Golexanolone Eases Cognitive, Motor Symptoms in Parkinson’s Rat Model

Experimental therapy is being developed for hepatic encephalopathy, primary biliary cholangitis

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Golexanolone, an investigational small molecule from Umecrine Cognition, reversed cognitive and motor symptoms in a rat model of Parkinson’s disease, in addition to easing signs of fatigue, anxiety, and depression.

The experimental therapy is in clinical development for hepatic encephalopathy and primary biliary cholangitis, two conditions marked by toxic molecules accumulating that are thought to disrupt brain signaling and cause neuroinflammation.

The preclinical study was conducted in collaboration with Vicente Felipo, PhD, the director of the laboratory of neurobiology at Centro de Investigación Príncipe Felipe in Valencia, Spain.

“We are proud of our productive collaboration with Dr. Felipo and his renowned research group,” said Anders Karlsson, CEO of Umecrine, in a company press release. “The intriguing preclinical results announced today open new possibilities to expand the development of golexanolone from primary biliary cholangitis and hepatic encephalopathy into Parkinson’s disease, as well as other CNS [central nervous system] diseases that share similar underlying mechanisms.”

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CNS diseases are those that affect the brain and spinal cord.

Gamma-aminobutyric acid, or GABA, is one of the brain’s major signaling molecules that exerts its effects by binding to its receptors, GABAA and GABAB. While GABA signaling is critical for proper brain functioning, GABAA receptor over-activation can result in impairments to brain function, cognitive problems, and sedation.

An excess of GABA signaling is observed in the brains of Parkinson’s patients and animal models, which is thought to contribute to the mechanisms that drive Parkinson’s symptoms, according to Umecrine.

Golexanolone is a new small molecule that works by blocking neurosteroids, a type of molecule that binds to GABAA receptors and promotes their activity.

The therapy is expected to prevent the receptors from over-activating without completely blocking them, unlike traditional GABAA suppressors. Completely suppressing GABAA receptor activity can lead to serious side effects such as seizures and unconsciousness. Golexanolone may also ease neuroinflammation, another mechanism involved in Parkinson’s disease, researchers believe.

The treatment has been tested in more than 150 healthy volunteers and people with hepatic encephalopathy, in whom it’s proven safe and well tolerated.

Testing golexanolone on a Parkinson’s rat model

“We hypothesized that golexanolone, a well-tolerated GABAA receptor-modulating steroid [blocker] in clinical development, that reduces GABAA receptors’ activation and neuroinflammation, may improve some motor and non-motor deficits in a widely used model of Parkinson’s disease,” Felipo said.

Scientists used a rat model of Parkinson’s wherein a neurotoxin called 6-hydroxydopamine (6-OHDA) is injected directly into one side of an animal’s brain.

This standard model of the disease induces the selective death of dopamine-producing nerve cells, which are progressively lost in Parkinson’s patients, thereby driving hallmark Parkinson’s symptoms.

Compared with healthy animals, 6-OHDA-treated rats exhibited impairments in motor and cognitive function, and increased signs of fatigue, anxiety, and depression.

Golexanolone significantly eased short-term memory deficits and motor function problems, including coordination issues, according to Umecrine. It also significantly reversed increases in fatigue, anxiety, and anhedonia, which is a reduced ability to experience pleasure that’s thought to be a symptom of depression.

“Together, these results show that golexanolone treatment may be useful to improve a variety of the symptoms that severely affect the quality of life of the patients: anxiety and depression, fatigue, some aspects of motor coordination and of locomotor gait, and some aspects of cognitive function,” Felipo said.

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