Resveratrol Inhibits Neuronal Apoptosis and Elevated Ca2+/Calmodulin-Dependent Protein Kinase II Activity in Diabetic Mouse Retina

Abstract

OBJECTIVEThis study investigated the effects of resveratrol, a natural polyphenol with neuroprotective properties, on retinal neuronal cell death mediated by diabetes-induced activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII).RESEARCH DESIGN AND METHODSDiabetes was induced in C57BL/6 mice by five consecutive intraperitoneal injections of 55 mg/kg streptozotocin (STZ). Control mice received buffer. All mice were killed 2 months after the injections, and the extent of neuronal cell death, CaMKII, and phospho-CaMKII protein expression levels and CaMKII kinase activity were examined in the retinas. To assess the role of CaMKII in the death of retinal neurons, a small-interfering RNA (siRNA) or specific inhibitor of CaMKII was injected into the right vitreous humor, and vehicle only was injected into the left vitreous humor, 2 days before death. Resveratrol (20 mg/kg) was administered by oral gavage daily for 4 weeks, beginning 1 month after the fifth injection of either STZ or buffer.RESULTSThe death of retinal ganglion cells (RGCs), CaMKII, phospho-CaMKII protein levels, and CaMKII activity were all greatly increased in the retinas of diabetic mice compared with controls, 2 months after induction of diabetes. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL)-positive signals co-localized with CaMKII- and phospho-CaMKII immunoreactive RGCs. However, in addition to CaMKII knockdown and inhibition by siRNA or a specific inhibitor, respectively, resveratrol provided complete protection from diabetes-induced retinal cell death.CONCLUSIONSIn the present study, resveratrol prevented diabetes-induced RGC death via CaMKII downregulation, implying that resveratrol may have potential therapeutic applications for prevention of diabetes-induced visual dysfunction.

<b><i>Aralia elata</i></b> Prevents Neuronal Death by Downregulating Tonicity Response Element Binding Protein in Diabetic Retinopathy

“…Increased cellular apoptosis is reportedly associated with Bax overexpression and the latter may be responsible for neuronal cell loss in the GCL of diabetic rats [26] . Additionally, Ca 2+ /calmodulin-dependent protein kinase II is possibly involved in the cell death pathway of RGCs in the STZ-induced diabetic retina [27] . Furthermore, protein kinase C-δ activation apparently contributes to neuroretinal apoptosis in the diabetic rat by inhibiting Akt-mediated signaling pathways [27] .…”

The Significance of Vascular and Neural Apoptosis to the Pathology of Diabetic Retinopathy

“…111,112 Changes in intracellular calcium signaling as a result of extracellular glutamate activity or changes in the expression of calcium-binding proteins and the activity of calcium-responsive enzymes such as CamKII could also alter the physiological output of the retina. 62,113 Early compromise of specific visual functions, such as contrast sensitivity and dark adaptation, are indicators of functional changes within the photoreceptors or other neuronal components of the retina. 114 -117 Alterations in the biochemistry and physiology of retinal neurons may occur independently or as a precursor to their ultimate demise by apoptosis, making loss of visual function a potential consequence of cell loss by apoptosis and maladaptive dysfunction of surviving cells.…”

Curcumin Inhibits Neuronal Loss in the Retina and Elevates Ca2+/Calmodulin-Dependent Protein Kinase II Activity in Diabetic Rats

“…9,48,49 Previous studies, which have investigated the relationship between diabetes and CaMKII, have reported that diabetes stimulates the action of CaMKII, which plays an important role in the pathogenesis of diabetic complications, such as diabetic retinopathy. [49][50][51][52] In this study, we found that compared with the healthy rats of the control group, active CaMKII (p-CaMKII) and cleaved caspase-3 levels were significantly increased in STZ-induced diabetic rats. However, these increases in the levels of active CaMKII (pCaMKII) and cleaved caspase-3 levels were minimized by treating the diabetic rats with curcumin.…”

“…Our results agree well with the results of a study that showed resveratrol, another polyphenol whose physiological properties are similar to those of curcumin, suppresses CaMKII action and CaMKII-mediated RGC loss induced by diabetes. 50 We have not been able to clearly determine the precise mechanism by which curcumin inactivates CaMKII action and prevents neuronal death. However, we believe that this mechanism is also involved in the regulation of glutamate levels.…”