Harder and colleagues report significant changes in pathways that regulate the metabolism of glucose and pyruvate in glaucomatous mice (DBA/2J strain) using multiple techniques including RNA sequencing and metabolomics. Their findings are consistent with a decline in retinal pyruvate levels and altered glucose metabolism prior to detectable optic nerve degeneration. Oral supplementation of pyruvate or rapamycin, an mTOR inhibitor, provided strong neuroprotection against glaucomatous degeneration using a number of in vitro and in vivo paradigms. Functional outcome measures included enhanced retinal function in DBA/2J mice, measured by pattern electroretinogram recordings, and anterograde axonal transport visualized by cholera toxin B subunit accumulation in brain targets. Collectively, these findings suggest that dysfunctional metabolism underlies retinal ganglion cell vulnerability and have promising clinical implications for the use of pyruvate or rapamycin oral supplementation as neuroprotective therapy for glaucoma. This study is important and adds new knowledge to our current understanding of metabolic deficits in retinal ganglion cells as an important contributing factor to vision loss in glaucoma.
Dysfunctional metabolism underlies retinal ganglion cell vulnerability
An issue that needs careful consideration, however, is the clinical use of rapamycin as neuroprotectant. Other groups have demonstrated that rapamycin-mediated inhibition of mTOR is detrimental for retinal ganglion cell survival and regeneration.1-3 The inconsistency in outcomes with rapamycin treatment, often paradoxical, has been well documented not only in the context of neurobiology but also in cancer and metabolic research. This disparity has been attributed to non-specific effects depending on the time-course of rapamycin administration.4,5 Specifically, chronic rapamycin treatment can lead to off target effects and activation of compensatory pathways unrelated to mTOR inhibition.6-8 For example, prolonged rapamycin treatment in mice increases longevity by reducing mTOR, but leads to glucose intolerance and insulin resistance through disruption of other signaling pathways.8 Therefore, caution should be exercised regarding the use of chronic rapamycin as neuroprotective treatment for glaucoma.