AV-101 Reduces Parkinson’s Dyskinesia Without Amantadine Side Effects, Preclinical Study Suggests

VistaGen Therapeutics’ candidate, AV-101, reduced levodopa-induced dyskinesia (abnormal involuntary movements) while maintaining levodopa activity in a non-human primate model of Parkinson’s disease.

Importantly, AV-101 treatment did not cause the adverse side effects observed with amantadine, a therapy that works similar to AV-101 to ease Parkinson’s symptoms.

Hallmark motor symptoms of Parkinson’s disease include tremor, slowness of movement (bradykinesia), stiffness (rigidity), jerky movements (dyskinesia) and poor balance. As the disease progresses, patients typically need to gradually increase treatment dose for maximum benefit. Even after that, symptoms sometimes reappear or worsen due to the dopaminergic therapy’s gradual loss of efficiency.

Dyskinesia is one of the complications of long-term levodopa therapy that affects many patients with advancing Parkinson’s. These sudden, involuntary movements can be treated with amantadine, which acts on a specific part of NMDA receptors — molecular structures involved in neuronal communication — in the brain.

Amantadine’s exact mechanism of action is not fully understood, but studies indicate it inhibits NMDA receptors and reduces the levels of a chemical messenger called acetylcholine, which increases dopamine activity and provides anti-parkinsonian effects.

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Nonetheless, the dose of amantadine needed to treat dyskinesia is often associated with side effects such as depression and cognitive impairment.

AV-101, developed by VistaGen, is an oral NMDA receptor antagonist that, unlike amantadine, acts on a different part of the receptor.

Researchers compared AV-101’s effectiveness to lower levodopa-induced dyskinesia to that of amantadine.

AV-101 was given to non-human primates that had been treated previously with MPTP, a neurotoxin that induces death of dopamine-producing neurons and mimics Parkinson’s symptoms.

AV-101 significantly reduced the abnormal, involuntary movements without affecting the timing, extent, or duration of the therapeutic benefits of levodopa.

“The antidyskinetic activity of AV-101 that we measured compares favorably with our observation with amantadine in parkinsonian monkeys,” Thérèse Di Paolo, PhD, one of the study’s authors, said in a press release.Di Paolo is on the faculty of pharmacy at Laval University in Quebec, Canada. Di Paolo is amongst the world’s leading researchers focused on Parkinson’s disease and levodopa-induced dyskinesia.

Importantly, the experimental therapy did not raise any safety concerns. “Better than amantadine, with its known side effects (in humans with Parkinson’s disease and in parkinsonian monkeys), we observed no adverse effects with AV-101,” Di Paolo said.

“We believe these preclinical data and AV-101’s positive safety profile in all clinical studies to date support AV-101’s potential to treat LID [levodopa-induced dyskinesia], while both maintaining the antiparkinsonian benefits of levodopa and without causing hallucinations or other serious side effects that may be associated with current amantadine-based therapy for LID,” noted H. Ralph Snodgrass, PhD, VistaGen’s chief scientific officer.

Scientists plan to present the preclinical results at an upcoming conference.