An international group of scientists from the University of Liverpool and the University of Washington Department of Medicine has identified a novel compound — called α-methyl-α-phenylsuccinimide (MPS) — that protects against neurodegeneration in nematode worms Caenorhabditis elegans. The results appear in the journal Neurobiology of Disease.
MPS is a novel neuroprotective molecule that is more than two orders of magnitude more potent than the related molecule, ethosuximide. The discovery may enable novel treatments for human neurodegenerative diseases to be developed in the future. Image credit: National Institute on Aging / National Institutes of Health.
With the predicted growth of the global aging population, cases of age-associated neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis are expected to rise.
However, most current therapies do not decelerate or modify disease, and efforts to develop new treatments have been met with high attrition rates.
The antiepileptic drug ethosuximide has recently been shown to protect against neurodegeneration in various C. elegans and rodent models.
It is therefore a promising repurposing candidate for the treatment of multiple neurodegenerative diseases.
However, high concentrations of the drug are required for its protective effects in animal models, which may limit its translational potential and impede the identification of its molecular mechanism of action.
University of Liverpool’s Professor Alan Morgan and co-authors set out to develop more potent neuroprotective compounds based on ethosuximide.
“Chemoinformatic approaches were used to identify compounds with structural similarity to ethosuximide and to prioritize these based on good predicated blood-brain barrier permeability and C. elegans bioaccumulation properties,” they said.
“Selected compounds were initially screened for anti-convulsant activity in C. elegans, and then assessed for neuroprotective properties.”
“The most potent compound screened, MPS, ameliorated the locomotion defects and extended the shortened lifespan of the worms.”
“MPS also directly protected against neurodegeneration by reducing the number of neuronal breaks and cell body losses in motor neurons.”
MPS is chemically similar to ethosuximide, but is 100-fold more potent, according to the team.
“This discovery may have translational potential for the treatment of amyotrophic lateral sclerosis and potentially other neurodegenerative diseases,” Professor Morgan said.
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Shi Quan Wong et al. 2018. α-Methyl-α-phenylsuccinimide ameliorates neurodegeneration in a C. elegans model of TDP-43 proteinopathy. Neurobiology of Disease 118: 40-54; doi: 10.1016/j.nbd.2018.06.013
