Cannabidiol Reduces Intestinal Inflammation through the Control of Neuroimmune Axis

Abstract

Enteric glial cells (EGC) actively mediate acute and chronic inflammation in the gut; EGC proliferate and release neurotrophins, growth factors, and pro-inflammatory cytokines which, in turn, may amplify the immune response, representing a very important link between the nervous and immune systems in the intestine. Cannabidiol (CBD) is an interesting compound because of its ability to control reactive gliosis in the CNS, without any unwanted psychotropic effects. Therefore the rationale of our study was to investigate the effect of CBD on intestinal biopsies from patients with ulcerative colitis (UC) and from intestinal segments of mice with LPS-induced intestinal inflammation. CBD markedly counteracted reactive enteric gliosis in LPS-mice trough the massive reduction of astroglial signalling neurotrophin S100B. Histological, biochemical and immunohistochemical data demonstrated that S100B decrease was associated with a considerable decrease in mast cell and macrophages in the intestine of LPS-treated mice after CBD treatment. Moreover the treatment of LPS-mice with CBD reduced TNF-α expression and the presence of cleaved caspase-3. Similar results were obtained in ex vivo cultured human derived colonic biopsies. In biopsies of UC patients, both during active inflammation and in remission stimulated with LPS+INF-γ, an increased glial cell activation and intestinal damage were evidenced. CBD reduced the expression of S100B and iNOS proteins in the human biopsies confirming its well documented effect in septic mice. The activity of CBD is, at least partly, mediated via the selective PPAR-gamma receptor pathway. CBD targets enteric reactive gliosis, counteracts the inflammatory environment induced by LPS in mice and in human colonic cultures derived from UC patients. These actions lead to a reduction of intestinal damage mediated by PPARgamma receptor pathway. Our results therefore indicate that CBD indeed unravels a new therapeutic strategy to treat inflammatory bowel diseases.

The endocannabinoid system in inflammatory bowel diseases: from pathophysiology to therapeutic opportunity

“…Cannabidiol (CBD), present in Cannabis sativa, has antioxidant, anti-inflammatory, and immunomodulatory effects and is devoid of psychoactive properties [82]. It has very low affinity for CB 1 and CB 2 receptors and could exert part of its actions through a PPARg pathway [3,83]. CBD effectively reduces colon alterations in TNBS-and DNBS-induced colitis [56,84].…”

“…Moreover, CBD reduced nitrite production in vivo and oxidative stress in vitro in Caco-2 cells and in human colonic cultures derived from UC patients. This could be beneficial in this setting because oxidative stress is a tissue-destructive factor playing a role in IBD pathogenesis [56,83]. In another experiment, CBD potentiated the beneficial effects of D…”

Cannabinoid activation of peroxisome proliferator‐activated receptors: an update and review of the physiological relevance

“…O'Sullivan et al 35 O'Sullivan et al 35 O'Sullivan et al, 35 Esposito et al, 36 and De Filippis et al 37 …”

Phytotherapeutical implications in pain perception - focusing on schizophrenia

“…One of the conditions that has increased occurrence in schizophrenic disorder and that raises pain experiences encounters is irritable bowel syndrome [75]. There is evidence that this CBD, extracted from Cannabis sativa plant and also cannabingerol (CBG) extracted from the same plant could be used in the treatment of intestinal inflammation [76,77] and therefore in reducing pain phenomenon caused by this pathology. In addition, our group is also interested in testing pain perception in a rat model of irritable bowel syndrome, and is currently working on a special model of restraint stress-induced intestinal deficits [78] in pain perception and negative symptoms similar to the ones encountered in schizophrenia.…”

“…Because current results are in need of confirmation we are eager to engage in this controversial research. We present below several plants relevant for pain and/or schizophrenia in the Antihypertensive [51],hypoglycaemic [52], wound healing [53], anti-HIV [54], antidepressant [55], antihelmitic, aphrodisiac [56], treatment of diarrhea, urinary disorders and skin disorders [57] Cannabis sativa (Cannabaceae) cannabidiol (CBD) -neuropathic pain [68,70], inflammatory pain [68], cancer pain [71]; cannabingerol (CBG) -intestinal inflammation pain [76,77]; cannabinoids -cancer pain [71], rheumatoid arthritis pain [72], neuropathic orofacial pain [70]; THC(∆ 9 -tetrahydrocannabidiol) -cancer pain [71] CBDPharmacological profile similar to atypical antipsychotic [69], antipsychotic effect (86) hallucinogen proprieties [67]; ∆ 9 -tetrahydrocannabidiol (THC) -potential schizophrenia outcomes [87]; cannabinoidsimproves spasticity in MS patients [73]; CBDtreatment of intestinal inflammation [76,77] diuretic, anti-emetic, antiepileptic, anti-inflammatory, painkilling and antipyretic properties [97] Corydalis yanhuso (Papaveraceae) Antinociceptive effect in pain animal models, inflammatory pain relief amendment of neuropathic pain [93] anxiolytic properties [98]; primary dysmenorrhea [99]; improve the efficacy of chemotherapy [100]; extract -attenuated cardiac hypertrophy [101]; treatment of various pains [98], insomnia, reducing inflammation and several compounds present antidepressant, antimicrobial and anti-inflammatory activities [95], sedative, and hypnotic properties …”