Inorganic nitrate stores, astrocyte metabolism and brain health: An emerging paradigm

Abstract

Inorganic nitrate plays a crucial role in the regulation of cerebral blood flow and neurotransmission through its conversion to nitric oxide (NO). Astrocytes are star-shaped glial cells and contribute to maintain the blood-brain barrier integrity, regulate neuronal metabolism, support synaptic plasticity and facilitate neurovascular coupling. Inorganic nitrate widely distributed through all organs, with main reservoirs in skeletomuscular and skin tissues. These reserves are easily accessible via bloodstream and processed into nitrite and NO mainly in liver. Processing nitrate/nitrite into NO at organ with main glycogen stores, could suggest an evolutionary coordination between energy metabolism and NO generating pathways. Such spatial arrangement may facilitate the synchronised mobilisation during periods of enhanced metabolic demand, optimising both fuel utilisation and vascular response and assuring optimal fuel distribution. Astrocytes store glycogen in the brain, which support neuronal metabolism during periods of increased neural activity and hypoglycaemia.

This review explores the hypothesis that inorganic nitrate may be stored alongside glycogen in astrocytes and serve as critical reserves for NO production in the brain, particularly during hypoxic conditions. We examine the emerging evidence that astrocytes serve as key mediators in this alternative nitrate-nitrite-NO pathway, potentially influencing cerebrovascular regulation, neuronal energetics, and cognitive function. The integration of findings across molecular, cellular, and systems neuroscience offers new perspectives on how inorganic nitrate intake might support brain metabolism and could inform both preventive strategies and therapeutic interventions for neuro-degenerative disorders such as age-related dementia, stroke or Parkinson's Disease.