Molina-Holgado E, Vela JM, Arevalo-Martin A, Almazan G, Molina-Holgado F, Borrell J, Guaza CCannabinoids promote oligodendrocyte progenitor survival: involvement of cannabinoid receptors and phosphatidylinositol-3 kinase/Akt signaling. J Neurosci 22:9742-9753

Department of Neural Plasticity, Cajal Institute, Consejo Superior de Investigaciones Cientificas, 28002 Madrid, Spain.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 12/2002; 22(22):9742-53.
Source: PubMed


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.

Download full-text


Available from: Angel Arevalo-Martin,
  • Source
    • "The activation of CB receptors inhibits cAMP formation through its coupling to Gi proteins, resulting in decreased protein kinase A-(PKA-) dependent phosphorylation [7] [8]. CB receptors also couple to extracellular signal-regulated kinase (ERK) and specifically p42/p44 and p38 [2], participating in phosphatidylinositol 3-kinase (PI3K) and ceramide signaling [9]. Other receptors are also attached to the ECS like transient receptor potential cation channel subfamily V member 1 (TRPV-1), peroxisome proliferatoractivated receptors (PPARs), and non-CB1/CB2 G-proteincoupled receptors GPR55 [7, 8]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The endocannabinoid system is comprised of cannabinoid receptors (CB1 and CB2), their endogenous ligands (endocannabinoids), and proteins responsible for their metabolism participate in many different functions indispensable to homeostatic regulation in several tissues, exerting also antitumorigenic effects. The present study aimed to evaluate the clinical significance of CB1 and CB2 expression in human benign and malignant thyroid lesions. CB1 and CB2 proteins’ expression was assessed immunohistochemically on paraffin-embedded thyroid tissues obtained from 87 patients with benign ( n = 43 ) and malignant ( n = 44 ) lesions and was statistically analyzed with clinicopathological parameters, follicular cells’ proliferative capacity, and risk of recurrence rate estimated according to the American Thyroid Association (ATA) staging system. Enhanced CB1 and CB2 expression was significantly more frequently observed in malignant compared to benign thyroid lesions ( p = 0.0010 and p = 0.0005 , resp.). Enhanced CB1 and CB2 expression was also significantly more frequently observed in papillary carcinomas compared to hyperplastic nodules ( p = 0.0097 and p = 0.0110 , resp.). In malignant thyroid lesions, elevated CB2 expression was significantly associated with the presence of lymph node metastases ( p = 0.0301 ) . Enhanced CB2 expression was also more frequently observed in malignant thyroid cases with presence of capsular ( p = 0.1165 ) , lymphatic ( p = 0.1989 ) , and vascular invasion ( p = 0.0555 ) , as well as in those with increased risk of recurrence rate ( p = 0.1165 ) , at a nonsignificant level though, whereas CB1 expression was not associated with any of the clinicopathological parameters examined. Our data suggest that CB receptors may be involved in malignant thyroid transformation and especially CB2 receptor could serve as useful biomarker and potential therapeutic target in thyroid neoplasia.
    01/2015; 2015(22):1-7. DOI:10.1155/2015/839403
  • Source
    • "Exogenous administration of CBs has also been shown to be beneficial in several animal models of MS [150] [151] [152] [153] [154]. CBs have anti-inflammatory and neuroprotective activities as well as promote oligodendrocyte survival [121] [155]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The central nervous system (CNS) innate immune response includes an arsenal of molecules and receptors expressed by professional phagocytes, glial cells and neurons that is involved in host defence and clearance of toxic and dangerous cell debris. However, any uncontrolled innate immune responses within the CNS are widely recognized as playing a major role in the development of autoimmune disorders and neurodegeneration, with multiple sclerosis (MS) and Alzheimer's disease (AD) being primary examples. Hence, it is important to identify the key regulatory mechanisms involved in the control of CNS innate immunity and which could be harnessed to explore novel therapeutic avenues. Neuroimmune regulatory proteins (NIReg) such as CD95L, CD200, CD47, sialic acid, complement regulatory proteins (CD55, CD46, fH, C3a), HMGB1, may control the adverse immune responses in health and diseases. In the absence of these regulators, when neurons die by apoptosis, become infected or damaged, microglia and infiltrating immune cells are free to cause injury as well as an adverse inflammatory response in acute and chronic settings. We will herein provide new emphasis on the role of the pair CD200-CD200R in MS and its experimental models: experimental autoimmune encephalomyelitis (EAE) and Theiler's virus induced demyelinating disease (TMEV-IDD). The interest of the cannabinoid system as inhibitor of inflammation prompt us to introduce our findings about the role of endocannabinoids (eCBs) in promoting CD200-CD200 receptor (CD200R) interaction and the benefits caused in TMEV-IDD. Finally, we also review the current data on CD200-CD200R interaction in AD, as well as, in the aging brain.
    Current pharmaceutical design 01/2014; 20(29). DOI:10.2174/1381612820666140130202911 · 3.45 Impact Factor
  • Source
    • "MS therapy could therefore be founded on strategies aiming to reduce or slow down the demyelination and neurodegeneration processes, peculiar of this disease. The synthetic cannabinoid agonists HU210 or WIN 55212-2 protect oligodendrocytes from apoptosis induced by trophic elements deprivation, acting on both CB1 and CB2 receptors; they suppress the production of inflammatory molecules, like IL-1b, TNF-a and NO, by astrocytes and microglial cells (21, 22), as well as they enhance the release of anti-inflammatory cytokines IL-4, IL-10, IL-6 and interleukin-1 receptor antagonist (IL-1ra) (23, 24); finally, cannabinoid receptors activation has protective effects on neurons and oligodendrocytes and, attenuating pro-inflammatory mediators, suppresses chronic inflammatory responses. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background:Following the characterization of the chemical structure of D9-tetrahydrocannabinol (THC), the main psychoactive constituent of marijuana, researchers have moved on with scientific valuable explorations.Objectives:The aim of this review is to highlight the role of endocannabinoid system in neurodegenerative diseases.Materials and Methods:The article is a critical analysis of the most recent data currently present in scientific literature on the subject; a qualitative synthesis of only the most significant articles has been performed.Results:In central nervous system, endocannabinoids show a neuromodulatory function, often of retrograde type. This way, they play an important role in synaptic plasticity and in cognitive, motor, sensory and affective processes. In addition, in some acute or chronic pathologies of central nervous system, such as neurodegenerative and neuroinflammatory diseases, endocannabinoids can perform a pro-homeostatic and neuroprotective function, through the activation of CB1 and CB2 receptors. Scientific evidence shows that an hypofunction or a dysregulation of the endocannabinoid system may be responsible for some of the symptoms of diseases such as multiple sclerosis, amyotrophic lateral sclerosis, Huntington’s, Parkinson’s and Alzheimer’s diseases.Conclusions:The important role played by endocannabinoid system promises interesting developments, in particular to evaluate the effectiveness of new drugs in both psychiatry and neurology.
    12/2013; 2(3):100-106. DOI:10.5812/ijhrba.9222
Show more