Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The goal of this study was to determine the effect of two somatostatin analogs, Woc4D and octreotide, on oxygen induced retinopathy in the mouse. Oxygen induced retinopathy was produced in C57BL6 mice. Octreotide and Woc4D were administered from post-natal day 12-16. Retinopathy was assessed by a retinal scoring system utilizing fluorescein perfused retinal whole mounts. Animals treated with Woc4D and octreotide, respectively, had median retinopathy scores of 4(3,5) [median(25th, 75th quartile)] with P = 0.01 and 3.5(2.9,4.3) with P = 0.01 compared to oxygen and sham treated oxygen animals with scores of 6.6(5.3,8.5) and 7.4(5.8,8.6), respectively. Woc4D and octreotide treated animals had decreased blood vessel tufts and decreased extra-retinal neovascularization when compared to oxygen treated animals. Pituitary growth hormone (GH) mRNA expression was increased 8.3-fold by Woc4D treatment and 106-fold by oxygen exposure, and GH and mRNA was markedly reduced by Woc4D as well as octreotide. Growth as measured by animal weight was unaffected by either treatment. Woc4D and octreotide inhibited retinal neovascularization in an equally effective manner in the mouse model of oxygen induced retinopathy.
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PMID:Somatostatin analogs inhibit neonatal retinal neovascularization. 1207 76

Proliferative retinopathies account for the majority of cases of vision loss throughout the world. Currently accepted therapy for retinopathy consists of retinal ablation by panretinal laser photocoagulation or cryotherapy. This technique is not without deleterious effects to patients, including diminished night vision, reduced peripheral vision and loss of precise vision, decreasing visual acuity by one to two lines in magnitude. One promising area of research into pharmacotherapeutics for retinopathies, especially proliferative diabetic retinopathy, involves the use of synthetic analogues of somatostatin. The rationale for somatostatin as a therapeutic agent for retinal neovascularization is discussed. Somatostatin analogues such as octreotide have shown promise as a safe and effective treatment for severe proliferative diabetic retinopathy by blocking the local and systemic production of growth hormone and insulin-like growth factor type 1 associated with angiogenesis and endothelial cell proliferation. There are also observations suggesting an autocrine and paracrine effect of somatostatin, perhaps directly on retinal cells, which are known to express somatostatin receptors (SSTR). SSTR2 and SSTR3 are the most important receptor subtypes mediating growth hormone secretion and endothelial cell cycle arrest, retinal endothelial cell apoptosis and release of insulin. Thus, analogues that target these receptor subtypes may prove more useful. Long-acting somatostatin analogues are currently being tested for treatment of diabetic retinopathy and are, in fact, the only therapeutic alternative for patients who fail panretinal photocoagulation. Whether such a therapy may also prove effective for other retinal vascular proliferative diseases such as retinopathy of prematurity and age-related macular degeneration remains an open question that deserves attention, given our new understanding of the cellular and molecular mechanisms by which somatostatin may exert its antiangiogenic effects.
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PMID:Somatostatin analogues as drug therapies for retinopathies. 1258 62

Angiogenesis, the development of new blood vessels is a crucial process both for tumor growth and metastatic dissemination. Additionally, dysregulation in angiogenesis has been implicated in the pathogenesis of cardiovascular disease, proliferative retinopathy, diabetic nephropathy, and rheumatoid arthritis (RA). The neuropeptide somatostatin has been shown to be a powerful inhibitor of neovascularization in several experimental models. Furthermore, somatostatin receptors (sst) are expressed on endothelial cells; particularly, sst2 has been found to be uniquely up-regulated during the angiogenic switch, from quiescent to proliferative endothelium. The present manuscript reviews the anti-angiogenic activity of somatostatin and its analogues in neoplastic and nonneoplastic disease. The role of sst subtypes particularly sst2 in mediating its angioinhibitory activity is described. Somatostatin agonists may also exert their anti-angiogenic activity indirectly by inhibition of growth factors like vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis or through its immunomodulatory effects. However, the therapeutic utility of somatostatin agonists as anti-angiogenic drugs in these diseases remains confusing because of conflicting results from different studies. More basic research, as well as patient-oriented studies, is required to firmly establish the clinical potential of somatostatin agonists in therapeutic angiogenesis. The currently available somatostatin agonists have high affinity of sst2 with lower affinities for sst3 and sst5. The emergence of novel somatostatin agonists especially bispecific analogues (agonists targeting multiple cellular receptors) and conjugates (synthesized by chemically linking somatostatin analogues with other antineoplastic agents) with improved receptor specificity signify a new generation of anti-angiogenics, which may represent novel strategies in the treatment of neovascularization-related diseases.
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PMID:Somatostatin analogues: multiple roles in cellular proliferation, neoplasia, and angiogenesis. 1505 99

The role of somatostatin and growth hormone in eye diseases recently became a matter of interest because of its link with proliferative diabetic retinopathy. In diabetic patients the pathologic proliferation of blood vessels as a result of retinal ischemia is a major cause of blindness. The hypoxic portions of the retina release angiogenic factors, stimulating neovascularization. Somatostatin is a natural peptide hormone that affects the release of a number of other hormones, such as growth hormone, glucagon, insulin and gastrin. The somatostatin analog promises to be safe and effective treatment for severe diabetic retinopathy. This compound has been shown to block the local and systemic production of insulin-like growth factor 1 and growth hormone, which promote the angiogenesis and endothelial cell proliferation associated with proliferative retinopathy. Several studies have confirmed that using somatostatin analogs to block insulin-like growth factor 1 production is effective in reducing neovascularization and preventing disease progression to proliferative stage of diabetic retinopathy. Long-acting somatostatin analogs are currently being tested for the treatment of diabetic retinopathy. The development of somatostatin analogs with increased selectivity for receptor subtypes will provide improved outcomes in the management of patients with diabetic retinopathy.
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PMID:Diabetes mellitus and retinopathy. 1507 18

Diabetic retinopathy is a leading cause of visual loss in industrialized countries. Its classification includes preclinical, nonproliferative (mild, moderate, and severe or preproliferative diabetic retinopathy) and proliferative stages (low risk, high risk, and advanced). Diabetic maculopathy (exudative, edematous, or ischemic) may be associated with either nonproliferative or proliferative retinopathy. Prevention requires the tightest possible control of both blood glucose and blood pressure. Laser photocoagulation remains the only procedure recommended for severe nonproliferative or proliferative retinopathy and maculopathy. Since it reduces legal blindness by more than 90% in proliferative retinopathy and prevents severe sight loss in diabetic maculopathy, photocoagulation is probably one of the most effective forms of treatment known today. Less destructive approaches are desirable, however, and those currently under phase 3 trial include blockade of angiotensin receptors, the beta-isoform of protein kinase C, and growth hormone secretion by long-acting analogues of somatostatin. Evidence from past randomized controlled studies does not support a role for inhibitors of platelet aggregation, aldose reductase, and advanced glycosylation end products in the prevention/treatment of retinopathy. Future approaches might include the use of thiamine and its analogues in the primary and secondary prevention of early retinopathy and blockers of vascular endothelial growth factor/vascular permeability factor in more advanced stages.
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PMID:Current approaches and perspectives in the medical treatment of diabetic retinopathy. 1536 82

Proliferative diabetic retinopathy is the main cause of vision loss in young and middle-aged adults. There is no accepted pharmaceutical therapy for this disease, although analogs of the naturally occurring growth hormone inhibitor, somatostatin, have been considered leading candidates for developing such therapies. This review examines the history of somatostatin analogs, especially octreotide, in the treatment of ocular complications of diabetes mellitus. The historical observations that indicated a role for somatostatin in retinopathy are discussed from an endocrinology perspective. The molecular mechanisms by which somatostatin may exert its anti-angiogenic effects, both indirect (through antagonism of the growth hormone axis) and direct (through direct antiproliferative and apoptotic effects on endothelial cells mediated by specific receptor subtypes) are described. Animal models that were used to demonstrate an anti-angiogenic effect of octreotide are detailed, as are the results of numerous clinical trials that used octreotide and other somatostatin analogs to treat diabetic retinopathy. The mixed results of these clinical results are examined along with possible explanations as to why these analogs both have and have not shown efficacy in limited clinical settings. Even with these mixed results, somatostatin analogs remain the only therapeutic alternative to patients with proliferative diabetic retinopathy who have failed to respond to panretinal photocoagulation.
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PMID:The potential role of octreotide in the treatment of diabetic retinopathy. 1605 37

Diabetic retinopathy is a leading cause of legal blindness in the adult population (30-70 year olds). The anatomical changes that occur in the retina during the course of disease are well defined in the literature but the causes are not yet fully understood. Laser photocoagulation of the retina and vitrectomy are currently used to treat diabetic retinopathy but the procedures are invasive and provide only temporary protection. The use of long-acting analogues of the naturally occurring peptide, somatostatin, has been considered by some a promising therapeutic option for retinopathy over the last decade. Experimental evidence supports its use in diabetic retinopathy but further clinical evidence, from larger treatment groups of longer trial duration, is required. Improved analogues with increased selectivity and modified bi-specific analogues are currently emerging and may help to make the use of somatostatin analogues a more realistic option in the treatment of diabetic retinopathy.
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PMID:Somatostatin in diabetic retinopathy. 1644 86

We previously documented protein kinase CK2 involvement in retinal neovascularization. Here we describe retinal CK2 expression and combined effects of CK2 inhibitors with the somatostatin analog octreotide in a mouse model of oxygen-induced retinopathy (OIR). CK2 expression in human and rodent retinas with and without retinopathy and in astrocytic and endothelial cultures was examined by immunohistochemistry, Western blotting, and reverse transcriptase-polymerase chain reaction. A combination of CK2 inhibitors, emodin or 4,5,6,7-tetrabromobenzotriazole, with octreotide was injected intraperitoneally from postnatal (P) day P11 to P17 to block mouse OIR. All CK2 subunits (alpha, alpha', beta) were expressed in retina, and a novel CK2alpha splice variant was detected by reverse transcriptase-polymerase chain reaction. CK2 antibodies primarily reacted with retinal astrocytes, and staining was increased around new intraretinal vessels in mouse OIR and rat retinopathy of prematurity, whereas preretinal vessels were negative. Cultured astrocytes showed increased perinuclear CK2 staining compared to endothelial cells. In the OIR model, CK2 mRNA expression increased modestly on P13 but not on P17. Octreotide combined with emodin or 4,5,6,7-tetrabromobenzotriazole blocked mouse retinal neovascularization more efficiently than either compound alone. Based on its retinal localization, CK2 may be considered a new immunohistochemical astrocytic marker, and combination of CK2 inhibitors and octreotide may be a promising future treatment for proliferative retinopathies.
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PMID:Expression of protein kinase CK2 in astroglial cells of normal and neovascularized retina. 1665 37

The diabetes epidemic continues unabated, leading to an increasing number of acute and chronic complications, including sight-threatening proliferative diabetic retinopathy. Currently, there is no accepted pharmaceutical therapy for diabetic retinopathy besides nearnormal glycemia, treatment of hypertension, and dyslipidemia. For an effective treatment of retinopathy, one would recommend a concept leading to the downregulation of endogenous angiogenic stimulators and the upregulation of endogenous angiogenic inhibitors, resulting in a restoration of the balance in angiogenic control. The naturally occurring growth hormone inhibitor, somatostatin, has been suggested as candidate for developing novel therapies. Somatostatin may exert its antiangiogenic effects, both through antagonism of the growth hormone axis and through direct antiproliferative and apoptotic effects on endothelial cells. Therefore, the use of long-acting somatostatin analogues will lead to an upregulation of antiangiogenic signaling. Use of long-acting somatostatin analogues in diabetic retinopathy would be an important extension of the initial concept that somatostatin is a regulator of growth hormone secretion only. Currently available analogues have already allowed to modulate the expression of diabetic retinopathy at various disease stages. Somatostatin analogues remain the only nondestructive therapeutic alternative to patients with proliferative diabetic retinopathy who have failed to respond to panretinal photocoagulation.
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PMID:Use of long-acting somatostatin analogue treatment in diabetic retinopathy. 1724 82

Neoangiogenesis is a response to retinal hypoxia that is inhibited by somatostatin (SRIF) through its subtype 2 receptor (sst2). Using a mouse model of hypoxia-induced retinopathy, we investigated whether inhibition of adenylyl cyclase (AC) is involved in SRIF anti-angiogenic actions. Hypoxia increased AC responsiveness in wild type (WT) retinas and in retinas lacking sst2, but not in sst2-overexpressing retinas. Hypoxia also altered AC isoform expression with different patterns depending on sst2 expression level. The AC VII isoform mRNA and protein resulted the most affected. Indeed, in hypoxia AC VII expression was enhanced in WT retinas and it was further increased in sst2-lacking retinas, whereas in sst2 overexpressing retinas the increase of AC VII was lower than in WT retinas. These data suggest an involvement of AC/cAMP in mediating both hypoxia-evoked retinal neoangiogenesis and SRIF protective actions. The AC VII isoform is a candidate to a main role in these mechanisms.
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PMID:Adenylyl cyclase/cAMP system involvement in the antiangiogenic effect of somatostatin in the retina. Results from transgenic mice. 1827 Aug 25


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