Anti-epilectic Compound Shows Neuroprotective Effects in ALS Worm Model, Study Reports

The active molecule of Petinutin (methsuximide), an anti-epileptic medication, eased motor deficits, extended the lifespan, and showed potent neuroprotective effects in a worm model of amyotrophic lateral sclerosis (ALS), suggesting a potential new treatment strategy for multiple neurodegenerative diseases, a study reports.

The study, “α-Methyl-α-phenylsuccinimide ameliorates neurodegeneration in a C. elegans model of TDP-43 proteinopathy,” appeared in the journal Neurobiology of Disease.

Neurodegenerative diseases such as ALS, Alzheimer’s, and Parkinson’s share features such as protein clumping and inflammation. These common features could potentially be targeted with more general therapeutic strategies, rather than the current disease-specific approaches, the study’s authors.

Recent research has shown that the anti-convulsant Zarontin (ethosuximide) prolonged the lifespan of a nematode worm model, while it also showed neuroprotective abilities in models of neurodegenerative diseases, including ALS. This protection was also seen in cell culture and rat models.

These results suggest that Zarontin may be useful for the treatment of multiple neurodegenerative diseases. However, it requires high doses in order to be effective in animal models, and the exact molecular pathway through which it works remains unknown.

To address these shortcomings, researchers at the University of Liverpool set out to find structurally similar compounds that showed therapeutic potential at lower concentrations while enabling the identification of molecular targets against neurodegeneration.

They selected compounds based on factors such as their ability to reach the brain by crossing the blood-brain barrier of a nematode worm model of ALS. They were then screened for their anticonvulsant properties, as well as for their neuroprotective ability, in the worm model.

The nematode worm Caenorhabditis elegans has been extensively used in the study of neurodegenerative disorders. Its short lifespan enables the quick assessment of neurodegeneration, while its simple nervous system and the relative ease of genetic manipulation allow for the creation of disease models. Additionally, because it is transparent, this worm enables the monitoring of fluorescently labeled neurons in vivo.

Results showed that alpha-methyl-alpha-phenylsuccinimide, or MPS, which is the active metabolite of Petinutin, an approved anti-epileptic medication, was the most potent compound. It eased locomotion deficits and prolonged the lifespan of the ALS worm model, while also protecting against neurodegeneration through a much lower concentration than ethosuximide.

Similar to reports for Zarontin, the findings suggested that the protective activity of MPS was delivered via a specific molecule participating in gene expression, called DAF-16, which has been associated with longevity.

“Our research has revealed a novel neuroprotective activity of MPS that is over 100 times more potent than ethosuximide,” Alan Morgan, PhD, the study’s lead author and a professor at the Institute of Translational Medicine at the University of Liverpool, said in a press release. “This discovery may have translational potential for the treatment of ALS and potentially other neurodegenerative diseases.”

“This increased potency will facilitate future biochemical studies to identify the direct molecular target(s) of both compounds,” the scientists wrote in the study.