1,721,156 research outputs found
Indirect blockade of vascular endothelial growth factor: the potential for eye disease therapy
No full textThe process of neovascularization is stimulated by proangiogenic growth factors, particularly vascular endothelial growth factor (VEGF), and the use of intravitreally injected anti-VEGF agents is currently the gold standard of care in the treatment of neovascular retinal pathologies. However, caution is needed as anti-VEGF agents display a variety of limitations and adverse side effects. In addition, there is evidence that VEGF is a neuroprotective factor supporting retinal neurons independently of its actions on vessels, thus direct VEGF blockade may interfere with neuronal survival. Therefore, additional therapies are needed to reduce these potential adverse effects of VEGF blockade. A number of new therapeutic approaches are being tested for their ability to indirectly target the VEGF system reducing retinal VEGF levels or the efficiency of VEGF signaling. Here, we briefly report some experimental observations on substances that may indirectly inhibit the deleterious effects of VEGF in eye disease
A safety review of drugs used for the treatment of retinopathy of prematurity
Full text linkRetinopathy of Prematurity (ROP) is a sight-threatening disease representing one of the main disabling diseases affecting premature newborns. Presently, ROP is treated by surgical interventions and drug therapies are limited to the off-label use of a little amount of molecules approved for other pathologies
Uso di oligonucleotidi antisenso per il trattamento di degenerazioni e neoplasie retiniche.
No full textBeta3-adrenergic receptors modulate vascular endothelial growth factor release in response to hypoxia through the nitric oxide pathway in mouse retinal explants
No full textBeta-adrenergic receptors (β-ARs) play a role in angiogenic processes that characterize neovascularization-associated retinal diseases, but the role of β3-ARs has not been disclosed yet. We used ex vivo retinal explants to investigate the role of β3-ARs in regulating vascular endothelial growth factor (VEGF) release associated with hypoxia. Whether nitric oxide (NO) mediates β3-AR regulation of VEGF release was also investigated. β3-AR activation was obtained using BRL 37344, whereas SR59230A, L-748,337 or specific siRNAs were used to block β3-ARs. Pharmacological approaches were used to interfere with the NO pathway. Western blot was used to determine β-AR levels. Enzyme-linked immunosorbent assay (ELISA) was used to measure VEGF release. NO production was assessed by a colorimetric assay. We found that hypoxia upregulates β3-ARs. In addition, we observed that β3-AR activation with BRL 37344 increases VEGF release in response to hypoxia. Either β3-AR blockers or β3-AR silencing downregulate drastically hypoxic levels of VEGF. With experiments using NO synthase (NOS) blockade with L-NAME, NOS activation with fluvastatin or NO supplementation with SNAP, we demonstrated that β3-ARs and VEGF are functionally coupled via the NO pathway. In summary, the data presented here support the assumption that β3-ARs are involved in the regulation of angiogenic responses to hypoxia through the NO signalling, a key pathway in hypoxic/ischemic diseases. Although extrapolation of these data to the human situation is difficult, these findings may help to explore the possible role of β3-ARs in vascularization-associated disorders
Different efficacy of propranolol in mice with oxygen-induced retinopathy: could differential effects of propranolol be related to differences in mouse strains?
No full textabstract not availabl
Targeting the Beta-Adrenergic System to Treat retinopathy of Prematurity: A New Therapeutic Approach?
No full textRetinopathy of prematurity (ROP) is a hypoxia-induced neovascular retinal disease representing the major cause of blindness and visual impairment in children. Currently, surgical approaches (i.e. vitrectomy and laser photocoagulation) are the treatments of choice for ROP although they may result in a variety of complications, and new therapeutic strategies are eagerly required. In general, intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents represent the most promising form of therapy to treat neovascular retinal disorders and there is expectancy for the use of these drugs to also treat ROP. However, for the use of these substances in ROP, the optimal choice of agent and dose remain unknown, while the possibility that the treatment may interfere with serum VEGF levels, and therefore affect normal vessel growth in developing tissues, remains to be considered. The serendipitous demonstration that a non-selective β-adrenergic receptor (β-AR) antagonist, propranolol, promotes the regression of infantile hemangiomas, the most common vascular tumor of infancy, aroused an interest around the involvement of the β-adrenergic system in angiogenic processes in humans. In particular, accumulating evidence indicates that the β-adrenergic system is involved in the hypoxia-induced neo-angiogenesis that is typically observed in ROP. In this respect, animal studies carried out in the mouse model of oxygen-induced retinopathy (OIR), which replicates the main features of ROP, have shown that β-AR blockade is effective in reducing pathological angiogenesis. For instance, propranolol has been demonstrated to inhibit hypoxia-induced VEGF expression and neo-angiogenesis when administered to OIR mice. Consequent to the encouraging results obtained in the animal model, a pilot clinical trial has shown that propranolol administered orally protects newborns from ROP progression. Indeed, compared to newborns with ROP stage 2 receiving standard treatment, the newborns with ROP stage 2 treated with oral propranolol showed a reduced progression to stage 3 or stage 3 plus and no newborns progressed to stage 4. However, some serious adverse effects of oral propranolol have been also reported. Therefore, this pilot study on the one hand has established the efficacy of propranolol treatment to counteract the progression of ROP, but on the other has indicated that the safety is a concern. Recent studies performed in rabbits have reported that the administration of propranolol through eye drops induces retinal concentrations of propranolol similar to those measured after oral administration, but with significantly lower plasma concentration. In addition, propranolol eye drops have been shown to reduce VEGF levels and retinal neovascularization in the mouse OIR model. These findings have opened the perspective of possible topical treatment with propranolol in newborns with ROP, and an ongoing study is indeed exploring the possibility of administering propranolol to newborns with ROP through eye drops with the objective to significantly reduce the side effects observed after oral propranolol administrations
Protective role of somatostatin receptor 2 against retinal degeneration in response to hypoxia
No full textIn mouse retinal explants, octreotide, a somatostatin (SRIF) receptor 2 (sst2) agonist, prevents the hypoxia-induced vascular endothelial growth factor upregulation. In mice with oxygen induced retinopathy (OIR), a model of retinopathy of prematurity, either sst2 overexpression or octreotide have been found to limit hypoxia-induced angiogenic processes. Here, we investigated whether sst2 influences retinal degeneration in response to hypoxia in wild type (WT), sst1- and sst2- knockout (KO) mice. In retinal explants, we determined the role of sst2 on apoptotic signals. In control condition, caspase-3 activity and the Bax/Bcl-2 ratio were lower in sst1-KO than in WT, but higher in sst2-KO than in WT retinas. In all strains, a comparable increase in caspase-3 activity and the Bax/Bcl-2 ratio was observed after hypoxia. The hypoxia-induced increase in apoptotic signals was recovered by octreotide in both WT and sst1-KO retinas. To investigate the role of sst2 on retinal function, we recorded electroretinogram (ERG) in response to light flashes in OIR mice. ERG responses did not differ between WT and KO mice with the exception of oscillatory potentials (OPs), which in sst1-KO mice, displayed much larger amplitude. In all strains, hypoxia drastically reduced a-, b-waves and OPs. In both WT and sst1-KO mice, octreotide recovered a- and b-waves, but did not recover OPs in sst1-KO mice. Neither apoptotic signals nor ERG were affected by octreotide in sst2-KO mice. These results show that sst2 may protect retinal cells from hypoxia, thus implementing the background to establish potential pharmacological targets based on sst2 pharmacology
Role of host β1- and β2-adrenergic receptors in a murine model of B16 melanoma: functional involvement of β3-adrenergic receptors
No full textComplex interactions between tumor cells and their surrounding compartment are strongly influenced by the host in which the tumor grows. In melanoma, for instance, stress associated norephinephrine (NE), acting at β-adrenergic receptors (β-ARs), stimulates melanoma cell proliferation and tumor angiogenesis. Among β-ARs, β3-ARs play a role acting not only at tumor cells but also at non-neoplastic stromal cells within the melanoma. In the present study, we used a murine model of B16 melanoma to evaluate the role of the host β1- and β2-ARs in melanoma growth and we determined whether the role of β3-ARs can be influenced by the absence of stromal β1- and β2-ARs. As compared to wild type mice, β1/2-AR knockout mice displayed i. increased intratumoral levels of both NE and β3-ARs, as evidentiated at both messenger and protein levels, ii. increased tumor vascularization, iii. decreased tumor cell proliferation but increased tumor cell apoptosis and iv. increased responsiveness to intratumoral injection of the β3-AR blocker L-748,337 in terms of decrease in tumor growth, tumor vascular response, tumor cell proliferation and increase in tumor cell death. These findings together validate the role of β-AR signalling in melanoma microenvironment suggesting that non-neoplastic stromal cells may be targeted by β-AR-related drugs. The additional fact that β3-ARs play an important role in melanoma growth suggest selective β3-AR antagonists as important proapoptotic agents
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