Deuterium‐reinforced linoleic acid lowers lipid peroxidation and mitigates cognitive impairment in the Q140 knock in mouse model of Huntington's disease

Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease which has no effective treatment and is characterized by psychiatric disorders, motor alterations, and dementia, with the cognitive deficits representing a devastating aspect of the disorder. Oxidative stress and elevated levels of lipid peroxidation (LPO) products are found in mouse models and patients with HD, suggesting that strategies to reduce LPO may be beneficial in HD. In contrast with traditional antioxidants, substituting hydrogen with deuterium at bis-allylic sites in polyunsaturated fatty acids (D-PUFA) decreases the rate-limiting initiation step of PUFA autoxidation, a strategy that has shown benefits in other neurodegenerative diseases. Here, we investigated the effect of D-PUFA treatment in a knock-in mouse model of HD (Q140) which presents motor deficits and neuropathology from a few months of age, and progressive cognitive decline. Q140 knock-in mice were fed a diet containing either D- or H-PUFAs for 5 months starting at 1 month of age. D-PUFA treatment significantly decreased F -isoprostanes in the striatum by approximately 80% as compared to H-PUFA treatment and improved performance in novel object recognition tests, without significantly changing motor deficits or huntingtin aggregation. Therefore, D-PUFA administration represents a promising new strategy to broadly reduce rates of LPO, and may be useful in improving a subset of the core deficits in HD.

Threshold protective effect of deuterated polyunsaturated fatty acids on peroxidation of lipid bilayers

“…The degree of protection of nondeuterated PUFAs thus correlates with the degree of deuteration, or the total number of –CD 2 – equivalents, present in the lipid bilayer. This useful property of D‐PUFAs justifies their evaluation as potential preventive and/or therapeutic agents for various diseases in which LPO has been implicated, as attested by ongoing and completed trials in neurological diseases as well as several positive studies in animal models . Lastly, the current study suggests applications of D‐PUFAs in liposome‐based drug delivery approaches , as both the drug vehicles, and the drugs to be delivered.…”

“…By incorporating deuterium atoms at the bis‐allylic sites of PUFAs (D‐PUFAs), they become resistant to LPO, without a change in their chemical structure (Scheme 1). A useful ‘non‐linear’ feature of this approach is that LPO in cells is inhibited even when the D‐PUFAs are present in membranes at relatively low (around 20 molar %) levels , making the approach more practical . The exact nature of the latter effect is not fully understood, but a possibility that various pathways in a living cell might play a role cannot be ruled out.…”

ALSUntangled No. 47: RT001

“…The slower lipid peroxidation of D-PUFA may lessen or interrupt some of the downstream cellular damage associated with oxidative stress (1). Cell culture studies and animal models of Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease support the idea that RT001 and other D-PUFAs decrease oxidative stress (1,(9)(10)(11)(12)(13)(14)(15)(16)(17), but we could not find experimental evidence that D-PUFAs were more potent in a biological context compared to most other antioxidants.…”

Is anti-ageing drug discovery becoming a reality?

“…In particular, aging is accompanied by the accumulation of toxic products of peroxidation of polyunsaturated fatty acids, which are involved in the development of various age-related diseases [17]. Deuterium-reinforced linoleic acid lowers lipid peroxidation and mitigates cognitive impairment in the mouse model of Huntington's disease [18]. A randomized clinical trial with dPUFA has also commenced for its use in patients with Friedreich's ataxia [19].…”