Natural Compounds May Carry Therapeutical Benefits for Huntington’s

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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As therapeutics for Huntington’s disease (HD) are still a need, a number of natural compounds may hold promising beneficial effects, a review study shows.

The review “The Medicinal Chemistry of Natural and Semi-Synthetic Compounds Against Parkinson’s and Huntington’s Diseases” was published in the journal ACS Chemical Neuroscience.

As populations in western societies are increasingly older, there also is a rise in neurodegenerative diseases. Dementia is an ubiquitous hallmark of several of these conditions, including HD. The authors characterize dementia as “a general term for loss of memory and other mental abilities severe enough to interfere with daily life. It is caused by physical changes in the brain,” and there is an urgent need to find therapeutic strategies that can counteract dementia’s rising numbers, they wrote.

A team of researchers performed a review analysis of the currently available molecules (or combination of molecules) of a natural origin undergoing investigation for Huntington’s and Parkinson’s diseases. They searched for peer-reviewed articles using different online databases.

“Two major parameters were considered for the preparation of this review: particular attention was reserved to these research works presenting well-defined molecular mechanisms for the studied compounds, and, where available, papers reporting in vivo data were preferred,” authors wrote.

HD is caused by a genetic mutation in the gene encoding the huntingtin (HTT) protein and is characterized by different clinical signs, such as progressive motor, behavioral and cognitive declines. Dementia in these patients manifests in slow thought processes and executive dysfunction, and problems with attention and performance.

Currently, there are no available therapies for slowing disease progression. Since the disease is marked by a disruption of the normal levels of certain neurotransmitters, in particular dopamine, glutamate and gamma-aminobutyric acid, the majority of available therapeutics aim to restore the levels of neurotransmitters to physiological (normal) levels.

The only U.S. Food and Drug Administration (FDA)-approved drugs for one of the most debilitating symptoms of Huntington’s disease – chorea (abnormal involuntary movement) — are Xenazine (tetrabenazine) and Austedo (deutetrabenazine). Another drug that also is used as therapy to reduce chorea is Symmetrel (amantadine).

As the disease progresses, chorea coexists with, and gradually is replaced by, symptoms of Parkinsonian features, such as bradykinesia (slow movement), rigidity, and postural instability. At this stage, other therapeutic options are considered and may include Levodopa.

“Considering the actual opportunities of treatment and the fact that none of these are really effective on the aetio-pathologic mechanism of HD, [it] seems to be urgent the development of new pharmacological strategies able to block the progression of this pathology should be considered,” authors wrote.

At the moment, there are a couple of natural compounds under investigation as potential therapies for Huntington’s. These include xyloketal B, a marine compound isolated from marine mangrove fungi and some synthetic derivatives. These molecules showed a protective effect in a worm (Caenorhabditis elegans) model of human HD. They are thought to interfere with the aggregation of the abnormal HTT protein.

Neferine, a compound isolated from the aquatic plant Indian lotus (Nelumbo nucifera) also may help remove the neurotoxic protein aggregates that underlie HD by activating an intracellular degradation pathway called autophagy.

More recent studies suggest that natural molecules targeting a class on enzymes (proteins) called caspases  also are a potential therapeutical strategy for HD. Caspases, particularly caspase-1 and caspase-3, have been linked to progression of neurodegenerative diseases. In fact, in animal models of HD, these enzymes were found to be highly active. As such, a set of small natural molecules – rosmarinic acid, curcumin, luteolin, huperzine A – are undergoing investigation as potential caspase inhibitors.

“Nature gives us the possibility to experiment with different structures that have a degree of complexity and heterogeneity which are difficult to obtain with a pure synthetic approach. For this reason, the use of natural compounds or natural derived molecules can lay the foundation for a new pharmacological approach for the treatment of these pathologies,” the authors concluded.