Somatostatin receptor 2 is activated in cortical neurons and contributes to neurodegeneration after focal 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.
Stumm
Ralf K
RK
Institute of Pharmacology and Toxicology, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany. ralf.stumm@medizin.uni-magdeburg.de
Zhou
Chun
C
Schulz
Stefan
S
Endres
Matthias
M
Kronenberg
Golo
G
Allen
Jeremy P
JP
Tulipano
Giovanni
G
Höllt
Volker
V
D000818:Animals; D001369:Axons / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D002544:Cerebral Infarction / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009410:Nerve Degeneration / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D013004:Somatostatin / Q000378:metabolism; D015854:Up-Regulation
C452813:BIM 23627; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D010455:Peptides; D017481:Receptors, Somatostatin; C099323:cortistatin; D013004:Somatostatin; C093733:somatostatin receptor 2