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E.K. Liu, Y. Khalifa, M. Al–Shabrawey, S. Liu, R.B. Caldwell, G.I. Liou; Anti–Inflammatory Effects of Cannabinoids in Endotoxin–Induced Uveitis . Invest. Ophthalmol. Vis. Sci. 2005;46(13):972.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Uveitis is a common disease caused by a variety of traumatic or immunogenic insults which may lead to profound and irreversible vision loss. In most cases, uveitis can be treated by corticosteroids or immunosuppressants. However, due to their severe side effects, new treatment options must be explored. Endotoxin–induced uveitis (EIU), a common animal model for clinical uveitis, is characterized by inflammation and apoptosis resulting from cytokine release, especially tumor necrosis factor alpha (TNF–α). Cannabidiol (CBD), a major non–psychotropic cannabinoid, exhibits anti–inflammatory properties through the modulation of cytokines. The purpose of this study is to evaluate the effects of CBD and WIN55.212–2 (a synthetic cannabinoid receptor agonist) on TNF– α, apoptotic cell death, and intracellular signaling pathways induced by EIU in the rat retina. Methods: Long–Evans rats were pre–treated with CBD, WIN55.212–2, or vehicle. The WIN55.212–2 group was further divided by SR141716 or SR144528 (CB1 and CB2 receptor antagonists, respectively) administration. EIU was induced by lipopolysaccharide (LPS). Twenty–four hours after LPS administration, retinal glial fibrillary acidic protein (GFAP) expression was determined by immunohistochemistry (IHC). Retinal cell death was evaluated with TUNEL analysis. TNF–α level and extracellular signal–regulated kinase (ERK) activation were evaluated by ELISA and Western analysis, respectively. Results: IHC showed localization of GFAP in astrocytes of the normal retina. LPS administration resulted in GFAP expression in Muller cells, increased levels of apoptosis in the inner nuclear layer of the retina, a significant increase in TNF–α level, and an increase in phosphorylated ERK (p–ERK) without any change in ERK expression. CBD and WIN55.212–2 treatment reduced Muller cell expression of GFAP, apoptotic cell death, TNF–α levels, and p–ERK in the LPS injected rats. The treatment outcome of WIN55.212–2 appears to be mediated by CB1 and CB2 receptors, as demonstrated by the effects of SR141716 and SR144528 administration. Conclusions: These results suggest cannabinoids may have a potential role in treating uveitis. Its ability to suppress cytokine release reduces the trigger for ERK activation which may play a critical role in protecting the retina from inflammation and apoptosis due to LPS damage. Non–psychotropic cannabinoids, such as CBD, may provide an alternative therapeutic modality in uveitis without the adverse effects caused by current treatment options.
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