title: Isotopic reinforcement of essential polyunsaturated fatty acids diminishes nigrostriatal degeneration in a mouse model of Parkinson's disease.
abstract: Oxidative damage of membrane polyunsaturated fatty acids (PUFA) is thought to play a major role in mitochondrial dysfunction related to Parkinson's disease (PD). The toxic products formed by PUFA oxidation inflict further damage on cellular components and contribute to neuronal degeneration. Here, we tested the hypothesis that isotopic reinforcement, by deuteration of the bisallylic sites most susceptible to oxidation in PUFA may provide at least partial protection against nigrostriatal injury in a mouse model of oxidative stress and cell death, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model. Mice were fed a fat-free diet supplemented with saturated acids, oleic acid and essential PUFA: either normal, hydrogenated linoleic (LA, 18:2n-6) and α-linolenic (ALA, 18:3n-3) or deuterated 11,11-D2-LA and 11,11,14,14-D4-ALA in a ratio of 1:1 (to a total of 10% mass fat) for 6 days; each group was divided into two cohorts receiving either MPTP or saline and then continued on respective diets for 6 days. Brain homogenates from mice receiving deuterated PUFA (D-PUFA) vs. hydrogenated PUFA (H-PUFA) demonstrated a significant incorporation of deuterium as measured by isotope ratio mass-spectrometry. Following MPTP exposure, mice fed H-PUFA revealed 78.7% striatal dopamine (DA) depletion compared to a 46.8% reduction in the D-PUFA cohort (as compared to their respective saline-treated controls), indicating a significant improvement in DA concentration with D-PUFA. Similarly, higher levels of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were detected in MPTP-exposure mice administered D-PUFA; however, saline-treated mice revealed no change in DA or DOPAC levels. Western blot analyses of tyrosine hydroxylase (TH) confirmed neuroprotection with D-PUFA, as striatal homogenates showed higher levels of TH immunoreactivity in D-PUFA (88.5% control) vs. H-PUFA (50.4% control) in the MPTP-treated cohorts. In the substantia nigra, a significant improvement was noted in the number of nigral dopaminergic neurons following MPTP exposure in the D-PUFA (79.5% control) vs. H-PUFA (58.8% control) mice using unbiased stereological cell counting. Taken together, these findings indicate that dietary isotopic reinforcement with D-PUFA partially protects against nigrostriatal damage from oxidative injury elicited by MPTP in mice.
authors: Retrotope, Inc., Pre-Clinical and Pharmaceutical Development, Los Altos Hills, CA 94022, USA. misha@retrotope.com
authors: Mikhail S
authors: MS
authors: Shchepinov
authors: Vivian P
authors: VP
authors: Chou
authors: Erik
authors: E
authors: Pollock
authors: J William
authors: JW
authors: Langston
authors: Charles R
authors: CR
authors: Cantor
authors: Robert J
authors: RJ
authors: Molinari
authors: Amy B
authors: AB
authors: Manning-Boğ
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects*; D003903:Deuterium; D004195:Disease Models, Animal; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D019787:Linoleic Acid / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism; D019301:Oleic Acid / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000378:metabolism / Q000517:prevention & control*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000517:prevention & control*; D013378:Substantia Nigra / Q000187:drug effects*; D017962:alpha-Linolenic Acid / Q000494:pharmacology
chemical_list: D005231:Fatty Acids, Unsaturated; D017962:alpha-Linolenic Acid; D015102:3,4-Dihydroxyphenylacetic Acid; D019301:Oleic Acid; D019787:Linoleic Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D003903:Deuterium