Oral pyruvate prevents glaucomatous neurodegeneration

Abstract

Intraocular pressure-sensitive retinal ganglion cell degeneration is a hallmark of glaucoma, the leading cause of irreversible blindness. Converging evidence indicates that agerelated bioenergetic insufficiency increases the vulnerability of retinal ganglion cells to intraocular pressure. To investigate further, we used metabolomics and RNA-sequencing to examine early glaucoma in DBA/2J mice. We demonstrate an intraocular pressure-dependent decline in retinal pyruvate levels coupled to dysregulated glucose metabolism prior to detectable optic nerve degeneration. Oral supplementation of pyruvate strongly protected from neurodegeneration in pre-clinical models of glaucoma. We detected mTOR activation at the mechanistic nexus of neurodegeneration and metabolism. Rapamycin-induced inhibition of mTOR robustly prevented glaucomatous neurodegeneration. Bioenergetic enhancement, in combination with intraocular pressure reduction, therefore provides a readily translatable strategy that warrants investigation in clinical trials.

Retinal energy metabolism in health and glaucoma

“…In vitro, we have recently demonstrated that pyruvate rescues RGCs from both glucose deprivation-induced death and oxidative injury. (Williams et al, 2020) We have also shown that oral pyruvate supplementation has a robust neuroprotective effect in both the DBA/2J mouse and the laser-induced rat model of glaucoma. (Williams et al, 2020) Furthermore, pyruvate and nicotinamide exhibit neuroprotective synergy in the DBA/2J model.…”

“…(Williams et al, 2020) We have also shown that oral pyruvate supplementation has a robust neuroprotective effect in both the DBA/2J mouse and the laser-induced rat model of glaucoma. (Williams et al, 2020) Furthermore, pyruvate and nicotinamide exhibit neuroprotective synergy in the DBA/2J model. (Williams et al, 2020) 6.2.6 mTOR mTOR (mammalian target of rapamycin) is a serine/threonine protein kinase that has been shown to have roles in cell growth, development and survival, as well as in response to upstream events including growth factors, hormones, DNA damage and energy metabolites.…”

“…(Williams et al, 2020) Furthermore, pyruvate and nicotinamide exhibit neuroprotective synergy in the DBA/2J model. (Williams et al, 2020) 6.2.6 mTOR mTOR (mammalian target of rapamycin) is a serine/threonine protein kinase that has been shown to have roles in cell growth, development and survival, as well as in response to upstream events including growth factors, hormones, DNA damage and energy metabolites. (Hwang et al, 2008;Jewell and Guan, 2013) Translational control by mTOR has been shown to be essential for neuronal and synaptic plasticity.…”

Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction

“…Continued elucidation of the mechanisms of Wallerian degeneration has further demonstrated the role of NAD in axon survival. NAD decreases in damaged axons (33), while expression of the Wld S allele or viral overexpression/modified localization of NMNATs are protective, restoring NAD levels (5,(34)(35)(36)(37). Increased NAD appears to exhibit numerous functional local roles in this context, including providing sufficient substrate to mitigate local SARM1-dependent NAD consumption and protecting against nicotinamide mononucleotide (NMN) induced axon damage (38,39).…”

Potential Therapeutic Benefit of NAD+ Supplementation for Glaucoma and Age-Related Macular Degeneration

“…Its age-related depletion affects the biological coping mechanisms associated with inflammation, oxidative stress, and accumulation of damaged molecules [ 16 ]. All these alterations are intrinsically linked to retinal degenerative pathologies, such as glaucoma and AMD, and with compelling evidence that NAD + supplementation would be a promising intervention in these diseases [ 17 ], alone or possibly in combination with other nutraceutical agents such as saffron [ 18 , 19 ] and zeaxanthin [ 20 , 21 ], or pyruvate [ 22 ], which together provide neuroprotection by targeting multiple disease mechanisms. This review focuses on the shared pathophysiological mechanisms of glaucoma and AMD and the potential role that NAD + may play in their mitigation.…”