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

Abstract

The multiplicity of peptidergic receptors and of the transduction pathways they activate offers the possibility of important advances in the development of specific drugs for clinical treatment of central nervous system disorders. Among them, retinal ischemia is a common clinical entity and, due to relatively ineffective treatment, remains a common cause of visual impairment and blindness. Ischemia is a primary cause of neuronal death, and it can be considered as a sort of final common pathway in retinal diseases leading to irreversible morphological damage and vision loss. Neuropeptides and their receptors are widely expressed in mammalian retinas, where they exert multifaceted functions both during development and in the mature animal. In particular, in recent years somatostatin and pituitary adenylate cyclase activating peptide have been reported to be highly protective against retinal cell death caused by ischemia, while data on opioid peptides, angiotensin II, and other peptides have also been published. This review provides a rationale for harnessing the peptidergic receptors as a potential target against retinal neuronal damages which occur during ischemic retinopathies.

Neuroprotection as a Therapeutic Target for Diabetic Retinopathy

“…The neuropeptide SST and its five receptor subtypes (sst 1 –sst 5 ) are expressed in the retina, where they are involved in multiple functions [ 195 ]. SST acting at sst 2 expressed by bipolar cells may control glutamate release in the retina [ 154 , 155 , 196 ], suggesting that SST may protect neurons from apoptosis caused by extracellular glutamate levels in DR.…”

Neuroprotective Peptides in Retinal Disease

“…These observations indicate a link between neural and vascular damage in these diseases and indicate that peptide neuroprotection may also prevent pathologic vascular changes. Additionally, there is a general agreement that neuropeptides are coupled to multiple components of transduction pathways [13,264], which may converge in restoring neuronal functions. The diversity of signaling reflects the pleiotropic actions of peptides; at the cellular level, many mechanisms are involved in the amplification effects.…”

“…Clinically, the fact that lower vitreous levels and lower intraocular production of SRIF were found in patients with diabetic macular edema, chronic uveitis macular edema, and quiescent intraocular inflammation [122,123] suggests that SRIF alterations may be directly involved in the pathogenesis of these conditions. On the other hand, different pre-clinical observations supported a role for SRIF as a neuroprotective factor in a variety of retinal diseases [13,112,124,125]. The importance of the SRIF system in protecting the retina from noxious stimuli has been confirmed in recent years.…”

“…By definition, neuropeptides are small protein-like molecules (in some cases “normal” proteins), which function primarily as transmitter molecules in neuronal cells [8]. Some of them have been found to be important for the regulation of cell death/survival in different neuronal systems [9,10,11,12,13]. In particular, neuropeptides and their receptors are expressed widely in mammalian retinas, where they exert multifaceted functions both during development and in the mature animal [14].…”

Current Evidence for a Role of Neuropeptides in the Regulation of Autophagy

“…NPY is one of the most abundant neuropeptides within the brain and exerts (through its receptors, named Y1 to 6) an important role in many physiological functions such as food intake, energy homeostasis, circadian rhythm, cognition, stress response, neurogenesis, and neuroprotection [6, 55–58]. …”