vasoactive-intestinal-peptide and Retinitis

Vasoactive intestinal peptide (VIP) is a pleiotropic neuropeptide, acting as a neuromodulator and neuroprotective peptide in the CNS after injuries. We have previously described that pituitary adenylate cyclase-activating polypeptide (PACAP), another member of the same peptide family, is retinoprotective in ischemic lesions. The aim of this study was to investigate the protective potential of VIP in bilateral common carotid artery occlusion (BCCAO)-induced ischemic retinal lesion. Two-month-old rats were subjected to BCCAO and treated with intravitreal VIP injection. Their retinas were processed for histology after 2 weeks of survival. We measured the number of the cells/100 μm of the ganglion cell layer and the thickness of each layer such as the outer nuclear, outer plexiform, inner nuclear, and inner plexiform layers as well as that of the whole retina. We found that treatment with 1,000 pmol VIP, but not 100 pmol VIP, had significant protective effects in BCCAO-injured retina, as shown by the morphometric analysis. Comparing the neuroprotective effects of VIP and PACAP in BCCAO-operated retinas, PACAP was more effective, already protective at 100-pmol doses. Similar to other studies, we found that VIP must be given at least in 10 times more concentration than PACAP to achieve a similar degree of neuroprotection in the retina.

Topics: Animals; Apoptosis; Carotid Artery, Common; Carotid Stenosis; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Intravitreal Injections; Ischemia; Male; Models, Neurological; Neuroprotective Agents; Pituitary Adenylate Cyclase-Activating Polypeptide; Rats; Rats, Wistar; Retinal Degeneration; Retinal Neurons; Retinal Vessels; Retinitis; Time Factors; Vasoactive Intestinal Peptide

The aim of this study was to investigate the effect of a single intravitreal (i.v.t.) injection of vasoactive intestinal peptide (VIP) loaded in rhodamine-conjugated liposomes (VIP-Rh-Lip) on experimental autoimmune uveoretinitis (EAU).. An i.v.t. injection of VIP-Rh-Lip, saline, VIP, or empty-(E)-Rh-Lip was performed simultaneously, either 6 or 12 days after footpad immunization with retinal S-antigen in Lewis rats. Clinical and histologic scores were determined. Immunohistochemistry and cytokine quantification by multiplex enzyme-linked immunosorbent assay were performed in ocular tissues. Systemic immune response was determined at day 20 postimmunization by measuring proliferation and cytokine secretion of cells from inguinal lymph nodes (ILNs) draining the immunization site, specific delayed-type hypersensitivity (DTH), and the serum concentration of cytokines. Ocular and systemic biodistribution of VIP-Rh-Lip was studied in normal and EAU rats by immunofluorescence.. The i.v.t. injection of VIP-Rh-Lip performed during the afferent, but not the efferent, phase of the disease reduced clinical EAU and protected against retinal damage. No effect was observed after saline, E-Rh-Lip, or VIP injection. VIP-Rh-Lip and VIP were detected in intraocular macrophages and in lymphoid organs. In VIP-Rh-Lip-treated eyes, macrophages expressed transforming growth factor-beta2, low levels of major histocompatibility complex class II, and nitric oxide synthase-2. T-cells showed activated caspase-3 with the preservation of photoreceptors. Intraocular levels of interleukin (IL)-2, interferon-gamma (IFN-gamma), IL-17, IL-4, GRO/KC, and CCL5 were reduced with increased IL-13. At the systemic level, treatment reduced retinal soluble autoantigen lymphocyte proliferation, decreased IL-2, and increased IL-10 in ILN cells, and diminished specific DTH and serum concentration of IL-12 and IFN-gamma.. An i.v.t. injection of VIP-Rh-Lip, performed during the afferent stage of immune response, reduced EAU pathology through the immunomodulation of intraocular macrophages and deviant stimulation of T-cells in ILN. Thus, the encapsulation of VIP within liposomes appears as an effective strategy to deliver VIP into the eye and is an efficient means of the prevention of EAU severity.

Topics: Animals; Arrestin; Autoimmune Diseases; Cell Proliferation; Cytokines; Disease Models, Animal; Injections; Liposomes; Lymph Nodes; Macrophages; Male; Rats; Rats, Inbred Lew; Retinitis; Rhodamines; T-Lymphocytes; Uveitis; Vasoactive Intestinal Peptide; Vitreous Body

Vasoactive intestinal peptide (VIP) exhibits immunomodulatory activities both in vivo and in vitro, including efficient inhibition of murine experimental arthritis. In this study, we investigated the effects of VIP treatment on the induction of experimental autoimmune uveoretinitis (EAU).. EAU was induced in B10.RIII mice by immunization with interphotoreceptor retinoid-binding protein (IRBP) using routine methods, but without treatment with pertussis toxin (PTX). VIP was injected i.p. at different doses into mice on alternate days. Mice were tested by conventional methods for ocular inflammation, antibody levels, lymphocyte proliferation, and cytokine release by cultured lymphocytes.. Treatment with VIP, at different doses, had essentially no effect on the development of EAU or antibody production in the B10.RIII mice. The treatment did have variable effects on the low interferon-gamma production by lymphocytes of these mice.. Unlike its inhibitory effect in the experimental arthritis system, VIP did not modulate the development of EAU in B10.RIII mice.

Topics: Animals; Antibody Formation; Autoimmune Diseases; B-Lymphocytes; Cytokines; Eye Proteins; Female; Immunoglobulin G; Injections, Intraperitoneal; Lymphocyte Activation; Mice; Neuroprotective Agents; Retinitis; Retinol-Binding Proteins; T-Lymphocytes; Uveitis; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP), a neuropeptide that is known to be present in lymphoid tissue microenvironments, shows prominent anti-inflammatory actions.. To examine the potential effect of VIP on the development of experimental autoimmune uveoretinitis (EAU).. We immunized C57BL/6 mice with human interphotoreceptor retinoid-binding protein peptide 1-20 (h-IRBP peptide). Vasoactive intestinal peptide was administered intraperitoneally on alternate days until day 21 after immunization (entire group). In some cases, VIP was injected at different time points after the induction of immunity with h-IRBP peptide (efferent group). In each experiment, a control group of mice was injected with phosphate-buffered saline instead of VIP. Development of EAU was evaluated by means of histological examination on day 21 after immunization. Furthermore, we determined whether intravenous injection of peritoneal exudate cells cultured with VIP overnight in vitro abrogated EAU. We analyzed delayed hypersensitivity for h-IRBP peptide and the occurrence and severity of EAU using evaluation of histopathological sections for inflammatory ocular disease.. Treatment with VIP suppressed the expression of delayed hypersensitivity responses to h-IRBP peptide significantly (positive control vs entire group, P =.02; positive control vs efferent group, P<.001). Mice treated with VIP (n = 10) showed a lower occurrence (40%) and decreased severity of EAU (entire group mean score, 0.3; median score, 0) compared with untreated mice (occurrence, 80%; mean score, 0.85; median score, 0.75), as assessed by histopathological analyses (P =.049). Suppressive effects of VIP on EAU were also observed, even when VIP was administered on days 8 through 20 after immunization (efferent group [n = 9] occurrence, 11%; mean score, 0.1; median score, 0) (P =.003). Moreover, expression of EAU was significantly suppressed when the animals were pretreated with peritoneal exudate cells pulsed with h-IRBP in the presence of VIP (control mean score, 1.2; median score, 1.0; occurrence, 80% [n = 10]) compared with the VIP-treatment group (mean score, 0.3; median score, 0; occurrence, 30% [n = 10]) (P =.004). In addition, VIP-treated peritoneal exudate cells generated regulator T cells in the spleens of recipient mice that were able to interfere with the development of EAU (control group mean score, 0.5; median score, 0.5; occurrence, 63% [n = 8]) compared with the VIP-treatment group (mean score, 0.08; median score, 0; occurrence, 17% [n = 6]) (P =.08).. Treatment with VIP is a highly effective therapy to suppress EAU.. As a result of its efficacy in preventing EAU, VIP might be considered as a novel therapeutic modality for human uveitis.

Topics: Animals; Autoimmune Diseases; Eye Proteins; Female; Hypersensitivity, Delayed; Injections, Intraperitoneal; Mice; Mice, Inbred C57BL; Peptides; Peritoneal Cavity; Retinitis; Retinol-Binding Proteins; Specific Pathogen-Free Organisms; Spleen; T-Lymphocytes; Uveitis; Vasoactive Intestinal Peptide