Rat study targets levodopa-induced dyskinesia

Experimental molecule ONO-2506 used to regulate astrocytes

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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An experimental molecule called ONO-2506 was found to reduce the occurrence of abnormal movements — dyskinesia — resulting from early levodopa treatment without compromising levodopa’s therapeutic effects in a rat model of Parkinson’s disease.

The mechanisms by which ONO-2506 was able to ease levodopa-induced dyskinesia (LID) appeared to involve the regulation of astrocytes, a type of nerve support cell, and clearance of the glutamate-signaling chemical in cells via specialized transporters.

“Interventions targeting astrocytes and glutamate transporters may be potential therapeutic targets for LID to delay the occurrence and development of LID,” the authors wrote. “Our findings provide new insights into the prevention and management of LID in patients with [Parkinson’s].”

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The study, “ONO-2506 Can Delay Levodopa-induced Dyskinesia in the Early Stage,” was published in Neuroscience.

Levodopa therapy is the mainstay treatment for Parkinson’s disease. It works to replace the brain’s supply of dopamine, the signaling chemical that’s progressively lost in Parkinson’s as the nerve cells that produce it die.

While its very effective at managing the motor symptoms of Parkinson’s disease, many patients will develop certain motor complications, such as LID, with long-term treatment.

The mechanisms underlying LID aren’t well-established, and treatments for it remain limited.

Research suggests that astrocytes, a type of star-shaped cell that supports the health of nerve cells, may play a role in Parkinson’s disease and developing LID. In animal models of LID, astrocyte activity is elevated significantly, and the cells produce more inflammatory factors, according to the authors.

ONO-2506 is a molecule designed to regulate astrocyte activity in response to injury. In preclinical studies, it’s been found to limit inflammatory changes in astrocytes and boost their ability to clear glutamate, a signaling molecule that becomes toxic to nerve cells when it is too abundant.

Reducing severity of levodopa-induced dyskinesia

Now, the researchers investigated whether ONO-2506 could reduce the severity of LID in a rat model via its ability to regulate astrocytes and clear glutamate.

Rats with experimentally induced Parkinson’s disease were treated daily with ONO2506 or a placebo, delivered directly into the brain, followed by an injection of levodopa into the abdominal cavity an hour later.

The animals then were monitored for dyskinesias and motor behavior for about a week.

Animals with induced Parkinson’s disease exhibited motor deficits and a loss of dopamine-producing cells in the brain. As expected, levodopa treatment was associated with improvements in motor function for the rats.

ONO-2506 did not affect motor function in the rat model, or influence the beneficial effects of levodopa.

It did, however, delay the emergence of abnormal involuntary movements associated with levodopa treatment, in addition to lessening their severity after five days of treatment compared with rats given a placebo.

“These results suggest that astrocyte intervention may be a potential therapeutic target for LID and can be used to delay the occurrence and progression of LID,” the researchers wrote.

With repeated daily administration, the gap in LID severity between the ONO-2506 and placebo groups gradually narrowed. More work will be needed to understand the long-term effects of the therapy, the researchers noted.

An analysis of brain tissue revealed that ONO-2506 significantly increased levels of glial fibrillary acidic protein (GFAP), a marker of astrocyte activation, relative to placebo.

Other inflammatory markers remained unchanged with ONO-256 treatment.

Moreover, the therapy was associated with elevated levels of GLT-1, a transporter protein that astrocytes use to clear excessive glutamate from the space surrounding cells.

Overall, the team believes the findings mean that glutamate clearance could be critical for easing LID in Parkinson’s.

Notably, the elevations in GLT-1 were most significant after four days, around the time that ONO-2506 was associated with the most significant reductions in LID.

Levels of the protein had declined slightly by day 8, when the therapy’s effects on LID also were less pronounced.

“We could not determine the reason behind the decline in the therapeutic effect of ONO-2506 … hence further investigations remain warranted,” the team noted.