Neurobiology of vitamin C: Expanding the focus from antioxidant to endogenous neuromodulator

Ascorbic acid (AA) is a water-soluble vitamin (C) found in all bodily organs. Most mammals synthesize it, humans are required to eat it, but all mammals need it for healthy functioning. AA reaches its highest concentration in the brain where both neurons and glia rely on tightly regulated uptake from blood via the glucose transport system and sodium-coupled active transport to accumulate and maintain AA at millimolar levels. As a prototype antioxidant, AA is not only neuroprotective, but also functions as a cofactor in redox-coupled reactions essential for the synthesis of neurotransmitters (e.g., dopamine and norepinephrine) and paracrine lipid mediators (e.g., epoxiecoisatrienoic acids) as well as the epigenetic regulation of DNA. Although redox capacity led to the promotion of AA in high doses as potential treatment for various neuropathological and psychiatric conditions, ample evidence has not supported this therapeutic strategy. Here, we focus on some long-neglected aspects of AA neurobiology, including its modulatory role in synaptic transmission as demonstrated by the long-established link between release of endogenous AA in brain extracellular fluid and the clearance of glutamate, an excitatory amino acid. Evidence that this link can be disrupted in animal models of Huntington's disease is revealing opportunities for new research pathways and therapeutic applications (e.g., epilepsy and pain management). In fact, we suggest that improved understanding of the regulation of endogenous AA and its interaction with key brain neurotransmitter systems, rather than administration of AA in excess, should be the target of future brain-based therapies.