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Pyrroloquinoline Quinone and NAD+ Metabolism in Glaucoma: A Molecular Rationale for Combined Neuroprotection
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DOI：10.3390/ph19081268.png)
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Abstract
En 中文
Glaucoma is the leading cause of irreversible blindness worldwide and a paradigmatic age-related neurodegenerative disease in which retinal ganglion cells (RGCs) are selectively lost through mechanisms that extend beyond intraocular pressure. Age-dependent NAD+ depletion in RGCs, compounded by the progressive impairment of NAD+ biosynthesis and by the hyperactivation of NAD+-consuming enzymes under oxidative stress, defines a metabolic vulnerability that current pressure-lowering therapy does not address. Pyrroloquinoline quinone (PQQ) is a tricyclic ortho-quinone present in plant-derived foods that acts on the NAD+ pool through a mechanism distinct from that of conventional precursors. Rather than expanding the pool by net synthesis, PQQ binds lactate dehydrogenase and oxidizes NADH to NAD+ through catalytic redox cycling, raising NAD+ availability without altering the total dinucleotide content and independently of the two biosynthetic enzymes selectively impaired in glaucomatous RGCs. The resulting increase in NAD+ availability activates sirtuin-dependent programs that drive mitochondrial biogenesis. PQQ additionally engages an NRF2-dependent antioxidant response, addressing molecular deficits directly implicated in glaucomatous RGC degeneration. In retinal cell models, PQQ preserves ATP content and viability under mitochondrial stress. In vivo, it protects RGC density in optic nerve degeneration models and elevates NAD+ along the visual pathway. A randomized clinical trial demonstrated functional improvement in glaucoma patients receiving a PQQ-containing combination. The redox biochemistry of PQQ places it at a mechanistic intersection with the NAD+ deficit that characterizes glaucomatous neurodegeneration. Its complementarity with conventional NAD+ precursors and neuroprotective compounds acting on distinct molecular targets supports the design of combination regimens addressing multiple dimensions of RGC vulnerability. Critical questions regarding bioavailability, molecular target characterization, and clinical validation in dedicated trials remain open.
Keywords:
pyrroloquinoline quinone
NAD<sup>+</sup> metabolism
aging
age-related disease
glaucoma
retinal ganglion cell
neuroprotection
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