The glial antioxidant network and neuronal ascorbate: protective yet permissive for H₂O₂ signaling

Abstract

Increasing evidence implicates reactive oxygen species, particularly hydrogen peroxide (H₂O₂), as intracellular and intercellular messengers in the brain. This raises the question of how the antioxidant network in the brain can be sufficiently permissive to allow messages to be conveyed yet, at the same time, provide adequate protection against oxidative damage. Here we present evidence that this is accomplished in part by differential antioxidant compartmentalization between glia and neurons. Based on the rationale that the glia-to-neuron ratio is higher in guinea-pig brain than in rat brain, we examined the neuroprotective role of the glial antioxidant network by comparing the consequences of H₂O₂ elevation in slices of guinea-pig and rat brain. The effects of exogenously applied H₂O₂ on evoked population spikes in hippocampal slices and on edema formation in forebrain slices were assessed. In contrast to the epileptiform activity observed in rat hippocampal slices after H₂O₂ exposure, no pathophysiology was seen in guinea-pig hippocampal slices. Similarly, elevated H₂O₂ caused edema in rat brain slices but not in guinea-pig brain tissue. The resistance of guinea-pig brain tissue to H₂O₂ challenge was lost, however, when glutathione (GSH) synthesis was inhibited (by buthionine sulfoximine), GSH peroxidase activity was inhibited (by mercaptosuccinate) or catalase was inhibited (by 3-amino-1, 2, 4, -triazole). Strikingly, exogenously applied ascorbate, a predominantly neuronal antioxidant, could compensate for the loss of any other single component of the antioxidant network. Together, these data imply significant roles for glial antioxidants and neuronal ascorbate in the prevention of pathophysiological consequences of the endogenous neuromodulator H₂O₂.