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] i by activating sst 2 receptors. Inhibition of AC activity is only partly responsible for this eect, and other transduction pathways may be involved.

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In the pathogenesis of many disorders, neuronal death plays a key role. It is now assumed that neurodegeneration is caused by multiple and somewhat converging/overlapping death mechanisms, and that neurons are sensitive to unique death styles. In this respect, major advances in the knowledge of different types, mechanisms, and roles of neurodegeneration are crucial to restore the neuronal functions involved in neuroprotection. Several novel concepts have emerged recently, suggesting that the modulation of the neuropeptide system may provide an entirely new set of pharmacological approaches. Neuropeptides and their receptors are expressed widely in mammalian retinas, where they exert neuromodulatory functions including the processing of visual information. In multiple models of retinal diseases, different peptidergic substances play neuroprotective actions. Herein, we describe the novel advances on the protective roles of neuropeptides in the retina. In particular, we focus on the mechanisms by which peptides affect neuronal death/survival and the vascular lesions commonly associated with retinal neurodegenerative pathologies. The goal is to highlight the therapeutic potential of neuropeptide systems as neuroprotectants in retinal diseases.

Of the five cloned somatostatin (SRIF: somatotropin release inhibitory factor) receptors (sst1-5), only sst2 and sst5 receptors appear to be endogenously expressed and functionally active in AtT-20 mouse anterior pituitary tumour cells. In this study, the presence and the functional coupling of SRIF receptors to G-protein in AtT-20 cells was evaluated by receptor autoradiography and guanosine-5'-Omicron-(3-[35S]thio)-triphosphate ([35S]GTPgammaS) binding, respectively. In addition, transcriptional effects via the serum response element (SRE) were assessed in AtT-20-SRE-luci cells, engineered to express constitutively SRE upstream of the luciferase reporter gene. [125I]LTT-SRIF-28, [125I]CGP 23996 and [125I]Tyr3-octreotide binding illustrates the high level of sst2/5 receptor in AtT-20 cell membranes. SRIF-14 and SRIF-28 produced a concentration-dependent increase in [35S]GTPgammaS binding (pEC50=6.72 and 7.45; Emax=79 and 74.9, respectively) which was completely abolished by pertussis toxin. sst2/5 receptor-selective ligands caused a concentration-dependent increase in [35S]GTPgammaS binding (pEC50=7.74-5.84; Emax=76.6-20.2) while sst1/3/4 receptor-selective ligands were devoid of activity. The binding profiles of [125I]LTT-SRIF-28 and the inhibition of cAMP accumulation correlated highly significantly with their corresponding [35S]GTPgammaS binding profiles (r=0.862 and 0.874, respectively). The effects of the sst2 receptor-preferring agonists Tyr3-octreotide and BIM 23027 on [35S]GTPgammaS binding, but not those of SRIF-14 and the sst5/1 receptor selective-agonist L-817,818, were competitively antagonised by the sst2 receptor antagonist d-Tyr8-CYN 154806 (pKB=7.36 and 7.72, respectively; slope factors not significantly different from unity). In AtT-20-SRE-luci cells, which carry a SRE-luciferase construct functioning in a very efficient manner, SRIF and its analogues did not affect luciferase activity. Taken together, these results demonstrate that in AtT-20 cells the expression of sst2 and sst5 receptors fit with their functional coupling to G(i/o)-proteins. The pharmacological implications of the existence of different ligand/receptor complexes are discussed. However, the intracellular pathways coupled to the activation of sst2 and sst5 receptors appear not to modulate the SRE-mediated transcriptional activity, suggesting that SRIF effects on gene expression coupled to mechanisms that have promoters other than SRE.

Dystrophin (dys) mutations predispose Duchenne muscular disease (DMD) patients to brain and retinal complications. Although different dys variants, including long dys products, are expressed in the retina, their function is largely unknown. We investigated the putative role of full-length dystrophin in the homeostasis of neuro-retina and its impact on synapsis stabilization and cell fate. Retinas of mdx mice, the most used DMD model which does not express the 427-KDa dys protein (Dp427), showed overlapped cell death and impaired autophagy. Apoptotic neurons in the outer plexiform/inner nuclear layer and the ganglion cell layer had an impaired autophagy with accumulated autophagosomes. The autophagy dysfunction localized at photoreceptor axonal terminals and bipolar, amacrine, and ganglion cells. The absence of Dp427 does not cause a severe phenotype but alters the neuronal architecture, compromising mainly the pre-synaptic photoreceptor terminals and their post-synaptic sites. The analysis of two dystrophic mutants of the fruit fly Drosophila melanogaster, the homozygous Dys E17 and Dys EP3397 , lacking functional large-isoforms of dystrophin-like protein, revealed rhabdomere degeneration. Structural damages were evident in the internal network of retina/lamina where photoreceptors make the first synapse. Both accumulated autophagosomes and apoptotic features were detected and the visual system was functionally impaired. The reactivation of the autophagosome turnover by rapamycin prevented neuronal cell death and structural changes of mutant flies and, of interest, sustained autophagy ameliorated their response to light. Overall, these findings indicate that functional full-length dystrophin is required for synapsis stabilization and neuronal survival of the retina, allowing also proper autophagy as a prerequisite for physiological cell fate and visual properties.

Somatostatin (SRIF) is a cyclic peptide widely distributed throughout the body with important physiological effects (mostly inhibitory) on several organ systems. SRIF may act as a neurohormone, neurotransmitter, neuromodulator or as a local factor, and exhibits potent antiproliferative activity. SRIF effects have formed the basis for the clinical use of SRIF analogues in the treatment of endocrine tumours, acromegaly and gastrointestinal disorders. Several data suggest that SRIF may also be a therapeutic target in a number of different diseases.The binding of SRIF to its five G-protein coupled receptors leads to modulation of multiple transduction pathways, including adenylyl cyclase, guanylyl cyclase, phospholipase C, K + and Ca 2+ channels, phospholipase A 2 , nitric oxide, Na + /H + exchanger, protein phosphatases and MAP kinases. The diversity of the transduction pathways reflects the pleiotropic actions of SRIF. However, our current understanding depicts a rather complicated picture and conflicting results have also been reported. Data are mostly based on in vitro experiments, and parallels with the real in vivo conditions are not so obvious. Due to the clinical relevance of the SRIF system, the elucidation of the intracellular role of endogenous SRIF receptors may offer new therapeutic perspectives. These will enable development of specific pharmacological signalling modulators which can be incorporated into the therapeutic arsenal.The present review represents a detailed and exhaustive summary which covers the latest advances in the transduction pathways of SRIF receptors.

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