A metabolic switch in brain: glucose and lactate metabolism modulation by ascorbic acid

Abstract

In this review, we discuss a novel function of ascorbic acid in brain energetics. It has been proposed that during glutamatergic synaptic activity neurons preferably consume lactate released from glia. The key to this energetic coupling is the metabolic activation that occurs in astrocytes by glutamate and an increase in extracellular [K+]. Neurons are cells well equipped to consume glucose because they express glucose transporters and glycolytic and tricarboxylic acid cycle enzymes. Moreover, neuronal cells express monocarboxylate transporters and lactate dehydrogenase isoenzyme 1, which is inhibited by pyruvate. As glycolysis produces an increase in pyruvate concentration and a decrease in NAD+/NADH, lactate and glucose consumption are not viable at the same time. In this context, we discuss ascorbic acid participation as a metabolic switch modulating neuronal metabolism between rest and activation periods. Ascorbic acid is highly concentrated in CNS. Glutamate stimulates ascorbic acid release from astrocytes. Ascorbic acid entry into neurons and within the cell can inhibit glucose consumption and stimulate lactate transport. For this switch to occur, an ascorbic acid flow is necessary between astrocytes and neurons, which is driven by neural activity and is part of vitamin C recycling. Here, we review the role of glucose and lactate as metabolic substrates and the modulation of neuronal metabolism by ascorbic acid.

Adenosine A2B receptor activation stimulates glucose uptake in the mouse forebrain

“…This predicts that A 2B R activation can regulate neuronal besides astrocytic metabolism in those brain areas. Normally, glutamatergic neurons use either glucose or lactate [42], so if A 2B R activation increases glucose use in pyramidal cells, those neurons would concomitantly take up less lactate. Consequently, A 2B R blockade would tip the balance to greater lactate uptake.…”

Targeting of multiple metabolites in neural cells monitored by using protein-based carbon nanotubes

“…Lactate is then oxidized by neurons to yield energy, playing a neuroprotective role after cerebral ischemia [32,33]. According to other authors, oxidation of lactate by neurons would only be possible if the glycolytic consumption of glucose or its transport were inhibited [34]. The cellular system employed in this study contains uniquely neuronal cells [35].…”

The neurochemical profile quantified by in vivo 1H NMR spectroscopy

“…Glutathione acts in concert with ascorbate that is also an enzyme co-factor in the brain and is involved in maintenance of brain homeosthasis. As such, ascorbate is involved in antioxidant protection and regulation of glucose metabolism (Castro et al, 2009), but not exclusively. It also plays a role in myelin formation (Eldridge et al, 1987), enhancement of synaptic activity (Rebec and Pierce, 1994) and direct protection from excitotoxicity (Qiu et al, 2007).…”

“…Lactate generated and released by astrocytes has been suggested to serve as an energy substrate for neurons, especially during synaptic activity (Pellerin and Magistretti, 1994) and during re-oxygenation after stroke ). Ascorbate may play a role in this process by regulating glucose transport and glycolysis (Castro et al, 2009). Cerebral ascorbate concentration decreases during development to adult age (Kulak et al, 2010;Terpstra et al, 2010) therefore suggesting that ascorbate-induced glucose transport inhibition and lactate transport stimulation may be higher in early developmental stages than in adulthood.…”