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Stroke is the leading cause of disability and a major cause of death in Germany and the western world. Ischemic stroke involves different pathophysiologic mechanisms such as thromboembolic vascular occlusion, cerebral micro- or macroangiopathy, extracranial arterial stenosis, and cardiac embolism. Experimental and clinical studies have shown that arteriogenesis, the adaptive growth of pre-existing collateral arteries, can be therapeutically enhanced in peripheral circulation and the heart. We examined the consequences to time course and hemodynamics of brain arteriogenesis in a chronic hypoperfusion model following systemic administration of the hemopoietic growth factor called granulocyte macrophage colony stimulating factor (GM-CSF). Treatment with GM-CSF led to the growth of intracranial collateral arteries, which improved the cerebral hemodynamic reserve and significantly reduced energy failure when brains were additionally challenged by hypotension. Therapeutically induced arteriogenesis may be of considerable interest for preventing infarction in patients with uncompensated cerebrovascular disease.

Neuronal injury following focal cerebral ischemia is widely attributed to the excitatory effects of glutamate. However, critical analysis of published data on glutamate toxicity in vitro and the comparison of this data with in vivo release of glutamate and the therapeutic effect of glutamate antagonists raises doubts about a neurotoxic mechanism. An alternative explanation for glutamate-mediated injury is energy failure due to peri-infarct spreading depression-like depolarizations. These depolarizations cause a sharp increase in metabolic activity and therefore produce a mismatch between blood flow and the oxygen requirements of the tissue. The generation of peri-infarct spreading depressions and the associated metabolic workload can be suppressed by glutamate antagonists. As a result, energy failure is also prevented, and the volume of ischemic infarct decreases. Interventions to improve ischemic resistance should therefore aim at improving the oxygen supply or reducing the metabolic workload, rather than interfering with the consequences of a putative excitotoxic injury cascade.

EEG and somatosensory evoked potentials were recorded in anesthetized rats before and up to 24 h after 30 min of global forebrain ischemia. Before ischemia, SEP (sweep time 1000 ms) included primary (N25P50) components and late potentials of low amplitude. During ischemia, SEP and EEG were isoelectric. During postischemic recirculation SEP evoked by stimulation at 1.0 Hz remained severely suppressed for 24 h, although long-latency potentials (100 ms) recovered. Using a very low stimulation frequency of 0.1 Hz, late components strongly increased in amplitude and the overall evoked activity in the averaged post-stimulus-EEG reached 90% of control. These results demonstrate that the SEP evoked at very low stimulation frequency may serve as an early indicator of functional brain recovery after prolonged cerebro-circulatory arrest.

In vivo NMR (nuclear magnetic resonance) spectroscopy allows for non-invasive measurement of the intracellular pH and the concentration of different metabolites in defined areas of the brain. Phosphocreatine, ATP and lactic acid are of prime interest in ischaemia research. Moreover, a distinction can be made between glycolysis and the oxidative breakdown of glucose after administering C-13-labelled glucose. Finally, spectroscopy of fluorine-containing inert gases such as Freon-23 allows for measuring cerebral blood flow and for directly relating the metabolic alterations to the changes in cerebral blood flow. Given the non-invasive character of NMR spectroscopy all metabolic process occurring throughout one experiment can for the first time be followed up. Thus metabolic alterations during ischaemia can directly be correlated with post-ischaemic recovery processes. It has been shown with the cerebral ischaemia model in the cat that recovery after circulatory failure rather depends on post-ischaemic changes such as the recirculation rate or the speed of high-energy phosphate formation than on the speed of energy metabolism breakdown or acidosis occurring during ischaemia. The future of nuclear magnetic resonance spectroscopy in experimental ischaemia research certainly lies in the therapeutic range. As the exact extent of ischaemic damage can be determined in each experiment it is possible for the first time to define the effect of a drug substance on metabolic dysfunction in each individual experiment. This method is not only expected to reduce the number of laboratory animals but also to dramatically improve statistical variability compared to group comparisons.

The effect of increasing static magnetic field strength up to 4.7 Tesla on the electrical function of the cat brain was studied by EEG frequency analysis and recording of somatosensory evoked potentials. While the latencies of the peaks P6 and P10 of the somatosensory evoked potentials were stable during the time course of the experiment, EEG intensity, EEG frequency index and the P10/N15 amplitude showed substantial fluctuations. EEG intensity varied between 67 and 156%, and EEG frequency index between 65 and 140% of the mean value averaged over the whole length of the experiment. The P10/N15 amplitude even varied between 16 and 186% of the mean amplitude. Despite these variations none of the variables correlated with the strength of the magnetic field. The observed changes are therefore interpreted as spontaneous fluctuations of vigilance and not as effects of the static magnetic field.

Immunohistochemical investigations were made of 170 tumours of the central nervous system, using anti-Leu-M1, with electron microscopy being used on 22 of them. At least focal Leu-M1 positive reactivity was established from 10 in 24 astrocytomas, four in 22 oligodendrogliomas, and 9 in 15 ependymomas. Unambiguous Leu-M1 positivity was recorded from 54% of Grade I gliomas and 20% of Grade II gliomas. Other malignant primary tumours of neuroepithelial origin as well as all meningiomas and neurinomas proved to be Leu-M1 negative. However, severe immunopositivity was exhibited in all cases by reactive cerebral tissue adjacent to tumours. Three of four carcinoma metastases were Leu-M1 positive. Investigations, using electron microscopy, have clearly shown that MMA positivity in reactive brain is associated primarily with extracellular space and with plasma membranes of gliocytes. No products of immune reaction were identified, on the other hand, not even ultrastructurally, from neoplastically dedifferentiated cells of anaplastic neuroepithelial tumours. This is likely to suggest that neoplastically transformed gliocytes are no longer capable of expressing lacto-N-fucopentose III. It has proved helpful in distinguishing between the benign and malignant nature of a tumour. More observations along those lines might contribute to more knowledge on dedifferentiation of gliocytes. Also, in electron microscopy, MMA positivity of carcinomas proved to be associated with glycocalyceal material.

The resistance of the brain to ischemia depends not only on the duration and severity of flow reduction but also on a number of pre- and post-ischemic metabolic and hemodynamic factors which are able to improve or impair the post-ischemic recovery process. Among pre-ischemic protective factors, the suppression of metabolic rate by drugs or hypothermia, the increase of brain tissue energy reserves and the inhibition of membrane permeability of cations are of particular importance. In contrast, increase of metabolic rate and increase of tissue acidosis induced by hyperglycemia or residual blood flow, reduce the ischemic tolerance of the brain. As long as cell membranes do not depolarize during ischemia, restitution of blood flow results in spontaneous recovery. After depolarization of membranes, however, numerous post-ischemic complications evolve, such as the no-reflow phenomenon, post-ischemic hypoperfusion, post-ischemic brain edema, disturbances of the coupling between metabolic activity and blood flow, etc. These complications require therapeutic intervention in order to prevent irreversible injury. By optimizing this therapy in a model of 1 hour complete normothermic brain ischemia in cat and monkeys, post-ischemic recovery of energy metabolism, protein synthesis, spontaneous and evoked electrocortical activity and even integrative neurological performance were observed. The resistance of the brain to ischemia, in consequence, is much higher than previously assumed and can be substantially improved by adequate post-ischemic treatment.

Gliomas were produced in 60 cats by stereotactic xenotransplantation of a rat glioma clone RG2. The animals were divided into two groups. One group was killed without any therapy 21 days after cell transplantation. The cats of the second group received 10 mg dexamethasone depot between the 14th and 19th day after cell transplantation. In all cases the animals were killed after one week. In the untreated animals there was marked peritumoral oedema and a high-grade infiltration of round cells to be found in the white matter of the whole left hemisphere. In the dexamethasone-treated cats peritumoral oedema and round-cell infiltration were definitely less pronounced than in the first group. The immunosuppressive effect of dexamethasone is discussed.