White matter (WM) of the mammalian brain is susceptible to anoxic injury, but little is known about the pathophysiology of this process. We studied the mechanisms of anoxic injury in WM using the isolated rat optic nerve, a typical central nervous system WM tract. Optic nerve function, measured as the area under the compound action potential, rapidly failed when exposed to anoxia and recovered to 28.5% ofcontrol after a standard 60-min period of anoxia. Irreversible anoxic injury was critically dependent on the molar concentration of extracellular calcium ([Ca2l] Orthodromic stimulation and recording from RONs were accomplished by using suction electrodes. Stimulus strength was set to 25% above the strength that elicited a maximal compound action potential (CAP). Area under the CAP was examined before and after various experimental manipulations by a method that corrected for changes in the recording electrode impedance. Stimuli (50-pus duration) were delivered by an isolation unit at 30-s intervals.Anoxia was achieved by switching to a 95% N2/5% CO2 atmosphere. To ensure that anoxia was complete and rapid, the partial pressure of 02 in the chamber was measured with a Po2 meter (Vascular Technologies; 402 Oxygen Alarm). The sensor was placed at the point in the chamber where the nerve was usually positioned. When the gas was switched from 02 to N2, oxygen tension decreased from 95% to 0% in about 2.5 min; the return to 95% 02 had a similar time course. After reoxygenation, the RONs were allowed a further 60-min recovery period before postanoxic activity was measured, since all nerves attained their maximal recovery by the end of this 60-min interval ( Fig. 1; ref. 15). RESULTSThe effects of anoxia on the CAP (measured as the area under the CAP and normalized to the control CAP area) are illustrated in Fig. 1. The CAP rapidly diminished after the start of anoxia; the CAP decreased to 50% of control by [2][3]
We investigated the postnatal development of axon sensitivity to the withdrawal of oxygen, glucose, or the combined withdrawal of oxygen + glucose in the isolated rat optic nerve (a CNS white matter tract). Removal of either oxygen or glucose for 60 min resulted in irreversible injury in optic nerves from adult rats, assessed by loss of the evoked compound action potential (CAP). Optic nerves at ages
Gray and white matter of the mammalian CNS are both damaged by anoxia. Anoxic injury in gray matter is mediated in part by excessive accumulation of excitotoxins like glutamate. Drugs such as ketamine, a dissociative anesthetic known to block glutamate (NMDA) receptors, reduce hypoxic neuronal injury in gray matter. In this study we used the isolated rat optic nerve preparation to determine if ketamine influences recovery after anoxia in a nonsynaptic system, ie, CNS white matter. Optic nerves from adult rats were exposed to a standard 60-minute period of anoxia. Ketamine (1 mM) improved recovery of the compound action potential (CAP) after anoxia. Since glutamate and aspartate (up to 10 mM) had no effect on CAP amplitude in the optic nerve, the effect of ketamine is probably not mediated by NMDA receptor blockade. These observations indicate that ketamine is able to protect CNS white matter, as well as gray matter, from anoxic injury.
In gray matter (GM), anoxia induces prominent extracellular ionic changes that are important in understanding the pathophysiology of this insult. White matter (WM) is also injured by anoxia but the accompanying changes in extracellular ions have not been studied. To provide such information, the time course and magnitude of anoxia-induced changes in extracellular K+ concentration ([K+]o) and extracellular pH (pHo) were measured in the isolated rat optic nerve, a representative central WM tract, using ion-selective microelectrodes. Anoxia produced less extreme changes in [K+]o and pHo in WM than are known to occur in GM; in WM during anoxia, the average maximum [K+]o was 14 +/- 2.9 mM (bath [K+]o = 3 mM) and the average maximum acid shift was 0.31 +/- 0.07 pH unit. The extracellular space volume rapidly decreased by approximately 20% during anoxia. Excitability of the rat optic nerve, monitored as the amplitude of the supramaximal compound action potential, was lost in close temporal association with the increase in [K+]o. Increasing the bath glucose concentration from 10 to 20 mM resulted in a much larger acid shift during anoxia (0.58 +/- 0.08 pH unit) and a smaller average increase in [K]o (9.2 +/- 2.6 mM). The increased extracellular glucose concentration presumably provided more substrate for anaerobic metabolism, resulting in more extracellular lactate accumulation (although not directly measured) and a greater acid shift. Enhanced anaerobic metabolism during anoxia would provide energy for operation of ion pumps, including the sodium pump, that would result in smaller changes in [K+]o. These effects were probably responsible for the observation that the optic nerve showed significantly less damage after 60 min of anoxia in the presence of 20 mM glucose compared to 10 mM glucose. Under normoxic conditions, increasing bath K+ concentration to 30 mM (i.e., well beyond the level shown to occur with anoxia) for 60 min caused abrupt loss of excitability during the period of application but minimal change in the amplitude of the compound action potential following the period of exposure. The anoxia-induced increase in [K+]o, therefore, was not itself directly responsible for irreversible loss of optic nerve function. These observations indicate that major qualitative differences exist between mammalian GM and WM with regard to anoxia-induced extracellular ionic changes.
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