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Treatment With AZD0328, Nicotine Loses Effectiveness as Parkinson’s Progresses, Study Shows

AZD0328 and Parkinson's

 

AZD0328 and nicotine, two nicotinic receptor agonists, lose their effectiveness in treating involuntary muscle movements as a consequence of long-term levodopa treatment throughout the course of Parkinson’s disease, a mouse study finds.

The study, “Dyskinesia and brain-derived neurotrophic factor levels after long-term levodopa and nicotinic receptor agonist treatments in female mice with near-total unilateral dopaminergic denervation,” was published in BMC Neuroscience.

The main cause of the motor symptoms in Parkinson’s disease is a lack of dopamine — a brain chemical — resulting from a loss of dopaminergic neurons in the substantia nigra, a brain area responsible for controlling voluntary muscle movements.

Levodopa, a dopamine replacement therapy, is often recommended to ease Parkinson’s symptoms. However, levodopa can have multiple side effects, including involuntary muscle movements, also known as levodopa-induced dyskinesia (LID).

Previous studies have shown that treatment with nicotinic acetylcholine receptor (nAChRs) agonists alleviate LID in different animal models of disease. However, it is still not clear whether treatment with nAChRs is effective once dopamine-producing neurons have been destroyed. nAChRs are a type of receptors found in nerve cells that control the transmission of electrical signals.

Studies have also suggested that high levels of brain-derived neurotrophic factor (BDNF) — a protein whose main function is to protect dopaminergic neurons — could be linked to LID.

Now, researchers from the University of Helsinki tested the effectiveness of AZD0328 and nicotine, two different nAChR agonists, in female mice that developed LID after long-term treatment with levodopa.

At the beginning of the experiments, animals were injected with oxidopamine — a neurotoxin that destroys dopamine-producing neurons — on one side of the brain (damaging only one brain hemisphere) to mimic the loss of dopaminergic neurons associated with Parkinson’s disease. A month later, mice started treatment with levodopa (6 mg/kg) that lasted until the end of the experiments.

After treatment with nAChR agonists, BDNF levels were measured in two regions of the brain: the prefrontal cortex and striatum. The prefrontal cortex is a region responsible for higher thought processes, such as decision making, planning and reasoning, while the striatum is involved in motor coordination.

Findings revealed that five-day treatment with increasing doses of AZD0328 (from 0.03 mg/kg to 1.0 mg/kg) failed to alleviate LID in these animals. The same was observed in mice treated with nicotine for 10 weeks.

No difference in BDNF levels between the lesioned and intact brain hemispheres was observed in either brain area. BDNF levels in the lesioned striatum were linked to higher LID severity.

“The observed correlation between BDNF and LID represents further evidence for a role for BDNF in LID,” researchers said. “However, the present findings do not directly support the hypothesis that LID is caused by a levodopa-induced elevation of corticostriatal BDNF that is further enhanced in conditions of dopaminergic denervation [loss].”

Nicotine treatment successfully decreased BDNF levels in the prefrontal cortex, but failed to do so in the striatum.

Altogether, these findings suggest that “a partially intact” dopaminergic circuitry seems to be required for the effectiveness of nAChR agonists in the treatment of LID and that “nAChR agonists may lose [their] effectiveness as the disease progresses.”

“These findings may be important to account for when drafting potential future strategies for the treatment of late-stage Parkinson’s disease with nAChR ligands,” researchers concluded.

The post Treatment With AZD0328, Nicotine Loses Effectiveness as Parkinson’s Progresses, Study Shows appeared first on Parkinson's News Today.

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