurology, Pharmacology, Neuroscience Huntington’s disease (HD) is a rare and fatal neurodegenerative disorder with no disease-modifying therapeutics. HD is characterized by extensive neuronal loss and is caused by the inherited expansion of the huntingtin (HTT) gene that encodes a toxic mutant HTT (mHTT) protein having expanded polyglutamine (polyQ) residues. Current HD therapeutics only offer symptomatic relief. In fact, Food and Drug Administration (FDA) approved two synthetic small-molecule VMAT2 inhibitors, tetrabenazine (1) and deutetrabenazine (2), for managing HD chorea and various other diseases in clinical trials. Therefore, the landscape of drug discovery programs for HD is evolving to discover disease-modifying HD therapeutics. Likewise, numerous natural products are being evaluated at different stages of clinical development and have shown the potential to ameliorate HD pathology. The inherent anti-inflammatory and antioxidant properties of natural products mitigate the mHTT-induced oxidative stress and neuroinflammation, improve mitochondrial functions, and augment the anti-apoptotic and pro-autophagic mechanisms for increased survival of neurons in HD. In this review, we have discussed HD pathogenesis and summarized the anti-HD clinical and pre-clinical natural products, focusing on their therapeutic effects and neuroprotective mechanism/s. Bentham Science Publishers 2023-03-30 2023-03-30 /pmc/articles/PMC10227909/ /pubmed/36797612 http://dx.doi.org/10.2174/1570159X21666230216104621 Text en © 2023 Bentham Science Publishers https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.
spellingShingle Medicine, Neurology, Pharmacology, Neuroscience
Bhat, Shahnawaz Ali
Ahamad, Shakir
Dar, Nawab John
Siddique, Yasir Hassan
Nazir, Aamir
The Emerging Landscape of Natural Small-molecule Therapeutics for Huntington’s Disease
title The Emerging Landscape of Natural Small-molecule Therapeutics for Huntington’s Disease
title_full The Emerging Landscape of Natural Small-molecule Therapeutics for Huntington’s Disease
title_fullStr The Emerging Landscape of Natural Small-molecule Therapeutics for Huntington’s Disease
title_full_unstemmed The Emerging Landscape of Natural Small-molecule Therapeutics for Huntington’s Disease
title_short The Emerging Landscape of Natural Small-molecule Therapeutics for Huntington’s Disease
title_sort emerging landscape of natural small-molecule therapeutics for huntington’s disease
topic Medicine, Neurology, Pharmacology, Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10227909/
https://www.ncbi.nlm.nih.gov/pubmed/36797612
http://dx.doi.org/10.2174/1570159X21666230216104621
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