Ibuprofen improves cerebral blood flow after global cerebral ischemia in dogs

In a canine model of global cerebral ischemia, 6 dogs received a saline placebo prior to the event and 5 received 12.5 mg/kg ibuprofen. Cerebral venous outflow from the confluence of the sagittal and transverse sinuses, systolic and diastolic arterial pressure, cardiac output, pH, Paco2, Pao2, and arterial and sagittal sinus thromboxane B2 and 6-keto-PGF1 alpha were measured at intervals up to 120 minutes thereafter. Postischemic cerebral hypoperfusion was significantly improved in the ibuprofen pretreatment group. Control dogs showed significant increases in sagittal sinus postischemic thromboxane B2 concentrations, but pretreated dogs showed nearly complete inhibition of postischemic thromboxane B2 production. Pretreated dogs also had significantly lower levels of 6-keto-PGF1 alpha from the sagittal sinus. There were no significant differences in the other variables at any interval. We conclude that ibuprofen ameliorates postischemic cerebral hypoperfusion, and that this improvement is associated with decreased sagittal sinus levels of thromboxane B2 and 6-keto-PGF1 alpha.     

Fenofibrate improves cerebral blood flow after middle cerebral artery occlusion in mice

Fibrates, one group of peroxisome proliferator-activated receptor (PPAR) activators, are lipid lowering drugs. Fibrates have been shown to attenuate brain tissue injury after focal cerebral ischemia. In this study, we investigated the impact of fenofibrate on cerebral blood flow (CBF) in male wild type and PPARα-null mice. Animals were treated for 7 days with fenofibrate and subjected to 2 h of filamentous middle cerebral artery occlusion and reperfusion under isoflurane anesthesia. Cortical surface CBF was measured by laser speckle imaging. Regional CBF (rCBF) in nonischemic animals was measured by ¹⁴C-iodoantipyrine autoradiography. Fenofibrate did not affect rCBF and mean arterial blood pressure in nonischemic animals. In ischemic animals, laser speckle imaging showed delayed expansions of ischemic area, which was attenuated by fenofibrate. Fenofibrate also enhanced CBF recovery after reperfusion. However, such effects of fenofibrate on CBF in the ischemic brain were not observed in PPARα-null mice. These findings show that fenofibrate improves CBF in the ischemic hemisphere. Moreover, fenofibrate requires PPARα expression for the cerebrovascular protective effects in the ischemic brain.     

Nimodipine improves cerebral blood flow and neurologic recovery after complete cerebral ischemia in the dog

Ten minutes of complete ischemia was produced in 11 dogs by temporary ligation of the aorta. Immediately before the ischemic episode, the dogs received nimodipine, a new calcium entry blocker, 10 micrograms kg-1, i.v., followed by an infusion of 1 microgram kg-1 min-1 for 2 h. Post-ischemic cerebral blood flow and metabolism were measured for 120 min in six dogs. Neurologic recovery was evaluated 48 h post-ischemia in five dogs. The results were compared to previously determined controls. Nimodipine nearly doubled cerebral blood flow in the delayed post-ischemic hypoperfusion period, compared to untreated dogs (approximately 45% versus 25% of pre-ischemic control values), but had no significant effect on metabolism. Nimodipine also improved neurologic recovery. Four of five treated dogs were normal and one was moderately damaged, whereas six of seven controls were either severely damaged or dead. This suggests that the delayed hypoperfusion state occurring after complete cerebral ischemia probably does contribute to the ultimate neurologic damage, and that nimodipine offers a potential protective effect.     

Local cerebral blood flow is preserved in sepsis

Sepsis is often complicated by encephalopathy, neuroendocrine dysfunction and cardiovascular autonomic failure. The cause of septic brain dysfunction is not fully understood. The aim of the present study is to explore whether septic brain dysfunction in a common septic model in the rat correlates with abnormalities either of local cerebral blood flow (LCBF) of defined brain areas or of whole brain blood flow (CBF). 45 male Wistar rats (320+/-13 g) were randomly assigned to a sepsis group (31 rats, cecal ligature and puncture, CLP) or a control group (14 rats, sham operation). Of these 45 rats, 16 rats were used for blood analysis; the remaining 29 rats were used for CBF/LCBF measurements. LCBF measurements were performed 24h after initial surgery using quantitative autoradiography with 4-iodo[N-methyl-(14)C]antipyrine, which allows to analyze CBF on a regional/local and global basis. In 42 different brain regions bilateral optical density measurements were performed. Septic rats (vs. control) presented tachycardia (507+/-37 vs. 452+/-44 min(-1), P<0.05), leukocytopenia (2.96+/-2.37 vs. 8.83+/-2.9710(9) x L(-1), P<0.05), hypocapnia (29.3+/-4.6 vs. 36.4+/-3.9 mmHg, P<0.05), and higher serum lactate concentrations (5.7+/-3.9 vs. 2.2+/-2.0 mmol x L(-1), P<0.05). LCBF of all 42 areas, as well as, CBF (116+/-59 vs. 115+/-52 m x 100 g(-1)min(-1), n.s.) did not differ. The results showed that severe sepsis (mortality rate of 43 %) did not induce alterations in mean CBF and LCBF. It is concluded that brain dysfunction is not reflected in changes of CBF during severe sepsis.     

Abnormalities of cerebral blood flow in the acute phase of bacterial meningitis in adults

Summary The frequency, course and clinical significance of changes in regional cerebral blood flow (rCBF) during bacterial meningitis were investigated in 14 adult patients. The results of^99mTc-hexamethylpropylene amine oxime (HMPAO) single photon emission computed tomography (SPECT) were compared with the clinical signs and findings using cerebral angiography and conventional CT. HMPAO SPECT was performed 2–15 days (median 4.5 days) after the onset of neurological disease. Decreased HMPAO accumulation was detected in 13 patients. SPECT studies revealed focal hypoperfusion cor responding to the clinical symptoms in 6 patients suffering from hemiparesis or hemiataxia. Conventional cranial CT disclosed brain infarction in only 1 patient. Focal hypoperfusion was also found in 7 of 8 patients without clinical evidence of focal neurological deficits. In 6 patients, HMPAO SPECT findings were abnormal although cerebral angiography was normal. At follow-up examinations 3–45 weeks after the acute disease, abnormalities revealed by HMPAO SPECT had improved or had even disappeared in all patients studied. Our results indicate that reduced rCBF is a frequent finding in bacterial meningitis in the adult. In most patients it probably represents a functional and reversible disorder without structural lesion detectable on CT.     

Postischemic canine cerebral blood flow is coupled to cerebral metabolic rate

Following complete global cerebral ischemia and reperfusion, a brief period of reactive hyperemia is followed by a prolonged period of low flow commonly referred to as the delayed postischemic hypoperfusion state. It is generally assumed that this low-flow state may be injurious because of inadequate substrate delivery, thus implying that flow is no longer coupled to metabolic needs. This relationship of CBF to CMRO2 was examined in six anesthetized dogs that were subjected to 12 min of complete ischemia induced either by CSF compression or aortic occlusion. Following reperfusion and onset of the low-flow state, which stabilized at 45 min postischemia, control normothermic (37 degrees C) measurements of CBF and CMRO2 were determined. Thereafter, femoral arterial blood was circulated through a heat exchanger (42.5 degrees C), and brain temperature was increased to 40 degrees C and measurements were repeated. The brain was then cooled back to 37 degrees C for a final set of normothermic measurements. Thereafter, brain biopsies were taken to determine the energy state of the brain. CMRO2 changed approximately 6%/degrees C. CBF paralleled the change in CMRO2. Accordingly, the ratio of CBF to CMRO2 remained constant throughout at a value of 8 to 9, demonstrating maintained coupling. The brain energy state was normal at the end of the study. The authors conclude that postischemic CBF is modulated by the brain's metabolic needs.     

Nimodipine pretreatment improves cerebral blood flow and reduces brain edema in conscious rats subjected to focal cerebral ischemia

The effect of nimodipine pretreatment on CBF and brain edema was studied in conscious rats subjected to 2.5 h of focal cortical ischemia. An infusion of nimodipine (2 micrograms/kg/min i.v.) or its vehicle, polyethylene glycol 400, was begun 2 h before the ischemic interval and was continued throughout the survival period. Under brief halothane anesthesia, the animals' right middle cerebral and common carotid arteries were permanently occluded, and 2.5 h later, they underwent a quantitative CBF study ([14C]iodoantipyrine autoradiography followed by Quantimet 970 image analysis). Nimodipine treatment improved blood flow to the middle cerebral artery territory without evidence of a "vascular steal" and reduced the volume of the ischemic core (cortex with CBF of less than 25 ml/100 g/min) and accompanying edema by approximately 50% when compared with controls (p = 0.006 and 0.0004, respectively). Mild hypotension induced by nimodipine did not aggravate the ischemic insult. The ischemic core volumes, however, were 50-75% smaller than the 24-h infarct volumes generated in a similar paradigm that demonstrated 20-30% infarct reduction with continuous nimodipine treatment. These results suggest that nimodipine pretreatment attenuates the severity of early focal cerebral ischemia, but that with persistent ischemia, cortex surrounding the ischemic core undergoes progressive infarction and the early benefit of nimodipine treatment is only partly preserved.     

alpha-Melanocyte-stimulating hormone is neuroprotective in rat global cerebral ischemia

The aim of the study was to investigate the effects of alpha-melanocyte-stimulating hormone (alpha-MSH), a tridecapeptide derived from proopiomelanocortin (POMC), on the neurodegeneration following global cerebral ischemia and reperfusion in the rat. The biological activities of alpha-MSH include inhibition of inflammatory responses and anti-pyretic effects. Male Sprague-Dawley rats were subjected to four-vessel occlusion (4-VO) global cerebral ischemia followed by reperfusion, and treated with alpha-MSH (intraperitoneally, i.p.) at 30 min, and 24, 48, 72 and 96 h post-ischemia. Stereological quantification of the pyramidal cells in the CA1 area of the hippocampus showed that the number of viable neurons in ischemic rats was 96,945+/-18,610 (means+/-SD) as compared to 183,156+/-49,935 in sham-operated rats (P<0.05). The number of viable neurons after treatment of ischemic rats with alpha-MSH was 162,829+/-34,757, i.e. significantly different from the number of viable neurons in ischemic rats injected with saline (P<0.01). Astrocyte proliferation due to the ischemic insult was markedly reduced by the treatment with alpha-MSH, and the loss in body weight was reduced by alpha-MSH. In conclusion, post-ischemic administration of alpha-MSH was found to provide neuroprotection in the CA1 pyramidal cell layer in the hippocampus, concomitant with a reduction in glial activation, indicating that alpha-MSH or mimetics thereof may have a potential in the treatment of stroke or other neurodegenerative diseases. Further studies will be required to define the post-ischemic time window for administration of alpha-MSH.     

Effect of short-term hyperventilation on cerebral blood flow autoregulation in patients with acute bacterial meningitis

BACKGROUND AND PURPOSE: Cerebral blood flow (CBF) autoregulation is impaired in patients with acute bacterial meningitis: this may be caused by cerebral arteriolar dilatation. We tested the hypothesis that CBF autoregulation is recovered by acute mechanical hyperventilation in 9 adult patients with acute bacterial meningitis. METHODS: Norepinephrine was infused to increase mean arterial pressure (MAP) 30 mm Hg from baseline. Relative changes in CBF were concomitantly recorded by transcranial Doppler ultrasonography of the middle cerebral artery, measuring mean flow velocity (V(mean)), and by measurement of arterial to jugular oxygen content difference (a-v DO(2)). The slope of the regression line between MAP and V(mean) was calculated. Measurements were performed during normoventilation and repeated after 30 minutes of mechanical hyperventilation. RESULTS: At normoventilation (median PaCO(2) 4.4 kPa, range 3.5 to 4.9), MAP was increased from 68 mm Hg (60 to 101) to 109 mm Hg (95 to 126). V(mean) increased with MAP from 48 cm/s (30 to 61) to 65 cm/s(33 to 86) (P<0.01), and a-v DO(2) decreased from 2.2 mmol/L (1.0 to 2.7) to 1.4 mmol/L (0.8 to 1.8) (P<0.05). During hyperventilation (PaCO(2) 3.5 kPa, range 3.3 to 4.1), MAP was increased from 76 mm Hg (58 to 92) to 109 mm Hg (95 to 121). V(mean) increased from 45 cm/s (29 to 55) to 53 cm/s (33 to 78) (P<0.01), and a-v DO(2) decreased from 2.5 mmol/L (1.8 to 3.0) to 1.8 mmol/L (1.2 to 2.4) (P<0.05). Four patients recovered autoregulation completely during hyperventilation. The slope of the autoregulation curve decreased during hyperventilation compared with normoventilation (P<0.05). CONCLUSIONS: CBF autoregulation is partially recovered during short-term mechanical hyperventilation in patients with acute bacterial meningitis, indicating that cerebral arteriolar dilation in part accounts for the regulatory impairment of CBF in these patients.     

Failure of alpha-melanocyte stimulating hormone to attenuate cerebral complications in experimental pneumococcal meningitis

Alpha-melanocyte-stimulating hormone (alpha-MSH) is an endogenous neuroimmunomodulatory peptide that can inhibit a broad range of inflammatory mediators known to be involved in the pathophysiology of bacterial meningitis. We evaluated the effect of alpha-MSH in a rat model of pneumococcal meningitis. Rats were intracisternally infected with Streptococcus pneumoniae and treatment was started 6 h after infection. Both systemic and intracisternal alpha-MSH failed to influence blood-brain barrier disruption, increased intracranial pressure, brain cytokine concentrations (IL-1beta, IL-6, TNF-alpha, MIP-2, and IL-10), CSF bacterial titers, and clinical parameters of disease severity (weight loss, body temperature, and blood pressure), although the treatment strongly increased the CNS concentrations of alpha-MSH. However, systemic but not intracisternal alpha-MSH slightly reduced the CNS leukocyte accumulation, indicating that leukocyte extravasation is inhibited by alpha-MSH from the blood side. Our results show that alpha-MSH reduces the CNS leukocyte accumulation by its systemic action, but does not attenuate meningitis-associated intracranial complications.     

Regional cerebral blood flow in children--normal value and regional distribution of cerebral blood flow in childhood

The changes in CBF and rCBF through the entire age range include the rapid period in childhood was reported. Sixteen children between the ages of 1 and 15 and 14 adults were studied. These 30 subjects were either volunteers of out-patients without CT and EEG abnormalities. rCBF was measured by the 133Xe intravenous injection method using Varmet rCBF analyzer. Ther relationship between age and CBF, the correlation coefficient was calculated based on the regression equations and the regression curve with the highest correlation was chosen. For the analysis of rCBF, he mean rCBF values (ISI) of 3 channels corresponding to the frontal, temporal, parietal and occipital lobes were expressed as a percentage of the hemispheric CBF. The hemispheric blood flow (ISI and CBF gray) of children less than 5 years of age was approximately twice that found in adults. This value decreased rapidly with age and in the 10-15 years the blood flow was approximately 1.3-fold that of adults. Thereafter, there was a slow decrease and a negative correlation with age was found. The decrease showed the correlation on the following equations; y = 146.5 - 58.5 log x. (r = -0.903) for ISI and log y = 2.26 - 0.29 log x. (r = -0.881) for CBF gray, which was statistically significant. In contrast, the CBF white showed a slightly higher value in the 1-2 years old children, but thereafter the CBF did not show a notable decreases with age. Through the entire age range, a best fit for the Fw values was found with : y = 18.3 + 37.5/x. (r = 0.798), which was also statistically significant.     

Anxiety and cerebral blood flow

The relationship between anxiety and cerebral blood flow (CBF) is of considerable clinical and research significance. Although a considerable amount of information is available on mechanisms through which anxiety may influence CBF, this topic has not received much attention in psychiatry. Earlier techniques for the measurement of CBF were cumbersome and invasive. With the advent of noninvasive techniques, study of CBF in psychiatric disorders, including anxiety, became easier, and a number of such studies have been conducted. In this article the literature on psychophysiological and clinical aspects of changes in CBF associated with anxiety is reviewed.     

7-nitroindazole reduces cerebral blood flow following chronic nitric oxide synthase inhibition

Blood flow and glucose utilization were measured in rat brain after chronic L-NAME treatment followed by acute 7-nitroindazole. Following chronic L-NAME, blood flow was not significantly different from control. Treatment with acute 7-nitroindazole reduced blood flow to the same extent in both chronic saline and L-NAME groups. Glucose utilization was unaffected. These results suggest that residual NOS activity in brain is sufficient to provide tonic, NO-dependent cerebrovascular dilator tone.