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Cormac O. Maher, Robert E. Anderson, Heidi S. Martin, Robyn L. McClelland and Fredric B. Meyer

Object. The effects of interleukin (IL)-1β on the cerebral vasculature are complex and incompletely understood. Many pathophysiological states in which inflammatory cascades have been implicated also have varying degrees of cerebral hypoperfusion. The purpose of this investigation was to examine the long-term effects of this proinflammatory cytokine and its antagonist on cerebral blood flow (CBF) following global cerebral hypoperfusion.

Methods. Sprague—Dawley rats were randomly assigned to 12 groups and given continuous intracerebroventricular (ICV) infusions of IL-1β, the IL-1 receptor antagonist (IL-1ra), or saline vehicle (control). Global cerebral hypoperfusion was produced by occlusion of both carotid arteries and one vertebral artery. Cerebral blood flow was measured at baseline and again after initiation of the infusions by performing a 133Xe clearance study.

Prolonged ICV administration of IL-1β resulted in a significant decrease in CBF compared with that in controls. Prolonged administration of the antagonist IL-1ra resulted in significant increases in CBF compared with that in both IL-1β—treated animals and controls.

Conclusions. This experiment demonstrates that long-term treatment with the proinflammatory cytokine IL-1β adversely affects CBF.

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Bernard A. Coert, Robert E. Anderson and Fredric B. Meyer

Object. A nitric oxide (NO) donor that has been successfully used in the treatment of myocardial infarction, 3-morpholinosydnonimine (SIN-1), may be a potential neuroprotective agent. Production of NO in brain microsomes is dependent on the pH. The purpose of this study was to determine the efficacy of SIN-1 and its dependence on pH in vivo during periods of focal cerebral ischemia.

Methods. At 0.1 or 1 mg/kg, SIN-1 was administered to 54 Wistar rats 30 minutes before a 2-hour period of focal cerebral ischemia under moderate hypo-, normo-, and hyperglycemic conditions. Measurements of brain intracellular pH (pHi); regional cortical blood flow, and the redox state of nicotinamide adenine dinucleotide were obtained in three additional animals to confirm the effects of the serum glucose manipulations. The animals were killed at 72 hours after the ischemic period to obtain infarction volumes. Administration of SIN-1 significantly reduced infarction in normoglycemic animals and, to a lesser extent, in hyperglycemic animals, indicating that SIN-1 was less effective under hyperglycemic conditions. At either dose SIN-1 had no significant effect on infarction volume in moderately hypoglycemic animals because moderate hypoglycemia in itself significantly (p < 0.005) reduced infarction volume.

Conclusions. The NO donor SIN-1 may be a useful intraoperative cerebral protective agent. Furthermore, it is hypothesized that a mechanism that could explain the published discrepancies regarding the effects of NO donors in vivo may be affected by differences in ischemic brain acidosis.

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Jonathan A. Friedman, Robert E. Anderson and Fredric B. Meyer

Understanding the physiological mechanisms of cerebral blood flow (CBF) is of great importance to neurosurgeons engaged in the management of patients with cerebrovascular disease. Over the past 50 years, techniques to measure CBF and mathematical methods to calculate CBF have evolved substantially. For the cerebrovascular surgeon, intra-operative CBF monitoring is an important adjunct in certain intra- and extracranial procedures. The authors review current techniques in use for the intraoperative measurement of CBF.

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Bert A. Coert, Robert E. Anderson and Fredric B. Meyer

Object. A critical review of the literature indicates that the effects of nitric oxide synthase (NOS) inhibitors on focal cerebral ischemia are contradictory. In this experiment the authors methodically examined the dose-dependent effects of two NOS inhibitors and two NO donors on cortical infarction volume in an animal model of temporary focal cerebral ischemia simulating potential ischemia during neurovascular interventions.

Methods. Ninety-two Wistar rats underwent 3 hours of combined left middle cerebral artery and bilateral common carotid artery occlusion after having been anesthetized with 1% halothane. A nonselective NOS inhibitor, NG-nitro-l-arginine-methyl-ester (l-NAME), and two NO donors, 3-morpholinosydnonimine hydrochloride and NOC-18, DETA/NO, (Z)-1-[2(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate, were administered intravenously 30 minutes before ischemia was induced. A selective neuronal NOS inhibitor, 7-nitroindazole (7-NI), was administered intraperitoneally in dimethyl sulfoxide (DMSO) 60 minutes before ischemia was induced. Two ischemic control groups, to which either saline or DMSO was administered, were also included in this study. Seventy-two hours after flow restoration, the animals were perfused with tetrazolium chloride for histological evaluation.

Cortical infarction volume was significantly reduced by 71% in the group treated with 1 mg/kg l-NAME when compared with the saline-treated ischemic control group (27.1 ± 37 mm3 compared with 92.5 ± 26 mm3, p < 0.05). The NOS inhibitor 7-NI significantly reduced cortical infarction volume by 70% and by 92% at doses of 10 and 100 mg/kg: 35.2 ± 32 mm3 (p < 0.05) and 9 ± 13 mm3 (p < 0.005), respectively, when compared with the DMSO-treated ischemic control group (119 ± 43 mm3). There was no significant difference between the saline-treated and DMSO-treated ischemic control groups. Treatment with NO donors did not significantly alter cortical infarction volume.

Conclusions. These results support an important role for NO in ischemic neurotoxicity and indicate that neuronal NOS inhibition may be valuable in reducing cortical injury in patients suffering temporary focal cerebral ischemia during neurovascular procedures.

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Brian A. Iuliano, Robert E. Anderson and Fredric B. Meyer

✓ The authors examined the effects of both intermittent reperfusion and nitric oxide synthase (NOS) inhibition, caused by NG-nitro-l-arginine methyl ester (l-NAME) during episodes of focal cerebral ischemia induced to simulate the neurosurgical setting. Seventy-eight Wistar rats underwent single (60 minutes of ischemia) or repetitive (four 15-minute periods of ischemia separated by 5 minutes of reperfusion) episodes of middle cerebral artery occlusion while under anesthesia (1.0% halothane). Twenty-four hours after the procedure, the animals were given neurological examinations and then sacrificed for histological preparation and examination. The intermittent reperfusion groups tended to have smaller mean cortical infarctions. There was also a trend showing a decrease in infarction size in groups given l-NAME. The combination of intermittent reperfusion and preischemic administration ofl-NAME (10 mg/kg) resulted in a 65% reduction in infarction size (p < 0.05) when compared to that caused by 60 minutes of single occlusion without l-NAME. The use of NOS inhibition combined with intermittent reperfusion may be a technique to provide intraoperative cerebral protection during neurovascular procedures that require temporary vascular occlusion.

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Marc S. Goldman, Robert E. Anderson and Fredric B. Meyer

✓ There is controversy regarding the role of intermittent reperfusion employed as a cerebroprotective measure when temporary arterial occlusion is necessary during repair of difficult aneurysms. The intraluminal suture middle cerebral artery (MCA) occlusion technique was used in 23 Wistar rats under barbiturate anesthesia to induce 60, 90, or 120 minutes of uninterrupted MCA occlusion. The total infarcted areas obtained were compared to those occurring in 27 animals subjected to identical cumulative ischemic periods but with 5 minutes of reperfusion after every 10-minute ischemic period. The mean total infarcted areas in the groups with 60-minute (1.8 ± 0.89 sq mm), 90-minute (1.08 ± 1.02 sq mm), and 120-minute (8.72 ± 5.89 sq mm) intermittent reperfusion were significantly smaller than those occurring in the 60-minute (12.02 ± 3.10 sq mm), 90-minute (11.54 ± 2.68 sq mm), or 120-minute (30.43 ± 6.51 sq mm) control groups, respectively (p < 0.05). Furthermore, there was no difference in the occurrence of blood-brain barrier breakdown, intraparenchymal hemorrhage, hemispheric edema, or seizures between control and intermittent reperfusion groups. The results support the hypothesis that intermittent reperfusion is beneficial if vessel occlusion is required during aneurysm repair.

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Treatment of experimental focal cerebral ischemia with mannitol

Assessment by intracellular brain pH, cortical blood flow, and electroencephalography

Fredric B. Meyer, Robert E. Anderson, Thoralf M. Sundt Jr. and Tony L. Yaksh

✓ Intracellular brain pH, cortical blood flow (CBF), and electrocorticograms were recorded in regions of severe and moderate ischemia in 10 control rabbits and 10 rabbits given mannitol, 1 gm/kg, after occlusion of a major branch of the middle cerebral artery. Pooling the data from all 20 animals, preocclusion CBF was 46.4 ±3.6 ml/100 gm/min and intracellular brain pH was 7.01 ± 0.04 (means ± standard error of the means). Although mannitol administration mildly improved CBF in regions of severe ischemia, this increase was not sufficient to prevent metabolic deterioration as assessed by brain pH. However, in regions of moderate ischemia, CBF improved significantly with mannitol and the gradual decline in brain pH observed in control animals was prevented. For example, in the treated moderate ischemia sites 4-hour postocclusion CBF and pH values were 31.8 ml/100 gm/min and 6.89 ± 0.09, respectively, as compared to control values of 14.3 ml/ 100 gm/min and 6.75 ± 0.06. These results suggest that mannitol may be of benefit in stabilizing regions of moderate, but not severe, ischemia after vessel occlusion.

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Fredric B. Meyer, Robert E. Anderson, Tony L. Yaksh and Thoralf M. Sundt Jr.

✓ Intracellular brain pH, cortical blood flow, and electroencephalograms (EEG's) were recorded in severely and moderately ischemic regions in 10 control and 10 nimodipine-treated rabbits prior to and following major branch occlusion of the middle cerebral artery (MCA). Preocclusion cortical blood flow was 51 ml/100 gm/min and intracellular brain pH was 7.01 in both the control and the treated animals. After MCA occlusion, the severely ischemic regions in the control group showed initial and 4-hour postocclusion flows of 12.7 and 5.2 ml/100 gm/min with a brain pH of 6.64 and 6.08, respectively. In animals given nimodipine after MCA occlusion, blood flow increased from 10.5 to 18.8 ml/100 gm/min, with an associated elevation in intracellular brain pH from 6.57 to 6.91. Comparable findings were observed in areas of moderate ischemia. Improvements in cortical blood flow, intracellular brain pH, and EEG attenuations produced by nimodipine were all statistically significant. Inspection of the cortex revealed reversal of cortical pallor and small-vessel spasm following treatment with nimodipine. It is hypothesized that nimodipine exerts its effects through reversal of ischemia-induced secondary vasoconstriction, and that this drug may be an important adjunctive treatment for patients with focal cerebral ischemia.