cortistatin-14 and Nerve-Degeneration

Cortistatin (CST), a neuropeptide with strong structural and functional similarities to somatostatin, is abundant in the vitreous fluid, and it is decreased in patients with proliferative diabetic retinopathy. The aims of the present study were to explore whether the retina produces CST, and to compare its expression between diabetic and nondiabetic donors. Retinal neurodegeneration was assessed by measuring glial fibrilar acidic protein (GFAP) by confocal laser microscopy and counting the apoptotic TUNEL positive cells in which nuclear fragmentation as well as condensation were present.. Human postmortem eyes (10) from five diabetic donors were compared with 10 eyes from five nondiabetic donors, matched by age. CST mRNA (RT-PCR) and CST (confocal laser microscopy) were measured separately in both the neuroretina and retinal pigment epithelium (RPE). Retinal neurodegeneration was assessed by measuring glial fibrillar acidic protein (GFAP) by confocal laser microscopy and counting the apoptotic cells by TUNEL.. CST was found to be produced by the human retina, and higher levels of CST mRNA were found in RPE than in the neuroretina. CST mRNA levels in diabetic donors were significantly lower in both the RPE (p=0.001) and the neuroretina (p=0.03) in comparison with nondiabetic donors. CST immunofluorescence was in agreement with mRNA expression, but the differences were only significant when comparing neuroretinas (p=0.03). Increased GFAP and a higher degree of apoptosis were observed in diabetic retinas in comparison with nondiabetic retinas. These changes were inversely related with CST levels.. CST is expressed in the human retina. There is more CST in the RPE than in the neuroretina. A lower expression of CST exists in diabetic retinas and it is associated with retinal neurodegeneration.

Topics: Aged; Apoptosis; Case-Control Studies; Diabetic Retinopathy; Female; Glial Fibrillary Acidic Protein; Humans; Male; Middle Aged; Nerve Degeneration; Neuroglia; Neuropeptides; Retina; Tissue Donors

Somatostatin receptor 2 (SSTR2) mediates neuromodulatory signals of somatostatin and cortistatin in the cerebral cortex. Recently, SSTR2 has been shown to enhance conserved death ligand- and mitochondria-mediated apoptotic pathways in non-neuronal cells. Whether somatostatin receptors are activated in cerebrocortical neurons and contribute to neurodegeneration after experimental focal ischemia was unknown until now. Here we examined internalization of SSTR2 in a rat model of middle cerebral artery occlusion (MCAO) by confocal microscopy. At 3 and 6 hr after MCAO, SSTR2 was internalized excessively in cerebrocortical neurons adjacent to the infarct, which was prevented by intracerebroventricular application of the SSTR2-selective antagonist BIM-23627. SSTR2 internalization was associated with a transient depletion of somatostatin from axonal terminals and increased expression of SSTR2 mRNA. The initial loss of somatostatin was followed by an increase in somatostatin mRNA levels, whereas cortistatin mRNA expression was decreased. In SSTR2-deficient mice with lacZ under the control of the SSTR2 promoter, MCAO-induced upregulation of SSTR2 gene expression was less pronounced than in wild types. SSTR2-deficient mice exhibited a 40% reduction of infarct size after permanent distal MCAO and a 63% reduction after transient proximal MCAO. In summary, we provide direct evidence for activation of SSTR2 by an endogenous ligand after focal ischemia. Activation of functional SSTR2 receptors contributes to increased SSTR2 gene expression and postischemic neurodegeneration.

Topics: Animals; Axons; Brain Ischemia; Cell Line; Cerebral Cortex; Cerebral Infarction; Fluorescent Antibody Technique; Humans; Immunoenzyme Techniques; In Situ Hybridization; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Confocal; Nerve Degeneration; Nerve Tissue Proteins; Neurons; Neuropeptides; Peptides; Rats; Rats, Long-Evans; Receptors, Somatostatin; Somatostatin; Up-Regulation