Symptom‐relieving and neuroprotective effects of the phytocannabinoid Δ9‐THCV in animal models of Parkinson’s disease

Summary & key facts

In rats and mice that had brain lesions used to model Parkinson's disease, the plant compound Δ9-THCV reduced movement problems after a single dose and, with repeated dosing, reduced loss of dopamine-producing neurons in the brain region called the substantia nigra. Some effects seem linked to antioxidant actions and, in an inflammation-based mouse model, to activation of CB2 receptors. These results come from animal experiments and do not prove the same effects happen in people.

Key facts:

• Acute (single) intraperitoneal injection of Δ9-THCV at 2 mg·kg−1 reduced motor inhibition caused by 6-hydroxydopamine in rats.
• Chronic intraperitoneal treatment with Δ9-THCV at 2 mg·kg−1 for 14 days, started 16 hours after lesioning, reduced the loss of tyrosine hydroxylase–positive neurons in the rat substantia nigra caused by 6-hydroxydopamine.
• A cannabidiol (CBD)-enriched botanical extract (4.63 mg·kg−1, equivalent to 3 mg·kg−1 pure CBD) given for 14 days reproduced the neuron-preserving effect seen with chronic Δ9-THCV in the 6-hydroxydopamine rat model, suggesting an antioxidan
• In a mouse model where inflammation was induced by lipopolysaccharide (LPS), the substantia nigra showed stronger up-regulation of CB2 receptors, and chronic Δ9-THCV treatment preserved tyrosine hydroxylase–positive neurons in that model.
• The selective CB2 receptor agonist HU-308 (5 mg·kg−1) also preserved tyrosine hydroxylase–positive neurons in the LPS mouse model, supporting involvement of CB2 receptors in that setting.
• Mice genetically lacking CB2 receptors were more vulnerable to LPS lesions, and CB2-deficient mice responded to 6-hydroxydopamine in a similar way to wild-type mice, indicating differing roles for CB2 depending on the lesion type.
• Many experiments used groups of about 5–6 animals per group (n = 5–6), and reported differences reached conventional statistical significance (for example, P < 0.05 in the tests cited).
• The authors conclude that, because Δ9-THCV can block CB1 receptors, activate CB2 receptors, and has antioxidant properties, it has a pharmacological profile that could be promising for slowing disease processes and easing symptoms in Parkin

Abstract

Acute administration of Δ(9)-THCV attenuated the motor inhibition caused by 6-hydroxydopamine, presumably through changes in glutamatergic transmission. Moreover, chronic administration of Δ(9)-THCV attenuated the loss of tyrosine hydroxylase-positive neurones caused by 6-hydroxydopamine in the substantia nigra, through an effect related to its antioxidant properties (it was reproduced by cannabidiol -enriched botanical extract). In addition, CB(2) receptor-deficient mice responded to 6-hydroxydopamine in a similar manner to wild-type animals, and CB(2) receptors were poorly up-regulated in the rat substantia nigra in response to 6-hydroxydopamine. By contrast, the substantia nigra of mice that had been injected with LPS exhibited a greater up-regulation of CB(2) receptors. In these animals, Δ(9)-THCV also caused preservation of tyrosine hydroxylase-positive neurones. This effect probably involved CB(2) receptors as it was also elicited by the selective CB(2) receptor agonist, HU-308, and CB(2) receptor-deficient mice were more vulnerable to LPS lesions. CONCLUSIONS AND IMPLICATIONS Given its antioxidant properties and its ability to activate CB(2) but to block CB(1) receptors, Δ(9)-THCV has a promising pharmacological profile for delaying disease progression in PD and also for ameliorating parkinsonian symptoms.

Topics

Cannabis and Cannabinoid Research GABA and Rice Research Neuroscience and Neuropharmacology Research

Categories

Health Sciences Medicine Pharmacology

Tags

Agonist Cannabidiol Cannabinoid Cannabis Chemistry Disease Dopamine Endocrinology Hydroxydopamine Internal medicine Medicine Neurodegeneration Neuroprotection Parkinson's disease Pharmacology Psychiatry Receptor Substantia nigra Tyrosine hydroxylase