Article

Neuroprotective effects of cannabidiol in endotoxin-induced uveitis: Critical role of p38 MAPK activation

Department of Ophthalmology, Medical College of Georgia, Augusta, GA 30912, USA.
Molecular vision (Impact Factor: 2.25). 02/2008; 14:2190-203.
Source: PubMed

ABSTRACT Degenerative retinal diseases are characterized by inflammation and microglial activation. The nonpsychoactive cannabinoid, cannabidiol (CBD), is an anti-inflammatory in models of diabetes and glaucoma. However, the cellular and molecular mechanisms are largely unknown. We tested the hypothesis that retinal inflammation and microglia activation are initiated and sustained by oxidative stress and p38 mitogen-activated protein kinase (MAPK) activation, and that CBD reduces inflammation by blocking these processes.
Microglial cells were isolated from retinas of newborn rats. Tumor necrosis factor (TNF)-alpha levels were estimated with ELISA. Nitric oxide (NO) was determined with a NO analyzer. Superoxide anion levels were determined by the chemiluminescence of luminol derivative. Reactive oxygen species (ROS) was estimated by measuring the cellular oxidation products of 2', 7'-dichlorofluorescin diacetate.
In retinal microglial cells, treatment with lipopolysaccharide (LPS) induced immediate NADPH oxidase-generated ROS. This was followed by p38 MAPK activation and resulted in a time-dependent increase in TNF-alpha production. At a later phase, LPS induced NO, ROS, and p38 MAPK activation that peaked at 2-6 h and was accompanied by morphological change of microglia. Treatment with 1 microM CBD inhibited ROS formation and p38 MAPK activation, NO and TNF-alpha formation, and maintained cell morphology. In addition, LPS-treated rat retinas showed an accumulation of macrophages and activated microglia, significant levels of ROS and nitrotyrosine, activation of p38 MAPK, and neuronal apoptosis. These effects were blocked by treatment with 5 mg/kg CBD.
Retinal inflammation and degeneration in uveitis are caused by oxidative stress. CBD exerts anti-inflammatory and neuroprotective effects by a mechanism that involves blocking oxidative stress and activation of p38 MAPK and microglia.

0 Followers
 · 
129 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The p38 mitogen-activated protein kinase (MAPK) isoforms are phosphorylated by a variety of stress stimuli in neurodegenerative disease and act as upstream activators of myriad pathogenic processes. Thus, p38 MAPK inhibitors are of growing interest as possible therapeutic interventions. Axonal dysfunction is an early component of most neurodegenerative disorders, including the most prevalent optic neuropathy, glaucoma. Sensitivity to intraocular pressure at an early stage disrupts anterograde transport along retinal ganglion cell (RGC) axons to projection targets in the brain with subsequent degeneration of the axons themselves; RGC body loss is much later. Here we show that elevated ocular pressure in rats increases p38 MAPK activation in retina, especially in RGC bodies. Topical eye-drop application of a potent and selective inhibitor of the p38 MAPK catalytic domain (Ro3206145) prevented both the degradation of anterograde transport to the brain and degeneration of axons in the optic nerve. Ro3206145 reduced in the retina phosphorylation of tau and heat-shock protein 27, both down-stream targets of p38 MAPK activation implicated in glaucoma, as well as well as expression of two inflammatory responses. We also observed increased p38 MAPK activation in mouse models. Thus, inhibition of p38 MAPK signaling in the retina may represent a therapeutic target for preventing early pathogenesis in optic neuropathies.
    Neurobiology of Disease 07/2013; 59. DOI:10.1016/j.nbd.2013.07.001 · 5.20 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: An accumulating body of evidence suggests that endocannabinoids and cannabinoid receptors type 1 and 2 (CB1, CB2) play a significant role in physiologic and pathologic processes, including cognitive and immune functions. While the addictive properties of marijuana, an extract from the Cannabis plant, are well recognized, there is growing appreciation of the therapeutic potential of cannabinoids in multiple pathologic conditions involving chronic inflammation (inflammatory bowel disease, arthritis, autoimmune disorders, multiple sclerosis, HIV-1 infection, stroke, Alzheimer's disease to name a few), mainly mediated by CB2 activation. Development of CB2 agonists as therapeutic agents has been hampered by the complexity of their intracellular signaling, relative paucity of highly selective compounds and insufficient data regarding end effects in the target cells and organs. This review attempts to summarize recent advances in studies of CB2 activation in the setting of neuroinflammation, immunomodulation and HIV-1 infection.
    Journal of Neuroimmune Pharmacology 03/2013; DOI:10.1007/s11481-013-9445-9 · 3.17 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cannabidiol (CBD), a nonpsychotropic, nontoxic compound has been shown to block diabetes- and endotoxin-induced retinal damage. However, the protective mechanism of this anti-inflammatory cannabinoid is not completely understood. The goal of this study is to determine the role of adenosine signaling in retinal inflammation and its potential modulation by CBD. The adenosine receptor (AR) subtypes expressed in rat retinal microglial cells were assessed by quantitative real-time RT-PCR. AR function was determined via in vitro and in vivo inflammatory models. Microglial cells or rats were treated with or without lipopolysaccharide (LPS) in the presence or absence of adenosine, adenosine receptor agonists/antagonists, or CBD. Adenosine uptake and tumor necrosis factor (TNF)-alpha release in cells or in retinas were determined. The results showed that A(2A)ARs are abundantly expressed in rat retinal microglial cells. When the cells or rats were treated with LPS, activation of the A(2A)AR was the most efficient in mediating AR agonist- or CBD-induced TNF-alpha inhibition. CBD inhibited adenosine uptake via equilibrative nucleoside transporter 1 and synergistically enhanced adenosine's TNF-alpha suppression after treatment with LPS. These results suggest that the activated A(2A)AR in the retinal microglial cells plays a major anti-inflammatory role in the retina and that CBD's anti-inflammatory effects are linked to the inhibition of adenosine uptake.
    Investigative ophthalmology & visual science 12/2008; 49(12):5526-31. DOI:10.1167/iovs.08-2196 · 3.66 Impact Factor