Abstract
Endocannabinoids (ECs) are involved in immunomodulation, neuroprotection and control of inflammation in the central nervous system (CNS). Activation of cannabinoid type 2 receptors (CB2) is known to diminish the release of pro-inflammatory factors and enhance the secretion of anti-inflammatory cytokines. Furthermore, the endocannabinoid 2-arachidonoyl glycerol (2-AG) has been proved to induce the migration of eosinophils in a CB2 receptor-dependent manner in peripheral blood and activate neutrophils independent of CB activation in humans. The aim of the current study was to investigate the influence of the endocannabinoid system in two different CNS inflammatory diseases of the dog, i.e. Steroid-Responsive Meningitis-Arteritis (SRMA) and Intraspinal Spirocercosis (IS). The two main endocannabinoids, anandamide (AEA) and 2-AG, were quantified by mass spectrometry in CSF and serum samples of dogs affected with Steroid- Responsive Meningitis-Arteritis in the acute phase (SRMA A), SRMA under treatment with prednisolone (SRMA Tr), intraspinal Spirocercosis and healthy dogs. Moreover, expression of the CB2 receptor was evaluated in inflammatory lesions of SRMA and IS and compared to healthy controls using immunohistochemistry (IHC). Dogs with SRMA A showed significantly higher concentrations of total AG and AEA in serum in comparison to healthy controls and in CSF compared to SRMA Tr (p<0.05). Furthermore, dogs with IS displayed the highest ECs concentrations in CSF, being significantly higher than in CSF samples of dogs with SRMA A (p<0.05). CSF samples that demonstrated an eosinophilic pleocytosis had the highest levels of ECs, exceeding those with neutrophilic pleocytosis, suggesting that ECs have a major effect on migration of eosinophils in the CSF. Furthermore, CB2 receptor expression was found in glial cells in the spinal cord of healthy dogs, whereas in dogs with SRMA and IS, CB2 was strongly expressed not only in glial cells but also on the cellular surface of infiltrating leukocytes (i.e. neutrophils, eosinophils, lymphocytes, plasma cells, and macrophages) at lesion sites. The present study revealed an upregulated endocannabinoid system in dogs with inflammatory CNS diseases, highlighting the endocannabinoid system as a potential target for treatment of inflammatory CNS diseases.
Highlights
In the last decades an increasing interest emerged in the use of derivatives of the plant Cannabis sativa and Cannabis indica commonly known as Marijuana to treat a variety of disorders both in humans and animals
All cerebrospinal fluid (CSF) samples in Steroid-Responsive Meningitis-Arteritis (SRMA) A and SRMA under treatment with prednisolone (SRMA Tr) and groups were obtained from the cerebellomedullary cistern
The present study revealed an upregulated endocannabinoid system in canines with inflammatory central nervous system (CNS) diseases, highlighting the endocannabinoid system as a potential target for treatment of inflammatory CNS diseases
Summary
In the last decades an increasing interest emerged in the use of derivatives of the plant Cannabis sativa and Cannabis indica commonly known as Marijuana to treat a variety of disorders both in humans and animals. One of the main reasons for such an effort is that numerous cannabinoids have potential medicinal effects lacking the psychoactive effects of some phytocannabinoids like Δ9–tetrahydrocannabinol (THC) [1, 2]. These compounds interact mainly with two receptors, cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2), which are expressed in several tissues in mammals [3] and together with their endogenous ligands (endocannabinoids) and the enzymes responsible for their synthesis and degradation constitute the endocannabinoid system [4, 5]. Endocannabinoids bind to local receptors only and are immediately inactivated under physiological conditions [12]
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