SUMMARYThe possibility that cerebral ischemia may initiate a series of pathological free radical reactions within the membrane components of the CNS was investigated in the cat. The normally occurring electron transport radicals require adequate molecular oxygen for orderly transport of electrons and protons. A decrease in tissue oxygen removes the controls over the electron transport radicals, and allows them to initiate pathologic radical reactions among cell membranes such as mitochondria. Pathologic radical reactions result in multiple products, each of which may be present in too small a concentration to permit their detection at early time periods. It is possible to follow the time course, however, by the decrease of a major antioxidant as it is consumed by the pathologic radical reactions. For this reason, ascorbic acid was measured in ischemic and control brain following middle cerebral artery occlusion. There was a progressive decrease in the amount of detectable ascorbic acid ranging from 25% at 1 hour to 65% at 24 hours after occlusion. The reduction of this normally occurring antioxidant and free radical scavenger may indicate consumption of ascorbic acid in an attempt to quench pathologic free radical reactions occurring within the components of cytomembranes.

The hypothesis that pathologic free-radical reactions are initiated and catalyzed in the major central nervous system (CNS) disorders has been further supported by the current acute spinal cord injury work that has demonstrated the appearance of specific, cholesterol free-radical oxidation products. The significance of these products is suggested by the fact that: (i) they increase with time after injury; (ii) their production is curtailed with a steroidal antioxidant; (iii) high antioxidant doses of the steroidal antioxidant which curtail the development of free-radical product prevent tissue degeneration and permit functional restoration. The role of pathologic free-radical reactions is also inferred from the loss of ascorbic acid, a principal CNS antioxidant, and of extractable cholesterol. These losses are also prevented by the steroidal antioxidant. This model system is among others in the CNS which offer distinctive opportunities to study, in vivo, the onset and progression of membrane damaging free-radical reactions within well-defined parameters of time, extent of tissue injury, correlation with changes in membrane enzymes, and correlation with readily measurable in vivo functions.

Two models have been used to study the effects of ethanol on injuries of the central nervous system. The spinal cords of cats were injured by delivering a 200 gm-cm impact to the exposed dura mater. A second group of animals received a similar injury to the exposed dura mater overlying the cerebral hemispheres. The animals were divided into two groups, those that received an infusion of ethanol before injury, and control animals that received no ethanol. The parameters of injury used in this model produced small and insignificant lesions in those animals that received no ethanol; however, when the animals were pretreated with ethanol, a considerable increase in the extent of the injury was noted. These include alterations in membranes-bound enzymes and clotting mechanisms, and alteration of cell membranes through abnormal free radical reactions.

The effect of naloxone on blood flow and somatosensory evoked potentials was studied in cats subjected to 400 gm-cm contusion injuries of the thoracic spinal cord. Eight cats were treated with 10 mg/kg naloxone 45 to 60 minutes after injury, 11 cats were given 10 ml of saline instead of naloxone, and six cats were neither injured nor treated. Hydrogen clearance was used to measure blood flow in the lateral white columns at the contusion site. Naloxone, given intravenously, significantly inproved the blood flow rates in the lateral column white matter. At 2 hours after injury, the mean blood flow in the saline-treated cats fell to 50% (p greater than 0.01) of preinjury flow rates, whereas it increased 6% (p greater than 0.50) in naloxone-treated cats, and 12% (p greater than 0.50) in uninjured cats. At the 3rd hour after injury, the respective flows fell 47% (p less than 0.01), and 6% (p greater than 0.50), and increased 15% (p greater than 0.50) of the preinjury flow rates. The naloxone-treated cats had striking preservation of sensory function and somatosensory evoked potentials at 24 hours after injury. At 24 hours, responses had returned in all the naloxone-treated cats and in only 11% of the saline-treated cats. The probability of this combination of events occurring by chance is 0.0030. The authors conclude that naloxone may be useful for the treatment of spinal cord injury. The mechanism of the effect is unknown.

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