Up-regulation of CB2 receptors in reactive astrocytes in canine degenerative myelopathy, a disease model of amyotrophic lateral sclerosis

Abstract

Targeting of the CB2 receptor results in neuroprotection in the SOD1G93A mutant mouse model of amyotrophic lateral sclerosis (ALS). The neuroprotective effects of CB2 receptors are facilitated by their upregulation in the spinal cord of the mutant mice. Here, we investigated whether similar CB2 receptor upregulation, as well as parallel changes in other endocannabinoid elements, is evident in the spinal cord of dogs with degenerative myelopathy (DM), caused by mutations in the superoxide dismutase 1 gene (SOD1). We used well-characterized post-mortem spinal cords from unaffected and DM-affected dogs. Tissues were used first to confirm the loss of motor neurons using Nissl staining, which was accompanied by glial reactivity (elevated GFAP and Iba-1 immunoreactivity). Next, we investigated possible differences in the expression of endocannabinoid genes measured by qPCR between DM-affected and control dogs. We found no changes in expression of the CB1 receptor (confirmed with CB1 receptor immunostaining) or NAPE-PLD, DAGL, FAAH and MAGL enzymes. In contrast, CB2 receptor levels were significantly elevated in DM-affected dogs determined by qPCR and western blotting, which was confirmed in the grey matter using CB2 receptor immunostaining. Using double-labelling immunofluorescence, CB2 receptor immunolabelling colocalized with GFAP but not Iba-1, indicating upregulation of CB2 receptors on astrocytes in DM-affected dogs. Our results demonstrate a marked upregulation of CB2 receptors in the spinal cord in canine DM, which is concentrated in activated astrocytes. Such receptors could be used as a potential target to enhance the neuroprotective effects exerted by these glial cells.

Pharmacokinetics of Sativex® in Dogs: Towards a Potential Cannabinoid-Based Therapy for Canine Disorders

“…Given the interest to evaluate whether this phytocannabinoid-based medicine has beneficial effects on different central and peripheral canine disorders, the pharmacokinetic profile of Sativex, when administered via sublingual delivery to naïve dogs, has been determined. This may help to determine the best dosage and timing for the future evaluation of Sativex in dogs affected by different pathologies (e.g., osteoarthritis [19], atopic dermatitis [20], epilepsy [21], degenerative myelopathy [22], some neuroinflammatory diseases (meningitis-asteritis and intraspinal spirocercosis) [23], and others [24]), although the effect that different pathologies may have on Sativex pharmacokinetics remains unknown.…”

“…It may also serve in Veterinary Medicine for the treatment of domestic animals, in particular for dogs affected by different pathological conditions. This may include pathologies as osteoarthritis [19], atopic dermatitis [20], epilepsy [21], degenerative myelopathy [22], some neuroinflammatory diseases (meningitis-asteritis and intraspinal spirocercosis) [23], and others [24]. It is important to remark that the information collected in studies with dogs with these pathologies is not only important for the development of Sativex in Veterinary Medicine but also for their equivalents in the human pathologies, thus representing suitable translational models for studying specific human pathologies.…”

Retrospective Observational Study and Analysis of Two Different Photobiomodulation Therapy Protocols Combined with Rehabilitation Therapy as Therapeutic Interventions for Canine Degenerative Myelopathy

“…One recent study has investigated changes in endocannabinoid elements, which could serve as a first step in the development of cannabinoid therapy for both dogs with DM and possibly, people with ALS. 74 Although this study was not prospective and limited by small sample size(s) and the inability to obtain postmortem histopathology on all dogs included in this study, it does suggest a possible beneficial effect of utilizing PTCL-B PBMt in combination with an intense rehabilitation therapy regimen. Absent effective therapies for DM, the challenges with preclinical trials for ALS, and the poor translation of success of novel neuroprotective therapeutics from small laboratory animal models to companion size animals and humans, PBMt combined with intense rehabilitation therapy should be considered for the palliative treatment of dogs suspected of being affected by DM, and may be an avenue for future research into therapy for humans with ALS.…”

Targeting glial cannabinoid CB2 receptors to delay the progression of the pathological phenotype in TDP‐43 (A315T) transgenic mice, a model of amyotrophic lateral sclerosis

“…This response has been currently found to occur in most neurodegenerative disorders (reviewed in Fernández‐Ruiz et al ., ; ), including ALS, for example, in postmortem ALS tissues (Yiangou et al ., ). Furthermore, an up‐regulation of CB 2 receptors has also been found in reactive astrocytes in mutant SOD1 mice (Espejo‐Porras et al ., unpublished results) and in canine ALS, so‐called degenerative myelopathy, which is also dependent on mutant SOD1 (Fernández‐Trapero et al ., ). This up‐regulation of glial CB 2 receptors appears to be of great interest from a pharmacological point of view.…”