Authors:
De Filippis D, Esposito G, Cirillo C, Cipriano M, De Winter BY, Scuderi C, Sarnelli G, Cuomo R, Steardo L, De Man JG, Iuvone T.
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.