Summary: HU-308, a cannabinoid CB2-selective compound, reduces L-dopa–induced dyskinesia in a mouse model and may offer a non-psychoactive treatment option for Parkinson’s disease patients.
Source: University of Technology Sydney
Promising non-psychoactive drug candidate HU-308 may reduce involuntary movements associated with long-term Parkinson’s treatment.
Researchers report that HU-308, a compound that targets the cannabinoid CB2 receptor, can lessen the severe involuntary movements known as dyskinesias that often arise after long-term treatment with l-dopa, the primary therapy for Parkinson’s disease. The work was conducted by the Centre for Neuroscience and Regenerative Medicine (CNRM) at the University of Technology Sydney (UTS) in collaboration with the Applied Medical Research Institute of St Vincent’s Hospital Sydney.
Published in Neurobiology of Disease, the preclinical study shows that HU-308 reduced l-dopa–induced dyskinesia (LID) in mice as effectively as amantadine, the only drug currently approved and commonly used to treat dyskinesias. Notably, when HU-308 was combined with amantadine, the two drugs produced a stronger reduction in dyskinetic movements than either drug alone, suggesting a potential additive or synergistic effect.
Professor Bryce Vissel, director of the CNRM and senior author of the study, said the findings point to new therapeutic possibilities for Parkinson’s patients who develop dyskinesias during chronic l-dopa therapy.
“Our results indicate that a compound derived from HU-308 — used either on its own or together with amantadine — could provide a safer and potentially more effective treatment for dyskinesias than unregulated medicinal cannabis,” Professor Vissel said. “Cannabis preparations vary widely, and they act on multiple receptors in the brain, producing effects that may not always be beneficial in people with Parkinson’s disease.”
Cannabis exerts its effects primarily through two receptor types in the brain: CB1 and CB2. The psychoactive “high” associated with cannabis is largely mediated by CB1 receptor activation. HU-308, by contrast, is selective for the CB2 receptor. Because CB2 receptors are largely associated with immune cells and glia rather than the neuronal CB1 pathway, targeting CB2 has the potential to provide therapeutic benefits without the psychoactive side effects such as drowsiness or intoxication.
Lead author Dr Peggy Rentsch emphasized that HU-308 represents a prototype drug designed to harness the potential benefits of cannabinoid signaling while avoiding unwanted psychoactive effects.
“Medicinal cannabis contains a mix of compounds, some of which can impair day-to-day functioning,” Dr Rentsch said. “Our research indicates that HU-308 could reduce dyskinesias while preserving cognitive clarity and daily activity levels for patients.”
The research team is particularly interested in the relationship between neuroinflammation and movement disorders. Their data indicate that both HU-308 and amantadine, whether administered separately or together, reduce markers of striatal neuroinflammation in the mouse model. This supports the hypothesis that neuroinflammation and altered glial function contribute to the development of LID and that modulating inflammation through CB2 signaling can alleviate dyskinetic symptoms.
“HU-308 works by reducing inflammation in the brain, affecting the neurons and immune cells.”
Professor Vissel explained that in many neurological disorders immune cells in the brain can become activated by adverse stimuli — including injury, metabolic stress, or other insults — and instead of supporting neurons they can become harmful. “By reducing this inflammatory activation with a CB2-targeted agent like HU-308, these immune cells may return to a supportive role and preserve normal neural function,” he said.
Study collaborator Dr Sandy Stayte highlighted the clinical relevance of the findings, noting the limitations of current therapies. “Amantadine has its own side effect profile and may lose effectiveness over time, and yet it remains the only approved drug for dyskinesias. Showing that HU-308 is as effective as amantadine — and that a combination can be more effective — is an exciting advance. It suggests a path forward to a more powerful treatment option for patients with LID.”
Source:
University of Technology Sydney
Media Contacts:
Marea Martlew – University of Technology Sydney
Image Source:
The image is in the public domain.
Original Research: Open access
“Targeting the cannabinoid receptor CB2 in a mouse model of l-dopa induced Dyskinesia”. Bryce Vissel et al.
Neurobiology of Disease doi: 10.1016/j.nbd.2019.104646.
Abstract
Targeting the cannabinoid receptor CB2 in a mouse model of l-dopa induced Dyskinesia
L-dopa induced dyskinesia (LID) is a debilitating side effect of l-dopa, the primary treatment used in Parkinson’s disease (PD). In this study, researchers evaluated the effects of HU-308, a CB2 receptor agonist, on LID using a mouse model of PD and LID induced by 6-OHDA followed by l-dopa treatment. HU-308 reduced LID as effectively as amantadine, the current frontline treatment. Moreover, combined treatment with HU-308 and amantadine produced a greater anti-dyskinetic effect than HU-308 alone, suggesting a potential synergistic interaction. Treatment with HU-308 and amantadine, individually or combined, also decreased striatal neuroinflammation, a mechanism implicated in the development of LID. These results support further investigation of CB2 agonists as therapeutic candidates for LID in PD patients and reinforce the role of altered glial function and neuroinflammation in dyskinesia development.