Cannabinoid Receptor Type 2, but not Type 1, is Up-Regulated in Peripheral Blood Mononuclear Cells of Children Affected by Autistic Disorders

Abstract

Autistic disorders (ADs) are heterogeneous neurodevelopmental disorders arised by the interaction of genes and environmental factors. Dysfunctions in social interaction and communication skills, repetitive and stereotypic verbal and non-verbal behaviours are common features of ADs. There are no defined mechanisms of pathogenesis, rendering curative therapy very difficult. Indeed, the treatments for autism presently available can be divided into behavioural, nutritional and medical approaches, although no defined standard approach exists. Autistic children display immune system dysregulation and show an altered immune response of peripheral blood mononuclear cells (PBMCs). In this study, we investigated the involvement of cannabinoid system in PBMCs from autistic children compared to age-matched normal healthy developing controls (age ranging 3-9 years; mean age: 6.06 ± 1.52 vs. 6.14 ± 1.39 in autistic children and healthy subjects, respectively). The mRNA level for cannabinoid receptor type 2 (CB2) was significantly increased in AD-PBMCs as compared to healthy subjects (mean ± SE of arbitrary units: 0.34 ± 0.03 vs. 0.23 ± 0.02 in autistic children and healthy subjects, respectively), whereas CB1 and fatty acid amide hydrolase mRNA levels were unchanged. mRNA levels of N-acylphosphatidylethanolamine-hydrolyzing phospholipase D gene were slightly decreased. Protein levels of CB-2 were also significantly increased in autistic children (mean ± SE of arbitrary units: 33.5 ± 1.32 vs. 6.70 ± 1.25 in autistic children and healthy subjects, respectively). Our data indicate CB2 receptor as potential therapeutic target for the pharmacological management of the autism care.

Endocannabinoid Signaling in Autism

“…These drugs could potentially ameliorate the epilepsy-related symptoms that commonly co-occur with ASD. On a final note, it seems of major interest that preliminary data, showing consistency between changes in distinct eCB system elements (i.e., CB 2 ) in animal models of ASD and in peripherabl blood mononuclear cells from young patients with ASD [106,107], support a role for these elements in the (early) diagnosis of the disease. Future work should test expression profiles for key players of the eCB system in prospective samples to test the potential of these as diagnostic biomarkers.…”

“…Indeed, genomic studies have highlighted an upregulation of mRNA levels of the CB 2 A, but not the CB 2 B, isoform in the cerebellum of BTBR T+tF/ J mice [105], which have an autism-like behavioral phenotype [106]. Also, an independent clinical study performed on young (3-9-year-old) children demonstrated that CB 2 is highly expressed, both at transcriptional and translational levels, in peripheral blood mononuclear cells of patients with autism, compared with matched healthy controls [107]. All the other elements of the eCB system remained unaltered, except for a The reduced empathy is therefore a product of this reduced attention to social stimuli.…”

Endocannabinoid System as Novel Therapeutic Target for Autism Treatment

“…Accordingly, sulfation deficits in acetaminophen (paracetamol) metabolism with the autism population could indirectly increase the endocannabinoids levels, which in turn are able to activate CB1/2 receptors triggering autism. Endocannabinoid-CB2 signalling dysregulation has been reported in monocytic cells extracted from autistic children [2]. More interesting, blood monocyte-derived macrophagic cells from autistic patients also reveal EC system dysregulation, further indicating the involvement of the EC system in autism associated immunological disruptions and pointed to a potential nexus between endocannabinoids, vitamin D and the immune dysregulations observed with autism [8].…”

“…Recently, several studies highlight a key involvement of endocannabinoid (EC) system in autism pathophysiology [2].…”

“…Recently, several studies highlight a key involvement of endocannabinoid (EC) system in autism pathophysiology [2].Endocannabinoids are arachidonic acid derived compounds and together with their receptors and the associated enzymes, they the EC system, an intricate network of lipid signalling pathways [3]. The EC "building blocks" are the N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), that exerts their effects through the G-protein-coupled cannabinoid receptors CB1 and CB2, which, in turn, are negatively coupled to adenylate cyclase enzyme [4].…”