Abstract
Somatostatin (SST) is a neuroprotective peptide but little is known regarding the potential role of its anti-inflammatory effects on retinal neuroprotection. In a previous study, we provided the first evidence that topical (eye drops) administration of SST prevents retinal neurodegeneration in streptozotocin (STZ)-induced diabetic rats. However, STZ by itself could cause neurotoxicity, thus acting as a confounding factor. The aims of the present study were: (1) to test the effect of topical administration of SST in the db/db mouse model, a spontaneous model of type 2 diabetes, thus avoiding the confounding effect of STZ on neurodegeneration; (2) to further explore the anti-inflammatory mechanisms of SST in glial cells. This task was performed by using mouse retinal explants and cell cultures. In summary, we confirm that SST topically administered was able to prevent retinal neurodysfunction and neurodegeneration in db/db mice. Furthermore, we found that SST prevented the activation of the classical M1 response of Bv.2 microglial cells upon Lipopolysaccharide (LPS) stimulation as a potent pro-inflammatory trigger. The anti-inflammatory effect of SST in Bv.2 cells was also observed in response to hypoxia. In conclusion, we provide evidence that the neuroprotective effect of SST in diabetic retinas can be largely attributed to anti-inflammatory mechanisms.
Highlights
Several reports indicate that somatostatin (SST) is locally produced by the retina in relatively abundant amounts and plays a key role in maintaining retinal normal homeostasis [1,2,3]
In diabetic retinopathy (DR), there is a downregulation of retinal expression of SST [4], which is associated with a dramatic decrease in intravitreal SST levels in both Proliferative Diabetic Retinopathy (PDR) [2,5] and Diabetic Macular Edema (DME) [6]
We provided the first evidence that topical administration of SST prevents retinal neurodegeneration in streptozotocin (STZ)-induced diabetic rats [7] and arrests the progression of neurodysfunction in subjects with type 2 diabetes [8]
Summary
Several reports indicate that somatostatin (SST) is locally produced by the retina in relatively abundant amounts and plays a key role in maintaining retinal normal homeostasis [1,2,3]. Direct histopathological evidence of specific neurotoxic damage caused by intracerebroventricular STZ administration in the fornix, anterior hippocampus and periventricular structures has been reported [13] For all these reasons, the use of a spontaneous model of diabetes seems recommendable for investigating the underlying mechanisms of retinal neurodegeneration associated with diabetes and for testing new drugs. This is an important issue because it is well-established that inflammation is a crucial underlying mechanism of glial (macro- and micro-) activation and neuronal death in the diabetic retina On this basis, the aims of the present study are: (1) to test the effect of topical administration of SST in a diabetes-induced model of retinal neurodegeneration, avoiding the potential confounding effects of STZ. This task was performed by using mouse retinal explants and cell cultures
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