Endocannabinoids in Inflammatory CNS Diseases in Dogs

Endocannabinoids (ECs) are lipids that bind to and activate the cannabinoid receptors CB1 and CB2, mimicking THC activity. They have immunomodulatory functions and regulate neurotransmission. ECs, along with their receptors and enzymes that control their synthesis and degradation, comprise the endocannabinoid system (ECS).

Anandemide (AEA), a CB1 agonist, and 2-arachidonoylglycerol (2-AG), a CB2 agonist, are the most bioactive and extensively studied ECs. They have immunomodulatory functions, including cell migration regulation.

CB1 receptors are expressed primarily on neurons and inhibit neurotransmitter release. CB2 receptors are highly expressed on immune cells and modulate cytokine release and cell migration. Interestingly, “many of the medicinal properties of cannabinoid compounds have been attributed to the CB2 receptor,” wrote the authors of a recent PLoS One publication on ECs in canine inflammatory CNS diseases.

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For their publication, the investigators examined the ECS in canine steroid-responsive meningitis-arthritis (SRMA) and intraspinal spirocercosis (IS). SRMA causes systemic vascular inflammation, particularly affecting the cervical leptomeninges, and IS is characterized by aberrant migration of the Spirocerca lupi nematode to the spinal cord.

The investigators retrospectively analyzed 41 CSF and 36 serum samples from client-owned dogs that had acute-stage SRMA (SRMA A), long-term prednisolone-treated SRMA (SRMA Tr), or were healthy (controls). Mass spectrometry quantified AEA and total AG (1-AG + 2-AG); the investigators noted that measuring total AG is often more accurate, in part because 2-AG spontaneously transforms into 1-AG. Immunohistochemistry measured CB2 expression in the inflammatory lesions and control samples.

Results

SMRA A CSF samples demonstrated neutrophilic pleocytosis, which is characteristic of SRMA A. IS CSF samples also had neutrophilic pleocytosis, along with moderate to severe eosinophilia.

EC Quantification

The investigators noted several important EC quantification findings:

• AEA and total AG concentrations were highest in the CSF and serum of dogs with IS and lowest in healthy dogs.
• EC concentrations were high in CSF samples with eosinophilic pleocytosis, suggesting ECs’ role in eosinophil migration to the CSF.
• AEA concentrations in the CSF were significantly higher in dogs with SRMA A than SRMA Tr.

CB2 Receptor Expression

In healthy dogs, CB2 was moderately to strongly expressed in the spleen (red pulp, white pulp, periarteriolar lymphoid sheath) and liver (hepatocytes, Kupffer cells). Within the spinal cord, CB2 expression was strong in glial cells but absent in the blood vessels and meninges.

In the spinal cord of dogs with inflammatory CNS disease, CB2 expression was strong on the cell surface of infiltrating leukocytes (ie, lymphocytes, plasma cells) and in glial cells near the inflammatory lesions. For SRMA, the investigators observed strong CB2 expression in the perivascular areas surrounding meningeal blood vessels. For IS, strongly CB2-positive leukocytes were located near parasites or parasite tracks. For both diseases, cytoplasmic CB2 expression was variably strong in the neurons of the dorsal and ventral horns.

Notably, CB2-positive glial cells in SRMA and IS samples underwent morphology changes, potentially due to astrogliosis or microglia activation.

Concluding Thoughts

The authors concluded that the ECS is upregulated in inflammatory CNS diseases in dogs, stating that “the development of new anti-inflammatory treatment strategies in canine CNS inflammation should involve the ECS.”

They also mentioned, though, that the ECS response depends on disease state and type. Progression of a neuroinflammatory disease, for example, may cause ECS dysregulation and a subsequent pro-inflammatory response due to CB2 overexpression and excessive EC production. “Thus,” the authors wrote, “both CB2 agonists and antagonists might be beneficial in counteracting the inflammatory consequences.”

Dr. Pendergrass received her Doctor of Veterinary Medicine degree from the Virginia-Maryland College of Veterinary Medicine. Following veterinary school, she completed a postdoctoral fellowship at Emory University’s Yerkes National Primate Research Center. Dr. Pendergrass is the founder and owner of JPen Communications, a medical communications company.