Cannabinoids Promote Oligodendrocyte Progenitor Survival: Involvement of Cannabinoid Receptors and Phosphatidylinositol-3 Kinase/Akt Signaling

Abstract

Cannabinoids exert pleiotropic actions in the CNS, including the inhibition of inflammatory responses and the enhancement of neuronal survival after injury. Although cannabinoid receptors are distributed widely in brain, their presence has not been investigated previously in oligodendrocytes. This study examined the expression of cannabinoid type 1 (CB1) receptors in rat oligodendrocytes in vivo and in culture and explored their biological function. Expression of CB1 receptors by oligodendrocytes was demonstrated immunocytochemically in postnatal and in adult white matter as well as in oligodendrocyte cultures. Reverse transcription-PCR and Western blotting further confirmed the presence of CB1 receptors. Oligodendrocyte progenitors undergo apoptosis with the withdrawal of trophic support, as determined by TUNEL assay and caspase-3 activation, and both the selective CB1 agonist arachidonyl-2'-chloroethylamide/(all Z)-N-(2-cycloethyl)-5,8,11,14-eicosatetraenamide (ACEA) and the nonselective cannabinoid agonists HU210 and (+)-Win-55212-2 enhanced cell survival. To investigate intracellular signaling involved in cannabinoid protection, we focused on the phosphatidylinositol-3 kinase (PI3K)/Akt pathway. HU210, (+)-Win-55212-2, and ACEA elicited a time-dependent phosphorylation of Akt. Pertussis toxin abolished Akt activation, indicating the involvement of G(i)/G(o)-protein-coupled receptors. The CB1 receptor antagonist SR141716A partially inhibited Akt phosphorylation in response to HU210 and (+)-Win-55212-2 and abolished the effects of ACEA. Trophic support deprivation downregulated Akt activity, and cannabinoids recovered phospho-Akt levels. Inhibition of PI3K abrogated the survival action and the recovery of Akt activity in response to cannabinoids. SR141716A prevented only the protection conferred by ACEA. Nevertheless, SR141716A and the selective CB2 receptor antagonist SR144528 in combination inhibited the prosurvival action of HU210, which is in accordance with the finding of CB2 receptor expression by oligodendroglial cells. These data identify oligodendrocytes as potential targets of cannabinoid action in the CNS.

Cannabinoids and neuroinflammation

“…In mouse mixed glial cultures, HU210 and CP55940 increase LPS-induced production of IL-1 receptor antagonist, an anti-inflammatory cytokine that blocks the actions of IL-1b, and SR141716A and SR144528 lower this response . In oligodendrocytes, ACEA, HU210, and WIN55212-2 enhance cell survival, and these effects are sensitive to SR141716A, suggesting possible CB 1 receptor involvement (Molina-Holgado et al, 2002a).…”

“…These conflicting results may indicate variations in CB 1 receptor expression due to differences in species, culture systems, CNS structures from which cultures are derived, ages of cultures, or activation levels of cells; CB 2 receptor expression by astrocytes has not been found (Walter & Stella, 2003b). Oligodendrocytes, which undergo degeneration in MS and EAE (reviewed in Kornek & Lassman, 2003), also express CB 1 and CB 2 receptors (Molina-Holgado et al, 2002a).…”

Lithium regulates adult hippocampal progenitor development through canonical Wnt pathway activation

“…Although Wnt, insulin, integrins, growth factors like EGF or FGF and endocannabinoids [37][38][39][40] signal through GSK-3b, a distinguishing feature of the canonical Wnt pathway is that GSK-3b phosphorylates b-catenin, targeting it for degradation. Binding of Wnt to Frizzled receptors on the cell surface downregulates GSK-3b, thereby elevating intracellular bcatenin levels.…”

A pilot clinical study of Δ9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme

“…Remarkably, this antiproliferative effect seems to be selective for brain-tumour cells as the survival of normal brain cells (astrocytes (Gómez del Pulgar et al, 2002), oligodendrocytes (Molina-Holgado et al, 2002) and neurons ) is unaffected or even favoured by cannabinoid challenge. On the basis of these preclinical findings, we have conducted a pilot clinical study aimed at assessing cannabinoid antitumoral action in patients with recurrent glioblastoma multiforme.…”