There are clear differences between astrocytes and oligodendrocytes grown in vitro to withstand oxidative stress. Thus there is an abundance of evidence that oligodendroglia are more susceptible than astroglia to oxidative stress [5, 7, 8, 11, 16, 17]. Immature oligodendrocytes are more susceptible than mature oligodendrocytes [1]. The increased vulnerability of oligodendrocytes is due to several reasons. One reason is that their high iron content facilitates the conversion of peroxides to strong oxidants [21]. Astrocytes as they age in culture become more vulnerable to oxidative stress even though their antioxidant defense systems seem to be maintained; this increase in vulnerability is related to their increase in iron content [18]. Altered iron deposition and metabolism has been implicated to play a causal role in a number of neurodegenerative diseases including Parkinsonism and Alzheimer’s disease [4, 14]

Another reason that oligodendrocytes are more vulnerable is that they have a poorer ability to scavenge peroxides, the source of many strong oxidants. Thus, oligodendrocytes have lower levels of reduced-glutathione (GSH) and lower glutathione peroxidase (GPx) activity [9]. The lower GSH content appears to be due to a poorer ability to synthesize GSH as well as a poorer ability to reduce oxidized-glutathione (GSSG) back to GSH [9]. Oligodendroglia also have much lower levels of phase II enzymes such as quinone reductase, suggesting that they have lesser abilities to cope with xenobiotic challange. In addition, oligodendroglia have a higher rate of oxidative metabolism compared to astrocytes (unpublished observations). All these factors result in oligodendroglia generating more strong oxidants under normal metabolic conditions than astrocytes and this production of oxidants dramatically increases when metabolism is disturbed.

More recently the distribution of immunocytochemically-detectable mitochondrial manganese superoxide dismutase (Mn-SOD) has been reported [19](see also papers by Perraut and Tholey and by Lindenau et al., in this Symposium). There is apparently no immunocytochemically detectable Mn-SOD in oligodendroglia. This suggests that strong oxidants such as singlet oxygen and peroxynitrite should form more easily in oligodendroglia than in astrocytes. Indeed, nitric oxide donors more readily injure oligodendroglia than they do astrocytes [13, 16]. The vulnerability of oligodendroglia to oxidative stress relative to astrocytes is indicated by the concentration of the redox cycler, menadione, required to kill the cells. A 2 µM concentration will kill oligodendrocyte precursors, a 5 µM concentration will kill mature oligodendrocytes (5 µM) while more than a 40 µM concetration is required to kill all the astrocytes (unpublished observations). Thus, the root cause of the vulnerability of oligodendroglia in vitro appears to be related to their greater rate of peroxide production, their greater ability to convert these peroxides to strong oxidants and their poor ability to scavenge peroxides. Do these findings in vitro have any relevance to the glia in vivo? This seems to be the case since we have demonstrated that a brief severe ischemic insult to the one-week-old rat pup preferentially kills immature oligodendroglia and has little effect upon the survival of microglia and astroglia [6].

It is generally considered that neurons are more vulnerable to oxidative stress than are astrocytes, although it is difficult to separate out vulnerability to oxidative stress from that of the remainder of the excitotoxic cascade. There is much evidence that the motoneurons of a small subset of amyotrophic lateral sclerosis (ALS) patients die because of the slight enhancement of oxidative stress due to mutation of the Cu,Zn-SOD [22] (see also paper by Yim et al. in this Symposium) and that oxidative stress plays a major role in neuronal death in Parkinson’s and Alzheimer’s disease [15, 20].

We have begun to to examine the abilities of other neural cell populations to withstand oxidative stress. Since peroxide scavenging lies at the root of the ability of cells to cope with oxidative stress, this has been our focus. In agreement with the findings of Mattson’s laboratory [3], we find that hippocampal neurons have barely detectable GPx activity. Cortical GABAergic neurons also have low GPx activity, whereas cerebellar glutamatergic neurons have moderate activity similar to that found in whole brain. Microglia have very high activity, comparable to that found with astrocytes.

Peroxides can give rise to strong oxidants and thus lie at the root of much of the oxidative stress experienced by cells. The extremely low activity of GPx found in hippocampal neurons, and certain other neural cells, suggests that these cells must also be using other mechanisms to scavenge peroxides. Recently several thoredoxin-dependent enzymes have been demonstrated to scavenge peroxides. Thoredoxin reductase, itself, has been demonstrated to be able to directly reduce lipid peroxides using NADPH as the electron donor [2]. In addition, there are several thioredoxin-dependent peroxidases that can scavenge peroxides [10]. Hence, we have become very interested in whether such non-glutathione-dependent peroxidase enzymes play a role in peroxide scavenging in neural tissue.

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