cortistatin-14 and Brain-Ischemia

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

This study investigated whether peptides acting at somatostatin receptors, such as somatostatin-14, octreotide or cortistatin-14, can influence the extent of brain damage after focal ischaemia in rats. The intracerebroventricular application of 0.1 or 1.0 nmol somatostatin-14 5 min after middle cerebral artery occlusion significantly reduced the infarct size assessed 7 days after the insult (by 47% and 57% of the saline control), whereas 10.0 nmol had no significant protective effect (9% reduction). A similar dose/response relationship was obtained after intracerebroventricular injection of octreotide. The lower doses of 0.1 or 1.0 nmol afforded significant neuroprotection (reduction of the infarct size by 72 and 57%), whereas 10 nmol actually increased the infarct size up to 348%. Cortistatin-14 (10 nmol) decreased the ischaemic damage by 52%. For comparison with the neuropeptides acting on somatostatin receptors, the kappa opiate agonist enadoline (10 nmol) also had a significant protective effect against the development of focal ischaemia; the extent of the brain damage was reduced by 60% after intracerebroventricular injection.

Topics: Animals; Benzofurans; Body Temperature; Brain Ischemia; Cerebral Cortex; Corpus Striatum; Hormones; Injections, Intraventricular; Male; Middle Cerebral Artery; Neurons; Neuropeptides; Neuroprotective Agents; Octreotide; Pyrrolidines; Rats; Rats, Wistar; Receptors, Opioid, kappa; Somatostatin