Early golexanolone treatment slows Parkinson’s progression in rats

Early treatment with the investigational small molecule golexanolone improved motor and cognitive function and eased signs of fatigue, anxiety, and depression in a rat model of Parkinson’s disease.

The Umecrine Cognition treatment also reduced neuroinflammation and improved dopamine levels, a study found. Golexanolone “could be considered for clinical evaluation in patients,” the researchers said.

“The mechanisms and effects reported here suggest that golexanolone treatment at early stages of Parkinson’s disease may delay disease progression and the need for L-DOPA treatment,” the researchers wrote. L-DOPA, or levodopa, is a mainstay of Parkinson’s treatment that alleviates motor symptoms by increasing dopamine levels.

Parkinson’s disease is caused by the progressive loss of dopaminergic neurons, nerve cells that produce dopamine. Dopamine is a neurotransmitter, a signaling molecule that neurons use to communicate, and its loss leads to Parkinson’s symptoms.

The study, “Golexanolone affords sustained improvement of Parkinson’s symptoms in rats by reducing microglia activation that restores the glutamate-GABA-dopamine pathway,” was published in Neuropharmacology.

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Golexanolone is designed to block neurosteroids, natural compounds that activate GABAA receptors in the brain. These receptors respond to the neurotransmitter GABA, and increased sensitivity of this system may contribute to Parkinson’s symptoms.

By reducing, but not shutting down, this excessive GABAA receptor activity, golexanolone aims to restore healthier brain signaling. The treatment may also help reduce neuroinflammation, another biological process linked to Parkinson’s progression.

In preclinical studies, golexanolone was shown to improve motor and nonmotor function in a rat model of Parkinson’s, including easing fatigue, anxiety, depression, and some cognitive changes, without causing dyskinesia. Dyskinesia refers to sudden, involuntary movements that may appear after long-term use of levodopa.

In this study, the researchers assessed the mechanisms underlying golexanolone’s beneficial effects and whether starting treatment early could lead to more positive long-term effects. They used a rat model of Parkinson’s in which a neurotoxin, called 6-hydroxydopamine (6-OHDA), is injected directly into one side of the brain, inducing the selective loss of dopaminergic neurons.

Compared with healthy animals, 6-OHDA-treated rats present motor and cognitive function impairments, and increased levels of fatigue, anxiety, and depressive-like behaviors.

The rats received golexanolone starting one week after 6-OHDA injection. The treatment improved motor coordination, walking patterns, and gait. It also reduced parameters related to slowed movements, freezing of gait, and rigidity, motor symptoms that severely affect quality of life.

Rats treated with golexanolone also showed a sustained reduction of fatigue and lack of movement, as well as improved cognitive function.

At the mechanistic level, treatment reduced the activation of microglia, the resident immune cells of the brain, which are involved in neuroinflammation. Golexanolone also increased dopamine levels and reduced GABAA receptor activation.

“Starting golexanolone treatment earlier, at 1 week after surgery, affords more beneficial effects, including a more sustained improvement of fatigue and of some aspects of motor function,” which were not improved in previous studies when treatment started later, the researchers said.

The treatment’s safety and tolerability are being assessed in a Phase 1/2 trial (EUCT 2024-515907-20-00) in people with the liver disease primary biliary cholangitis and clinically significant fatigue and cognitive symptoms, across eight European countries.