Gender-Specific Beneficial Effects of Docosahexaenoic Acid Dietary Supplementation in G93A-SOD1 Amyotrophic Lateral Sclerosis Mice.
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ABSTRACT:
SUBMITTER: Torres P
PROVIDER: S-EPMC7007454 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
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Gender-Specific Beneficial Effects of Docosahexaenoic Acid Dietary Supplementation in G93A-SOD1 Amyotrophic Lateral Sclerosis Mice.
Torres Pascual P Cacabelos Daniel D Pairada Jèssica J Bauer Kylynda C KC Boada Jordi J Fontdevila Laia L Rossi Chiara C Povedano Monica M Ferrer Isidre I Pamplona Reinald R Finlay B Brett BB Portero-Otín Manuel M Ayala Victòria V
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20200101 1
Docosahexaenoic acid (DHA) is an essential fatty acid modulating key nervous system functions, including neuroinflammation, and regulation of pre- and postsynaptic membrane formation. DHA concentration decreases in the lumbar spinal cord (LSC) of amyotrophic lateral sclerosis (ALS) patients and murine preclinical models. Using a dietary supplementation, we increased DHA levels (2% mean increase, p < 0.01) in the LSC of the familial ALS murine model B6SJL-Tg(SOD1*G93A)1Gur/J. This DHA-enriched di ...[more]
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Project description:Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease currently without a cure. Mutations in copper/zinc superoxide dismutase 1 (SOD1) have been implicated in the pathophysiology of this disease. Using a high-throughput screening assay expressing mutant G93A SOD1, two bioactive chemical hit compounds (1 and 2), identified as arylsulfanyl pyrazolones, were identified. The structural optimization of this scaffold led to the generation of a more potent analogue (19) with an EC(50) of 170nM. To determine the suitability of this class of compounds for further optimization, 1 was subjected to a battery of pharmacokinetic assays; most of the properties of 1 were good for a screening hit, except it had a relatively rapid clearance and short microsomal half-life stability. Compound 2 was found to be blood-brain barrier penetrating with a brain/plasma ratio=0.19. The optimization of this class of compounds could produce novel therapeutic candidates for ALS patients.
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