Modulation of the neuronal response to ischaemia by somatostatin analogues in wild‐type and knock‐out mouse retinas

Abstract

Somatostatin acts at five G protein‐coupled receptors, sst1‐sst5. In mouse ischaemic retinas, the over‐expression of sst2 (as in sst1 knock‐out mice) results in the reduction of cell death and glutamate release. In this study, we reported that, in wild‐type retinas, somatostatin, the multireceptor ligand pasireotide and the sst2 agonist octreotide decreased ischaemia‐induced cell death and that octreotide also decreased glutamate release. In contrast, cell death was increased by blocking sst2 with cyanamide. In sst2 over‐expressing ischaemic retinas, somatostatin analogues increased cell death, and octreotide also increased glutamate release. To explain this reversal of the anti‐ischaemic effect of somatostatin agonists in the presence of sst2 over‐expression, we tested sst2 desensitisation because of internalisation or altered receptor function. We observed that (i) sst2 was not internalised, (ii) among G protein‐coupled receptor kinases (GRKs) and regulators of G protein signalling (RGSs), GRK1 and RGS1 expression increased following ischaemia, (iii) both GRK1 and RGS1 were down‐regulated by octreotide in wild‐type ischaemic retinas, (iv) octreotide down‐regulated GRK1 but not RGS1 in sst2 over‐expressing ischaemic retinas. These results demonstrate that sst2 activation protects against retinal ischaemia. However, in the presence of sst2 over‐expression sst2 is functionally desensitised by agonists, possibly because of sustained RGS1 levels.

The Neuropeptide Systems and their Potential Role in the Treatment of Mammalian Retinal Ischemia: A Developing Story

“…These observations have been replicated in an ex vivo model of the ischemic mouse retina, where the neuroprotective effects of SRIF have been shown to be mediated by the sst2 receptor. Indeed, these studies showed that an increased expression of functional sst2 receptors [40] or the use of SRIF or SRIF receptor agonists, such as the multireceptor ligand pasireotide and the sst2 receptor agonist octreotide [41], are effective in reducing the number of apoptotic neurons, the expression of apoptotic markers, such as caspase-3 mRNA, and the release of glutamate. In contrast, cell death is significantly increased after blocking sst2 receptors with the sst2 receptor antagonist cyanamide [41].…”

“…Indeed, these studies showed that an increased expression of functional sst2 receptors [40] or the use of SRIF or SRIF receptor agonists, such as the multireceptor ligand pasireotide and the sst2 receptor agonist octreotide [41], are effective in reducing the number of apoptotic neurons, the expression of apoptotic markers, such as caspase-3 mRNA, and the release of glutamate. In contrast, cell death is significantly increased after blocking sst2 receptors with the sst2 receptor antagonist cyanamide [41]. In addition, intravitreal administration of SRIF or sst2 receptor agonists, have been reported to protect the retina from AMPA-induced neurotoxicity in vivo [42].…”

“…Indeed, in sst2 receptor over-expressing ischemic retinas, SRIF analogues increased cell death, and octreotide also increased glutamate release. This apparent contradiction has been clarified by experimental data at pharmacological and molecular level showing that over-expressed sst2 receptors are likely to be rapidly desensitized by agonists, thus resulting in a decrease of their functional activity [41]. …”

The β isoenzyme of Ca2+/calmodulin-dependent kinase type II as possible mediator of somatostatin functions in pituitary tumour cells

“…When indicated, GC cells were treated in the absence or in the presence of 100 nM SRIF (30 min) before the assay. Using published protocols (Cervia et al , 2008, total RNA was extracted with the RNeasy Mini Kit with DNAse digestion (Qiagen, Hilden, Germany), according to the manufacturer's recommended procedure. After solubilization in RNase-free water, total RNA was quantified by Bio-Rad SmartSpec 3000 spectrophotometer (Hercules, CA, USA).…”

Neuropeptides, Trophic Factors, and Other Substances Providing Morphofunctional and Metabolic Protection in Experimental Models of Diabetic Retinopathy

“…This drug proved to be effective in delaying or to some extent reverting symptoms of DR (Grant et al, 2000). Acting on sst2 receptors, it may possibly control inflammatory processes (Pinter et al, 2006), endothelial symptoms (Cervia et al, 2012), and also to some extent neural symptoms (Cervia et al, 2008;Vasilaki and Thermos, 2009;Vasilaki et al, 2002). Additional peptide and nonpeptide analogs should be involved in future experiments.…”