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

A. B. El-Remessy, Y. Tang, G. Zhu, S. Matragoon, Y. Khalifa, E. K. Liu, J. Y. Liu, E. Hanson, S. Mian, N. Fatteh, Gregory I Liou

Research output: Contribution to journalArticle

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Abstract

Purpose: 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. Methods: Microglial cells were isolated from retinas of newborn rats. Tumor necrosis factor (TNF)-α 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. Results: 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-α 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 μM CBD inhibited ROS formation and p38 MAPK activation, NO and TNF-α 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)2190-2203
Number of pages14
JournalMolecular Vision
Volume14
StatePublished - Dec 3 2008

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Cannabidiol
Uveitis
Neuroprotective Agents
p38 Mitogen-Activated Protein Kinases
Endotoxins
Microglia
Reactive Oxygen Species
Nitric Oxide
Inflammation
Lipopolysaccharides
Oxidative Stress
Tumor Necrosis Factor-alpha
Retina
Anti-Inflammatory Agents
Luminol
Retinal Diseases
Retinal Degeneration
Cannabinoids
NADPH Oxidase
Luminescence

ASJC Scopus subject areas

  • Ophthalmology

Cite this

El-Remessy, A. B., Tang, Y., Zhu, G., Matragoon, S., Khalifa, Y., Liu, E. K., ... Liou, G. I. (2008). Neuroprotective effects of cannabidiol in endotoxin-induced uveitis: Critical role of p38 MAPK activation. Molecular Vision, 14, 2190-2203.

Neuroprotective effects of cannabidiol in endotoxin-induced uveitis : Critical role of p38 MAPK activation. / El-Remessy, A. B.; Tang, Y.; Zhu, G.; Matragoon, S.; Khalifa, Y.; Liu, E. K.; Liu, J. Y.; Hanson, E.; Mian, S.; Fatteh, N.; Liou, Gregory I.

In: Molecular Vision, Vol. 14, 03.12.2008, p. 2190-2203.

Research output: Contribution to journalArticle

El-Remessy, AB, Tang, Y, Zhu, G, Matragoon, S, Khalifa, Y, Liu, EK, Liu, JY, Hanson, E, Mian, S, Fatteh, N & Liou, GI 2008, 'Neuroprotective effects of cannabidiol in endotoxin-induced uveitis: Critical role of p38 MAPK activation', Molecular Vision, vol. 14, pp. 2190-2203.
El-Remessy AB, Tang Y, Zhu G, Matragoon S, Khalifa Y, Liu EK et al. Neuroprotective effects of cannabidiol in endotoxin-induced uveitis: Critical role of p38 MAPK activation. Molecular Vision. 2008 Dec 3;14:2190-2203.
El-Remessy, A. B. ; Tang, Y. ; Zhu, G. ; Matragoon, S. ; Khalifa, Y. ; Liu, E. K. ; Liu, J. Y. ; Hanson, E. ; Mian, S. ; Fatteh, N. ; Liou, Gregory I. / Neuroprotective effects of cannabidiol in endotoxin-induced uveitis : Critical role of p38 MAPK activation. In: Molecular Vision. 2008 ; Vol. 14. pp. 2190-2203.
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T2 - Critical role of p38 MAPK activation

AU - El-Remessy, A. B.

AU - Tang, Y.

AU - Zhu, G.

AU - Matragoon, S.

AU - Khalifa, Y.

AU - Liu, E. K.

AU - Liu, J. Y.

AU - Hanson, E.

AU - Mian, S.

AU - Fatteh, N.

AU - Liou, Gregory I

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N2 - Purpose: 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. Methods: Microglial cells were isolated from retinas of newborn rats. Tumor necrosis factor (TNF)-α 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. Results: 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-α 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 μM CBD inhibited ROS formation and p38 MAPK activation, NO and TNF-α 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. Conclusions: 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.

AB - Purpose: 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. Methods: Microglial cells were isolated from retinas of newborn rats. Tumor necrosis factor (TNF)-α 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. Results: 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-α 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 μM CBD inhibited ROS formation and p38 MAPK activation, NO and TNF-α 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. Conclusions: 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.

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