Cannabis Research - Diabetes

Cannabidiol arrests onset of autoimmune diabetes in NOD mice

Lola Weiss a,*, Michael Zeira a, Shoshana Reich a, Shimon Slavin a, Itamar Raz b, Raphael Mechoulam c, Ruth Gallily d

Abstract - We have previously reported that cannabidiol (CBD) lowers the incidence of diabetes in young non-obese diabetes-prone (NOD) female mice. In the present study we show that administration of CBD to 11e14 week old female NOD mice, which are either in a latent diabetes stage or with initial symptoms of diabetes, ameliorates the manifestations of the disease. Diabetes was diagnosed in only 32% of the mice in the CBDtreated group, compared to 86% and 100% in the emulsifier-treated and untreated groups, respectively. In addition, the level of the proinflammatory cytokine IL-12 produced by splenocytes was significantly reduced, whereas the level of the anti-inflammatory IL-10 was significantly elevated following CBD-treatment. Histological examination of the pancreata of CBD-treated mice revealed more intact islets than in the controls. Our data strengthen our previous assumption that CBD, known to be safe in man, can possibly be used as a therapeutic agent for treatment of type 1 diabetes.
Keywords: Cannabinoids; Cannabidiol; Diabetes; NOD mice; Cytokines

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Cannabidiol lowers incidence of diabetes in non-obese diabetic mice

L. WEISS1, M. ZEIRA1, S. REICH1, M. HAR-NOY1, R. MECHOULAM2, S. SLAVIN1, & R. GALLILY3.

Abstract - Cannabidinoids are components of the Cannabis sativa (marijuana) plant that have been shown capable of suppressing inflammation and various aspects of cell-mediated immunity. Cannabidiol (CBD), a non-psychoactive cannabidinoid has been previously shown by us to suppress cell-mediated autoimmune joint destruction in an animal model of rheumatoid arthritis.We now report that CBD treatment significantly reduces the incidence of diabetes inNODmice from an incidence of 86% in non-treated control mice to an incidence of 30% in CBD-treated mice. CBD treatment also resulted in the significant reduction of plasma levels of the pro-inflammatory cytokines, IFN-g and TNF-a. Th1-associated cytokine production of in vitro activated T-cells and peritoneal macrophages was also significantly reduced in CBD-treated mice, whereas production of the Th2-associated cytokines, IL-4 and IL-10, was increased when compared to untreated control mice. Histological examination of the pancreatic islets of CBD-treated mice revealed significantly reduced insulitis. Our results indicate that CBD can inhibit and delay destructive insulitis and inflammatory Th1-associated cytokine production in NOD mice resulting in a decreased incidence of diabetes possibly through an immunomodulatory mechanism shifting the immune response from Th1 to Th2 dominance. Keywords: Type 1 diabetes, cannabidiol, Th1/Th2 biology, IFN-g

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Neuroprotective and Blood-Retinal Barrier-Preserving Effects of Cannabidiol in Experimental Diabetes

Azza B. El-Remessy, Mohamed Al-Shabrawey, Yousuf Khalifa, Nai-Tse Tsai, Ruth B. Caldwell, and Gregory I. Liou

Diabetic retinopathy is characterized by blood-retinal barrier (BRB) breakdown and neurotoxicity. These pathologies have been associated with oxidative stress and proinflammatory cytokines, which may operate by activating their downstream target p38 MAP kinase. In the present study, the protective effects of a nonpsychotropic cannabinoid, cannabidiol (CBD), were examined in streptozotocin-induced diabetic rats after 1, 2, or 4 weeks. Retinal cell death was determined by terminal dUTP nick-end labeling assay; BRB function by quantifying extravasation of bovine serum albumin-fluorescein; and oxidative stress by assays for lipid peroxidation, dichlorofluorescein fluorescence, and tyrosine nitration. Experimental diabetes induced significant increases in oxidative stress, retinal neuronal cell death, and vascular permeability. These effects were associated with increased levels of tumor necrosis factor-, vascular endothelial growth factor, and intercellular adhesion molecule-1 and activation of p38 MAP kinase, as assessed by enzyme- linked immunosorbent assay, immunohistochemistry, and/or Western blot. CBD treatment significantly reduced oxidative stress; decreased the levels of tumor necrosis factor-, vascular endothelial growth factor, and intercellular adhesion molecule-1; and prevented retinal cell death and vascular hyperpermeability in the diabetic retina. Consistent with these effects, CBD treatment also significantly inhibited p38 MAP kinase in the diabetic retina. These results demonstrate that CBD treatment reduces neurotoxicity, inflammation, and BRB breakdown in diabetic animals through activities that may involve inhibition of p38 MAP kinase. (Am J Pathol 2006, 168:235244; DOI: 10.2353/ajpath.2006. 050500)

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