R. Bullock

Ischemic brain damage in a model of acute subdural hematoma.

Ischemic brain damage is the most important neuropathological finding in humans who die after acute subdural hematoma; however, its causes are poorly understood. We have produced acute subdural hematoma in the rat by injecting 400 microliters of autologous blood (approximately 20% of intracranial volume) into the subdural space. Extensive areas of ischemic damage, involving 14 to 16% of the volume of the hemisphere, developed in this model at 4 and 24 hours after the lesion. The hematomas were associated with a brief peak in intracranial pressure (51 mm Hg), which remained at three times normal levels (14 mm Hg) for 3 hours. In this model, therefore, ischemic damage appears to be due to the local effects of blood overlying the cortex at 4 hours after the ictus, rather than to globally raised intracranial pressure. The implications for the pathophysiology of acute subdural hematomas in humans are discussed.

Focal Cerebral Ischemia in the Cat: Pretreatment with a Competitive NMDA Receptor Antagonist, D-CPP-ene:

The effects of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist D-(E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid (D-CPP-ene; SDZ EAA 494) upon ischemic brain damage have been examined in anesthetized cats. Focal cerebral ischemia was produced by permanent occlusion of the middle cerebral artery (MCA) and the animals were killed 6 h later. The amount of early ischemic brain damage was assessed in coronal sections at 16 predetermined stereotaxic planes. Pretreatment with D-CPP-ene (15 mg/kg i.v. followed by continuous infusion at 0.17 mg/kg/min until death), 15 min prior to MCA occlusion, significantly reduced the volume of ischemic brain damage (from 20.6 ± 9.9% of the cerebral hemisphere in vehicle-treated cats to 7.2 ± 4.4% in drug-treated cats; p < 0.01). The competitive NMDA receptor antagonist D-CPP-ene is as effective as noncompetitive NMDA antagonists in reducing the amount of ischemic brain damage in this model of focal cerebral ischemia in a gyrencephalic species.

Clinicopathological study of neurological complications due to hypertensive disorders of pregnancy.

Forty-three women with neurological complications secondary to eclampsia or severe pre-eclampsia were studied by CT scanning and in six intracranial pressure (ICP) monitoring was carried out. In seven women who died, neuropathological findings were correlated with clinical features. Cerebral oedema was present in 27 of the patients studied and the severity of oedema correlated to the duration of intermittent seizures. In five of the six women who had ICP measured, this was found to be transiently high. Intracranial haemorrhage was demonstrated in four of the 43 women, all of whom died. Hypoxic-ischaemic cerebral damage and fibrinoid necrosis were the most important neuropathological lesions identified. The management of neurological complications of eclampsia may be placed upon a more rational basis by an understanding of the mechanisms responsible for these lesions.

Neuroprotective Effect of the AMPA Receptor Antagonist LY-293558 in Focal Cerebral Ischemia in the Cat

The effects of the glutamate α-amino-3-hydroxy 5-methyl-4-isoxazole propionate (AMPA) receptor antagonist LY-293558 in reducing ischemic brain damage have been assessed in halothane-anesthetized cats. Focal cerebral ischemia was produced by permanent occlusion of one middle cerebral artery, and the animals were killed 6 h later. The amount of early irreversible ischemic damage was assessed at 16 predetermined stereotactic planes by an observer blinded to treatment paradigm employed. Treatment with LY-293558 (15 mg/kg i.v., plus infusion of 7 mg/kg/h) initiated 30 min prior to middle cerebral artery occlusion reduced significantly (p < 0.02) the volume of ischemic damage (from 3,423 ± 212 mm3 of the cerebral hemisphere in vehicle-treated cats to 2,822 ± 569 mm3 in LY-293558-treated cats). The present data demonstrate that an AMPA receptor antagonist can reduce focal ischemic damage in a gyrencephalic species in which key physiological variables have been controlled and monitored throughout the postischemic period. These data provide additional support for the clinical evaluation of AMPA receptor antagonists in focal cerebral ischemia in humans.

Local cerebral blood flow mapping before and after removal of acute subdural hematoma in the rat.

The cause of hemispheric swelling and high intracranial pressure after acute subdural hematoma is unknown, yet this is a major cause of death related to this condition. To investigate whether vascular engorgement is the cause of this form of hemisphere swelling, we have autoradiographically mapped regional cerebral blood flow before and after removal of acute subdural hematoma in a rat model. Hyperemia was patchy and infrequent. The major cause of the significant hemisphere swelling seen after hematoma removal was enlargement of the zone of focal tissue ischemia and edema under the hematoma.

Failure of cerebral blood flow-metabolism coupling after acute subdural hematoma in the rat.

We have used a recently introduced cerebral blood flow tracer, technetium-99-DL-hexamethylpropylene amine oxime, to map regional cerebral blood flow simultaneously with measurements of glucose metabolism ([14C]-2-deoxyglucose technique) using autoradiography. The technique was used to compare the acute effects of middle cerebral artery occlusion with the more complex events that occur after induction of an acute subdural hematoma (SDH) in the rat. Previous studies with this SDH model have shown that an infarction is induced in the cortex under the hematoma. In both models, the core of the infarct zone was associated with a reduction in both flow and metabolism to less than 15% of control values. In both models, the infarct core was surrounded by a band of tissue in which glucose metabolism increases by 60 to 70% and blood flow is reduced by the same amount. Global blood flow after the SDH was reduced by 14%, but remained unchanged after middle cerebral artery occlusion. In the hippocampus, a massive increase in metabolism (up to 157%) after SDH was accompanied by a paradoxical decrease in blood flow (32%). This discrepancy between blood flow and metabolism indicates loss of flow-metabolism coupling and provides a mechanism for infarct recruitment and delayed hippocampal damage after SDH.

Early Post-Traumatic Cerebral Blood Flow Mapping: Correlation with Structural Damage After Focal Injury

Focal post traumatic mass lesions such as contusions and intracerebral haematomas are common, and often difficult for neurosurgeons to manage, because little is known of their pathophysiology. We have mapped cerebral blood flow, and studied small vessel ultrastructure at different time points within the first three weeks of head injury, in patients with these lesions. A zone of ischaemic brain is always present around these lesions, and persists for weeks or months. This accords with astrocyte swelling and microvascular compression seen on electron microscopy. Focal zones of hyperaemia were also present in 42% of patients, within the first two weeks of injury, and this appeared only within apparently normal tissue as judged by late MRI or CT.

Prevention of Post-Traumatic Excitotoxic Brain Damage with NMDA Antagonist Drugs: A New Strategy for the Nineties

Excitotoxic mechanisms due to overactivity of the amino acid neurotransmitters glutamate and aspartate maybe responsible for brain damage after injury. In this review we examine ischaemia and shear injury, which are relevant to human head injury. The opportunities for treatment using glutamate antagonist drugs are discussed.

Massive Astrocytic Swelling in Response to Extracellular Glutamate — a Possible Mechanism for Post-Traumatic Brain Swelling?

Little attention has been paid to the responses of astrocytes in the brain to the application of neurotoxic excitatory transmitters such as glutamate. We have developed a simple model to study the responses of cells within the cerebral cortex to neurotoxic levels of glutamate. After short periods of perfusion with glutamate, perivascular and interstitial astrocytes swell and become electron lucent. The astrocyte swelling extends, with increasing periods of perfusion, up to 400 um into the adjacent, intact neuropil. After 90 minutes of glutamate perfusion, intermediate filament bundles and glycogen granules occur within the astrocyte cytoplasm. We obtained no evidence for compromised blood flow. We suggest that astrocyte swelling serves to limit the diffusion of glutamate from the site of the lesion.

Reproducible peracute glutamate-induced focal lesions of the normal rat brain using microdialysis

The neurotoxic effect of the excitatory amino acid neurotransmitter glutamate was first demonstrated 20 years ago, but the recent development of potent glutamate antagonist drugs with effects against ischaemic damage in vivo and their introduction in clinical studies has made excitotoxicity a major focus of current interest. Despite this, the factors influencing glutamate neurotoxicity in vivo are poorly understood, and the role of glutamate as a neurotoxin in vivo is contested. By using a microdialysis probe to deliver glutamate to the normal rat cortex, we have devised a reproducible model of peracute excitotoxic damage. We have demonstrated that concentrations of over 20 mM glutamate in the perfusate kill neurons in the intact brain in less than 90 min -20 to 200 times more than that required for toxicity in mixed cell culture. The histological and ultrastructural features of the glutamate lesion are very similar to those of acute ischaemia, although their development is much more rapid after glutamate. True extracellular glutamate concentrations estimated from microdialysis studies (about 4 mM) are not far from our results. The reproducible quantifiable nature of the glutamate lesions in this model make it well suited to study the factors affecting the excitotoxic process in vivo.