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

Department of Pharmacology and Toxicology, Medical College of Georgia, 1120 15th St., Augusta, GA 30912, USA.
American Journal Of Pathology (Impact Factor: 4.59). 02/2006; 168(1):235-44. DOI: 10.2353/ajpath.2006.050500
Source: PubMed


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-alpha, 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-alpha, 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.

Download full-text


Available from: Ruth B Caldwell,
  • Source
    • "We found that by four weeks after onset of diabetes, the number of RGCs was reduced by approximately 40% of the normal number and a gradual decrease in the number of RGCs was demonstrated. Therefore, there is general agreement that all mice strains have shown RGC loss or damage in diabetes [7], [15]–[23]. It is well-known that oxidative stress plays a crucial role in the development of diabetes mellitus [24], [25]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, is used for the clinical treatment of retinal injury. In this study, we investigated the protective effects of edaravone against diabetic retinal damage in the mouse. Diabetic retinopathy in the mouse was induced by injection of streptozotocin. Edaravone was given once-daily and was intraperitoneally (i.p.) treated at a dose of 3 mg/kg from streptozotocin injection to 4 weeks after onset of diabetes. Retinal ganglion cells (RGCs) damage was evaluated by recording the pattern electroretinogram (ERG). RGCs damage was also detected by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and the levels of reactive oxygen species (ROS) were determined fluorometrically. The expressions of phosporylated-ERK1/2, BDNF, and caspase-3 were determined by Western blot analysis. Retinal levels of ROS, phosphorylated ERK1/2, and cleaved caspase-3 were significantly increased, whereas the expression of BDNF was significantly decreased in the retinas of diabetic mice, compared to nondiabetic mice. Administration of edaravone significantly attenuated diabetes induced RGCs death, upregulation of ROS, ERK1/2 phosphorylation, and cleaved caspase-3 and downregulation of BDNF. These findings suggest that oxidative stress plays a pivotal role in diabetic retinal damage and that systemic administration of edaravone may slow the progression of retinal neuropathy induced by diabetes.
    PLoS ONE 06/2014; 9(6):e99219. DOI:10.1371/journal.pone.0099219 · 3.23 Impact Factor
  • Source
    • "Abu El-Asrar et al. reported that ganglion cells in diabetic retinas express several proapoptotic molecules, such as caspase-3, Fas, and Bax, suggesting that these cells are the most vulnerable population in diabetic retinopathy [9]. Another study showed that neurotoxicity causes permanent impairment of visual function due to cell death of the inner retinal and ganglion cells [10]. Intervention in the apoptosis of ganglion cells may allow us to therapeutically delay or ameliorate neural cell loss in retinal neurodegenerative conditions related to diabetes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the potential protective effects of total flavonoids from Flos Puerariae (TFF) on retinal neural cells in diabetic mice. C57BL/6J mice were intraperitoneally injected with streptozotocin to generate type I diabetes in a murine model, as indicated by blood glucose levels ≥11.1 mmol/l. TFF was administered intragastrically at a dose of 50, 100, or 200 mg/kg/day. After 10 weeks of administration, the mice were euthanized, and the eyes were dissected. Retinal histology was examined, and the thickness of the retina was measured. Ultrastructural changes in the retinal ganglion cells and capillary basement membrane were observed with electron microscopy. Apoptosis of retinal neural cells was determined with the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling assay. Bax and Bcl-2 expression in the retinal tissues was determined with immunohistochemical staining and western blotting. Compared with the diabetic mice, the blood glucose level decreased (p<0.01) and the bodyweight increased (p<0.05) in the 100 and 200 mg/kg TFF-treated groups. The thickness of the retina significantly increased (p<0.01), and the retinal capillary basement membrane (BM) thickness was reduced in the 100 and 200 mg/kg TFF-treated diabetic mice (DM). The 100 and 200 mg/kg TFF treatments also attenuated the diabetes-induced apoptosis of retinal neural cells. Consistent with these effects, TFF treatment decreased the Bax expression level and, concurrently, increased the ratio of Bcl-2 to Bax. TFF attenuated diabetes-induced apoptosis in retinal neurons by inhibiting Bax expression and increasing the ratio of Bcl-2 to Bax, which suggests that TFF might prevent retinal neuronal damage in diabetes mellitus.
    Molecular vision 09/2013; 19:1999-2010. · 1.99 Impact Factor
  • Source
    • "Therefore, there is a great need to identify contributing factors in PDR other than VEGF; in the hope of devising treatments that will preserve both retina vasculature and neuronal function. Diabetes-induced oxidative stress disturbs retinal homeostasis by activating glial cells, reducing neurotrophic support , and increasing proinflammatory cytokines including VEGF, IL-1í µí»½, and TNF-í µí»¼ [6] [7]. In addition to these known growth factors, recent findings using ocular fluids from diabetic patients and experimental models of diabetes suggest "
    [Show abstract] [Hide abstract]
    ABSTRACT: Proliferative diabetic retinopathy (PDR) is the leading cause of blindness in working age Americans. We demonstrated that diabetes disturbs the homeostasis of nerve growth factor (NGF) resulting in accumulation of its precursor proNGF. Increases in proNGF were positively correlated with progression of diabetic retinopathy, having the highest level in ocular fluids from PDR patients compared to nondiabetic patients. Here, we attempted to evaluate the contribution and the possible mechanism of proNGF to PDR. The angiogenic response of aqueous humor samples from PDR patients was examined in human retinal endothelial cells in the presence or absence of anti-proNGF antibody. Additional cultures were treated with mutant-proNGF in the presence of specific pharmacological inhibitors of TrkA and p75(NTR) receptors. PDR-aqueous humor samples exerted significant angiogenic response including cell proliferation, migration, and alignment into tube-like structures. These effects were significantly reduced by anti-proNGF antibody but not by IgG. Treatment of retinal endothelial cells with mutant-proNGF activated phosphorylation of TrkA and p38MAPK; however, it did not alter p75(NTR) expression. Inhibition of TrkA but not p75(NTR) significantly reduced mutant-proNGF-induced cell proliferation, cell migration, and tube formation. Taken together, these results provide evidence that proNGF can contribute to PDR at least in part via activation of TrkA.
    Journal of Diabetes Research 08/2013; 2013(33):432659. DOI:10.1155/2013/432659 · 2.16 Impact Factor
Show more