Background and purpose:Obesity is a severe health problem in the modernized world and understanding the central nervous mechanisms underlying food-seeking behaviour and reward are at the forefront of medical research. Cannabinoid receptors have proven an efficient target to suppress hunger and weight gain by their pharmacological inactivation. Experimental approach: A standard fasted protocol and a novel long-term home-cage observation system with free-feeding animals were used to assess the feeding behaviour of mice treated with the CB1 antagonist AM251. Similarly, the effects of the phytocannabinoid D 9 -tetrahydrocannabivarin (D 9 -THCV), which behaves like a CB1 antagonist, were also determined in free-feeding animals. Key results: AM251 suppressed food intake and weight gain in fasted and non-fasted animals. The suppression of food intake by AM251 (10 mg·kg -1 ) endured for a period of 6-8 h when administered acutely, and was continuous when injected for four consecutive days. Pure D 9 -THCV also induced hypophagia and weight reduction at doses as low as 3 mg·kg -1 . No rebound was observed on the following day with all drug groups returning to normal activity and feeding regimes. However, a D 9 -THCV-rich cannabis-extract failed to suppress food intake and weight gain, possibly due to residual D 9 -tetrahydrocannabinol (D 9 -THC) in the extract. This D 9 -THC effect was overcome by the co-administration of cannabidiol.
Conclusions and implications:The data strongly suggest (i) the long-term home-cage observation system is a sensitive and obesity-relevant tool, and (ii) the phytocannabinoid D 9 -THCV is a novel compound with hypophagic properties and a potential treatment for obesity.
Retinal pigment epithelial (RPE) cells form part of the blood-retina barrier and have recently been shown to produce various chemokines in response to proinflammatory cytokines. As the scope of chemokine action has been shown to extend beyond the regulation of leukocyte migration, we have investigated the expression of chemokine receptors on RPE cells to determine whether they could be a target for chemokine signaling. RT-PCR analysis indicated that the predominant receptor expressed on RPE cells was CXCR4. The level of CXCR4 mRNA expression, but not cell surface expression, increased on stimulation with IL-1β or TNF-α. CXCR4 protein could be detected on the surface of 16% of the RPE cells using flow cytometry. Calcium mobilization in response to the CXCR4 ligand stromal cell-derived factor 1α (SDF-1α) indicated that the CXCR4 receptors were functional. Incubation with SDF-1α resulted in secretion of monocyte chemoattractant protein-1, IL-8, and growth-related oncogene α. RPE cells also migrated in response to SDF-1α. As SDF-1α expression by RPE cells was detected constitutively, we postulate that SDF-1–CXCR4 interactions may modulate the affects of chronic inflammation and subretinal neovascularization at the RPE site of the blood-retina barrier.
SUMMARYChemokine production at the blood±retina barrier probably plays a critical role in determining the in¯ux of tissue-damaging cells from the circulation into the retina during in¯ammation. The blood± retina barrier comprises the retinal microvascular endothelium and the retinal pigment epithelium. Chemokine expression and production by human retinal microvascular endothelial cells (REC) have never been reported previously, so we examined the in vitro expression and production of monocyte chemoattractant protein-1 (MCP-1), regulated on activation of normal T-cell expressed and secreted (RANTES), macrophage in¯ammatory protein (MIP)-1a, MIP-1b, interleukin (IL)-8, epithelial cell-derived neutrophil activating protein-78 (ENA-78) and growth related oncogene a (GROa) in these cells, both unstimulated and stimulated by cytokines likely to be present during the evolution of an in¯ammatory response. We compared this to expression and production of these chemokines in vitro in human retinal pigment epithelial cells (RPE). MCP-1 was expressed and produced constitutively by REC but all the chemokines were produced in greater amounts upon stimulation with the proin¯ammatory cytokines IL-1b and tumour necrosis factor-a (TNF-a). MCP-1 and IL-8 were produced at much higher levels than the other chemokines tested. MIP-1a and MIP-1b were present only at low levels, even after stimulation with IL-1b and TNF-a. Cytokines with greater anti-in¯ammatory activity, such as IL-4, IL-10, IL-13, transforming growth factor-b (TGF-b) and IL-6, had little effect on chemokine production either by REC alone or after stimulation with IL-1b and TNF-a. RPE, although a very different cell type, showed a similar pattern of expression and production of chemokines, indicating the site-speci®c nature of chemokine production. Chemokine production by REC and RPE is probably signi®cant in selective leucocyte recruitment during the development of in¯ammation in the retina.
Systemic Rimonabant-induced deficits are due to anxiogenic properties of the drug. The difference between administration regimes is discussed in terms of CB(1) receptor blockade in multiple non-memory and memory-related brain regions and the possibility that selective inactivation of hippocampal CB(1) receptors may be memory enhancing.
Samples of iris ciliary body, choroid and retina from normal eyes and from 2 cases of sympathetic ophthalmitis (one acute and one late stage fibrosis) were examined for the expression of the VLA integrins beta 1 and alpha 1-6, and the integrin beta 3, in addition to ICAM-1, VCAM-1, ELAM-1 and CD44 using an APAAP staining technique. The expression of VLA-4, VLA-5, VCAM-1, ICAM-1, and CD44 was significantly increased and ELAM-1 was slightly increased in acute sympathetic ophthalmitis in comparison to fibrotic and normal eyes. VLA-6 was moderately increased in acute and fibrotic cases and VLA-2 VLA-3 and beta 3 were moderately expressed on all tissues examined. The differential expression of molecules known to be involved in lymphocyte activation and adhesion in acute sympathetic ophthalmitis suggests that certain adhesion molecules play a role in the pathogenesis of intraocular inflammation and may be suitable targets for immunotherapy.
This study has enabled us to identify the influence of the chemokine, macrophage inflammatory protein-1 § (MIP-1 § ), on leukocyte behavior at the blood-retina barrier in vivo and its link with the inflammatory process and disease pathogenesis. MIP-1 § has not previously been thought to be effective under conditions of physiological shear flow. However, short-term anti-MIP-1 § treatment inhibited leukocyte slowing and accumulation and subsequent extravasation of leukocytes at the blood-retina barrier in animals with experimental autoimmune uveoretinitis. This was effective predominantly in the post-capillary venules which have been shown to be the main site of passage of leukocytes across the blood-retina barrier. Long-term anti-MIP-1 § treatment also prevented decreased leukocyte velocity and reduced disease severity as measured clinically, histologically and in terms of blood-retina barrier breakdown.
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