Short-term use of NSI-189 Aids Cognitive and Motor Skills in Angelman Mouse Model, Study Says

Short-term use of NSI-189 Aids Cognitive and Motor Skills in Angelman Mouse Model, Study Says

Short-term treatment with Neuralstem‘s NSI-189 reversed cognitive and motor impairments in a mouse model of Angelman syndrome, according to study results.

This early finding could help to pave the way for this compound, in Phase 2 study for major depressive disorder and seen in an earlier trial to be safe in people, to become a treatment for Angelman patients.

The study, “Enhancement of synaptic plasticity and reversal of impairments in motor and cognitive functions in a mouse model of Angelman Syndrome by a small neurogenic molecule, NSI189,” was published in Neuropharmacology.

Angelman syndrome is caused by the loss or malfunction of the maternal copy of the UBE3A gene in neurons in specific brain regions. This gene provides instructions to make an enzyme called ubiquitin protein ligase E3A (UBE3A), which normally targets other proteins to be destroyed.

The exact mechanisms involved in the disease’s cognitive and motor impairments are not fully understood. One hypothesis to explain these symptoms is the occurrence of alterations in synaptic plasticity caused by the loss of maternal UBE3A.

Synaptic plasticity is the ability of synapses (the point of contact between two neurons) to strengthen or weaken over time, in response to high or low neuronal activity.

NSI-189, a compound that has been found to stimulate synaptic plasticity, is currently under development to possibly treat major depressive disorder; it was seen as safe, tolerable and able to improve patients’ cognition in a previous Phase 1 trial (NCT01520649) in people with major depressive disorder and is now in a Phase 2 study (NCT02695472).

Researchers at the Western University of Health Sciences tested the compound’s potential to treat Angelman syndrome in a mouse model of the disease.

Brain slices from healthy control animals were incubated with NSI-189, and results showed a time- and dose-dependent improvement in synaptic strengthening and neuronal transmission (long-term potentiation, LTP). The same effect was observed in mice lacking one copy of the UBE3A gene.

Daily injections of NSI-189 administered for a period of 16 days successfully restored cognitive and motor impairments in the diseased mice, and slightly improved performance in healthy animals used as controls.

“[I]mpairment in motor function was reversed within days of injection with NSI-189 and the rescue lasted for several weeks after the end of treatment,” the researchers wrote. “Since NSI-189 has a very short half-life (2 h in the mouse) the results indicate that these reversal effects are the consequences of long-lasting modifications of synaptic functions triggered by NSI-189.”

Mechanistically, the positive effects of NSI-189 on synaptic plasticity, cognitive and motor functions seemed to be linked with the activation of the TrkB and Akt signaling pathways, which are thought to regulate synaptic plasticity.

“[O]ur results indicate that NSI-189 by stimulating mechanisms implicated in synaptic plasticity can reverse impairment of cognitive and motor functions in adult AS [Angelman syndrome] mice,” the researchers wrote.

“These results suggest that NSI-189 could provide a new therapeutic approach for the treatment of several symptoms of AS in humans,” they added.

The team emphasized that further studies are needed to test if, indeed, NSI-189’s effect can be disease-modifying.

Leave a Comment

Your email address will not be published. Required fields are marked *