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

Abstract

Increasing evidence implicates reactive oxygen species, particularly hydrogen peroxide (H(2)O(2)), 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 elevated H(2)O(2) in guinea-pig and rat brain slices. The effects of exogenously applied H(2)O(2) 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 H(2)O(2) exposure, no pathophysiology was seen in guinea-pig hippocampal slices. Similarly, elevated H(2)O(2) caused edema in rat brain slices, whereas this did not occur in guinea-pig brain tissue. The resistance of guinea-pig brain tissue to H(2)O(2) 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, was able to compensate for 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, H(2)O(2).

H2O2Signaling in the Nigrostriatal Dopamine Pathway Via ATP-Sensitive Potassium Channels: Issues and Answers

“…This comparison was based on the rationale that the ratio of glia to neurons is higher in guinea pig brain than in rat brain, given the lower neuron density of guinea pig versus rat brain (133) and the relative constancy of glial density across species (20,62,69,113,134). We found initially that pathophysiological consequences of H 2 O 2 exposure seen in rat brain slices, including hyperexcitability, indicated by epileptiform activity in the hippocampus (10), and edema (26), are absent in guinea pig slices (13). The higher tolerance of guinea pig brain versus rat brain tissue to H 2 O 2 exposure implies that the higher glia-to-neuron ratio in this species provides additional antioxidant protection, particularly from glia.…”

“…We recently examined the neuroprotective role of glial antioxidants in a more nearly intact neuronal-glial microenvironment than possible in cell culture by comparing the consequences of oxidative stress caused by elevated H 2 O 2 in guinea pig and rat brain slices (13). This comparison was based on the rationale that the ratio of glia to neurons is higher in guinea pig brain than in rat brain, given the lower neuron density of guinea pig versus rat brain (133) and the relative constancy of glial density across species (20,62,69,113,134).…”

“…Brain slice preparations offer three main advantages for the kinds of questions we have addressed. First, local brain microcircuitry, including synaptic connections and neuron-glial interactions (13), is preserved in slices. Second, the three-dimensional cytoarchitecture of the tissue is maintained, so that normal intra-and extracellular compartments are intact (112).…”

Recent Advances in Analytical Methodology for in vivo Electrochemistry in Mammals

“…Amongt hese neurochemicals,a scorbate is am ajor anti-oxidant and neuromodulator occurring in high concentrations in the brain (several hundred micromolari ne xtracellular space and millimolar in cells),w hich plays important but less understood roles in brain functions and dysfunctions [9][10][11][12][13]39,40].S ince 2004, our group has been focusing and is still actively investigating into the in vivo sensing of ascorbate in the brain. In this section,w ew ill review the works of our group towardss elective in vivo monitoring of cerebral ascorbate,f rom online detection integrated with in vivo microdialysis sampling to on-site detectionw ith surface-functionalized carbon fiber microelectrodes.W ith these methods,w eh ave been able to monitor cerebrala scorbatea ctivities sensitively and selectively.I ni nvestigations of pathological models such as ischemia and tinnitus,w ed emonstrated that ascorbate fluctuations could be potentially used as ab iomarker to indicate the state of neuronal damage,a nd to evaluate the effects of anti-oxidant drugs on protecting the brain during these processes.…”

“…Readersc an refer to several excellent reviews for as ummarization of these works and related topics [8,9].I nt he later years,a scorbate receives more and more attention owing to its functions as aneuromodulator and as am ajor anti-oxidant that protects brain from neuronal toxicity [8][9][10][11][12][13].A mongt he easily oxidizable neurochemicals in the brain,a scorbate normallyr equiresahigh potential (0.2 V vs. Ag/AgCl) for its oxidation at the most frequently used electrodess uch as carbonf iber, glassy carbon and gold electrodes. At this potential, redox reactions of many other neurochemicals may occur as well.…”