Epilepsy Therapy Shows Neuroprotective Effects at Low Doses in Early Animal Study

An anticonvulsant medication called methsuximide may be a new approach for treating a neurodegenerative diseases that include Parkinson’s, because it shows a potential to be neuroprotective at low doses, early research reports.

Specifically, this epilepsy treatment’s active molecule — α-methyl-α-phenylsuccinimide — eased movement difficulties, extended lifespans, and showed itself to be neuroprotective in a worm model of neurodegeneration.

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

Global incidences of neurodegenerative diseases — such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis(ALS) — are expected to increase as populations worldwide age. But current therapies are rarely able to modify or slow the progression of these diseases.

Most drug development efforts are focused on treating each neurodegenerative disease individually, focusing on disease-related therapeutic targets. However, several processes are common across these diseases, such as protein accumulation and inflammation, making these processes possible common targets for treatments.

Caenorhabditis elegans, a type of worm, has been used by researchers to investigate neurodegenerative or age-related diseases for reasons that include its short-life span (three weeks) and simple nervous system allowing easy manipulation.

Recent chemical screens conducted in C. elegans disease models identified several compounds that demonstrate neuroprotective effects. Most of these have only been investigated in the context of a single disease, except for another antiepileptic treatment known as ethosuximide. This anticonvulsant, they noted, is still in use as a first-line treatment for children with absence seizures.

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Ethosuximide showed neuroprotective effects across multiple neurodegenerative C. elegans models, as well as with mammalian cells. But it is not very potent, and must be given at high doses to exert it such effects in worms and cells — meaning it’s unlikely to ever treat Parkinson’s or other neurodegenerative diseases.

Identifying a treatment’s target can also only be done by using a drug at very low doses — another likely reason, the researchers wrote, that ethosuximide’s molecular targets remain unknown despite it being prescribed for some 60 years.

The team instead screened 18 compounds structurally similar to ethosuximide, but with greater potency or efficacy so lower doses might be used.

Surprisingly, the researchers discovered a compound — α-methyl-α-phenylsuccinimide (MPS) — with far potency greater than that of ethosuximide with regard to neuroprotection, that also extended the lifespan from what is expected in a C. elegans neurodegenerative disease model.

“MPS is as effective as ethosuximide in ameliorating neurodegeneration despite being applied at a 160-fold lower external concentration,” they wrote.

MPS is the active compound of the antiepileptic therapy methsuximide, which is also used to treat absence seizures. Low doses of methsuximide could potentially treat people with Parkinson’s, ALS or other neurodegenerative diseases, the researchers said.

Additionally, its greater potency should allow future researchers to identify the direct molecular targets of both MPS and ethosuximide, as both these compounds share a common neuroprotective mechanism of action.

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