کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5814870 | 1556637 | 2014 | 8 صفحه PDF | دانلود رایگان |
- sst2 somatostatin receptor and somatostatin are expressed in cultured cortical neurons.
- Neuronal sst2 is activated by endogenous somatostatin during oxygen/glucose deprivation.
- sst2 activation reduces Akt phosphorylation in cortical neuronal cultures.
- sst2 signaling aggravates hypoxic/ischemic neuronal death.
- Use of sst2 antagonists in stroke might maintain Akt signaling and protect from neuronal death.
It is established that growth factors support neuronal survival through the phosphoinositide 3-kinase (PI3K)/Akt pathway but little is known about factors that inhibit Akt signaling in neurons. Given that the sst2 type somatostatin receptor exerts pro-apoptotic effects in tumor cells by inhibiting PI3K/Akt, we examined whether neuronal sst2 has similar effects. In primary cortical cultures heterozygously expressing a sst2 knockout/lacZ knockin allele, beta-galactosidase staining revealed expression of the sst2 gene in the vast majority of the cultured neurons. Somatostatin was identified in a subpopulation of neurons by immunocytochemistry. Immunoblots showed a strong reduction of Akt phosphorylation at S473 in wild type cultures undergoing stimulation with the sst2 agonist BIM-23244. While the sst2 agonist did not cause neuronal death under control conditions, it promoted hypoxic/ischemic neuronal death in cortical cultures subjected to oxygen/glucose deprivation. Treatment of wild type cultures with the sst2 antagonist BIM-23627 and homozygous deletion of the sst2 gene were protective in this paradigm, suggesting that endogenous somatostatin signals through sst2 during hypoxia/ischemia. In fact, examination of sst2 phosphorylation and sst2 internalization provided evidence for sst2 activation in neurons subjected to oxygen/glucose deprivation. Thus, somatostatin acts as a sensor of hypoxia/ischemia, inhibits Akt activity through sst2 and aggravates hypoxic/ischemic neuronal death. sst2-selective antagonists are proposed as neuroprotectants in stroke.
Journal: Neuropharmacology - Volume 77, February 2014, Pages 249-256