Antioxidant and bioenergetic coupling between neurons and astrocytes

Abstract

Oxidative and nitrosative stress underlie the pathogenesis of a broad range of human diseases, in particular neurodegenerative disorders. Within the brain, neurons are the cells most vulnerable to excess reactive oxygen and nitrogen species; their survival relies on the antioxidant protection promoted by neighbouring astrocytes. However, neurons are also intrinsically equipped with a biochemical mechanism that links glucose metabolism to antioxidant defence. Neurons actively metabolize glucose through the pentose phosphate pathway, which maintains the antioxidant glutathione in its reduced state, hence exerting neuroprotection. This process is tightly controlled by a key glycolysis-promoting enzyme and is dependent on an appropriate supply of energy substrates from astrocytes. Thus brain bioenergetic and antioxidant defence is coupled between neurons and astrocytes. A better understanding of the regulation of this intercellular coupling should be important for identifying novel targets for future therapeutic interventions.

Glutathione in multiple sclerosis: More than just an antioxidant?

“…21 Astrocytes also display higher basal and stress-induced activity of Nrf2, leading to enhanced expression of Phase II detoxification enzymes and antioxidant enzymes, such as γ-GCS, which contribute to increased GSH concentration. 20 On the other hand, neurons, although capable of synthesizing GSH, depend on neighboring astrocytes for the supply of GSH precursors. Neuronal GSH content is not complemented by direct GSH uptake, because extracellular GSH concentration is very low and so Figure 1.…”

“…18 The expression of the vast majority of antioxidant enzymes is controlled by binding of the transcription factor called nuclear factor-erythroid 2-related factor 2 (Nrf2) to the antioxidant response element in the promoters of target genes, such as heme oxygenase-1, NADPH:quinone oxidoreductase-1, peroxiredoxins and several proteins involved in glutathione (GSH) metabolism. 19,20 In inflammatory MS lesions, the expression of Nrf2-regulated antioxidant proteins increases. 7 This suggests that in response to oxidative and inflammatory damage, the main protective cellular antioxidant mechanisms, namely those regulated by Nrf2, are activated early in lesion formation; however, enhanced levels of endogenous antioxidants are detected concomitantly with several oxidative stress markers, indicating that the endogenous antioxidant response is not sufficient to restore the delicate redox-balance and prevent oxidative damage.…”

“…Neurons can, in turn, take up astrocyte-secreted glutamine and use it for GSH synthesis. 20,21 Although the de novo synthesis of GSH is essential to replenish its levels, a considerable amount can also be recycled by GR, which reduces GSSG and regenerates GSH at the expense of NADPH (Figure 1). NADPH is produced in the pentose phosphate pathway (PPP).…”

“…Moreover, astrocytes have a more efficient GSH metabolism, as they are able to utilize a wider variety of precursor substrates for GSH synthesis. 20,21 Astrocytes take up cystine through the cystine/glutamate exchanger (Xc -) and cystine is immediately reduced to cysteine and secreted or used for the synthesis of GSH. 21 Astrocytes also display higher basal and stress-induced activity of Nrf2, leading to enhanced expression of Phase II detoxification enzymes and antioxidant enzymes, such as γ-GCS, which contribute to increased GSH concentration.…”

Blue light potentiates neurogenesis induced by retinoic acid-loaded responsive nanoparticles

“…Antioxidant coupling between astrocytes and NSCs, such as the induction of glutathione synthesis [40], may eventually reduce intracellular laser-induced ROS levels and its effects, namely on neuronal differentiation, RARα upregulation and β-catenin activation. Nevertheless, we were able to successfully demonstrate a significant enhancement of the neurogenic potential of RA (released from LR-NP) when combined with laser light in vivo.…”