Insulin Signaling as a Therapeutic Target in Glaucomatous Neurodegeneration

Abstract

Glaucoma is a multifactorial disease that is conventionally managed with treatments to lower intraocular pressure (IOP). Despite these efforts, many patients continue to lose their vision. The degeneration of retinal ganglion cells (RGCs) and their axons in the optic tract that characterizes glaucoma is similar to neurodegeneration in other age-related disorders of the central nervous system (CNS). Identifying the different molecular signaling pathways that contribute to early neuronal dysfunction can be utilized for neuroprotective strategies that prevent degeneration. The discovery of insulin and its receptor in the CNS and retina led to exploration of the role of insulin signaling in the CNS. Historically, insulin was considered a peripherally secreted hormone that regulated glucose homeostasis, with no obvious roles in the CNS. However, a growing number of pre-clinical and clinical studies have demonstrated the potential of modulating insulin signaling in the treatment of neurodegenerative diseases. This review will highlight the role that insulin signaling plays in RGC neurodegeneration. We will focus on how this pathway can be therapeutically targeted to promote RGC axon survival and preserve vision.

Identifying TNF and IL6 as potential hub genes and targeted drugs associated with scleritis: A bio-informative report

“…In the case of IL6, insulin resistance and stimulation of IL6 seem to be mechanistically related (62). Currently, an increasing number of basic experiments and clinical studies have demonstrated that the modulation of insulin signaling has a considerable role in treating neurodegenerative disease (63)(64)(65). Insulin has anti-inflammatory effects, and the application of insulin can reduce pro-inflammatory mediators, especially TNFa and IL6, in animal models of endotoxemia (66-68).…”

Systemic Treatment with Pioglitazone Reverses Vision Loss in Preclinical Glaucoma Models

“…It is conceivable that resolution of either metabolic or neuroinflammatory stress through PPARγ activity reverses the dysregulation and leads to the observed increase in retinal function. Additionally, retinal function may be increased through a pioglitazone-induced increase in insulin signaling, which may play a critical role in a number of glaucoma phenotypes, including mitochondrial dysfunction, astrocytic activity, and synaptic plasticity [ 58 ]. RGC dendrite retraction is an early retinal response to elevated IOP that leads to functional deficits and neuronal death [ 10 ].…”

“…In mouse models of optic nerve injury, insulin administration—systemic or as eye drops—has the ability to promote regeneration of the dendrites and synapses of retinal neurons [ 61 , 62 ]. However, insulin signaling also supports RGC survival by decreasing neuroinflammation and altering the activity of retinal glial elements [ 58 ]. It is intriguing to speculate that pioglitazone-mediated activation of the insulin receptor intensifies the effect of the available insulin [ 63 ], leading to a similar protective effect as exogenous application.…”

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“…Preventing complement activation [192] and up-regulating protective endogenous genes and transcription factors [193,194] at the ONH/LC and thalamic and cortical regions is another useful strategy. Many other drugs and treatments [168,[195][196][197][198][199][200][201][202][203][204] including senolytic drugs [195], glutamate receptor antagonists [197], delta-opioids [198], histone deacetylase inhibitors [199], vascular-specific phosphatase blockers [168], alpha-2 adrenergic agonists [200], sigma-receptor agonists [201], and various neurotrophic factors [202,203]. Furthermore, new conjugate/hybrid drugs with multi-pharmacophoric activities [205][206][207][208][209][210] directed at different intervention points of the RGC soma and axonal demise [170][171][172][173][174][175][176] are showing promise as neuroprotective agents.…”