Association between liver fibrosis and cognition in a nationally representative sample of older adults.

BACKGROUND AND PURPOSE: Liver fibrosis, a common yet often subclinical manifestation of chronic liver disease, may have an unrecognized role in cognitive impairment. We evaluated the association between a validated liver fibrosis index and cognitive measures among older adults. METHODS: We examined the association between liver fibrosis and cognitive performance among participants aged 60 years and older in the US National Health and Nutrition Examination Survey. Liver fibrosis was measured with the validated Fibrosis-4 (FIB-4) liver fibrosis score. The outcomes were performance on four standardized cognitive tests of immediate and delayed verbal learning, verbal fluency, and attention/concentration. We used linear regression to evaluate the association between FIB-4 score and performance on cognitive tests while adjusting for potential confounders. In sensitivity analyses, we examined this association in participants without known liver disease. RESULTS: Among 3217 adult participants, the mean age was 69 years, and 54% were women. Standard liver chemistries were largely in the normal range. However, 5.0% [95% confidence interval (CI) 4.0-6.0] had liver fibrosis based on a validated cut-off. In adjusted linear regression models, higher liver fibrosis scores were associated with worse immediate recall (ß -0.39; 95% CI -0.58, -0.21), language fluency (ß -0.46; 95% CI -0.72, -0.21), and attention/concentration (ß -1.34; 95% CI -2.25, -0.43), but not delayed recall (ß -0.10; 95% CI -0.20, 0.01). Results were similar when limiting the study population to participants without known clinical liver disease. CONCLUSION: Liver fibrosis, including subclinical liver fibrosis, may be an independent risk factor for cognitive impairment among older adults.

The transcription factor interferon regulatory factor 1 is expressed after cerebral ischemia and contributes to ischemic brain injury.

The transcription factor interferon regulatory factor 1 (IRF-1) is involved in the molecular mechanisms of inflammation and apoptosis, processes that contribute to ischemic brain injury. In this study, the induction of IRF-1 in response to cerebral ischemia and its role in ischemic brain injury were investigated. IRF-1 gene expression was markedly upregulated within 12 h of occlusion of the middle cerebral artery in C57BL/6 mice. The expression reached a peak 4 d after ischemia (6.0 +/- 1.8-fold; P < 0.001) and was restricted to the ischemic regions of the brain. The volume of ischemic injury was reduced by 23 +/- 3% in IRF-1(+/-) and by 46 +/- 9% in IRF-1(-/-) mice (P < 0.05). The reduction in infarct volume was paralleled by a substantial attenuation in neurological deficits. Thus, IRF-1 is the first nuclear transacting factor demonstrated to contribute directly to cerebral ischemic damage and may be a novel therapeutic target in ischemic stroke.

Cerebral ischemia enhances polyamine oxidation: identification of enzymatically formed 3-aminopropanal as an endogenous mediator of neuronal and glial cell death.

To elucidate endogenous mechanisms underlying cerebral damage during ischemia, brain polyamine oxidase activity was measured in rats subjected to permanent occlusion of the middle cerebral artery. Brain polyamine oxidase activity was increased significantly within 2 h after the onset of ischemia in brain homogenates (15.8 +/- 0.9 nmol/h/mg protein) as compared with homogenates prepared from the normally perfused contralateral side (7.4 +/- 0.5 nmol/h/mg protein) (P <0.05). The major catabolic products of polyamine oxidase are putrescine and 3-aminopropanal. Although 3-aminopropanal is a potent cytotoxin, essential information was previously lacking on whether 3-aminopropanal is produced during cerebral ischemia. We now report that 3-aminopropanal accumulates in the ischemic brain within 2 h after permanent forebrain ischemia in rats. Cytotoxic levels of 3-aminopropanal are achieved before the onset of significant cerebral cell damage, and increase in a time-dependent manner with spreading neuronal and glial cell death. Glial cell cultures exposed to 3-aminopropanal undergo apoptosis (LD50 = 160 microM), whereas neurons are killed by necrotic mechanisms (LD50 = 90 microM). The tetrapeptide caspase 1 inhibitor (Ac-YVAD-CMK) prevents 3-aminopropanal-mediated apoptosis in glial cells. Finally, treatment of rats with two structurally distinct inhibitors of polyamine oxidase (aminoguanidine and chloroquine) attenuates brain polyamine oxidase activity, prevents the production of 3-aminopropanal, and significantly protects against the development of ischemic brain damage in vivo. Considered together, these results indicate that polyamine oxidase-derived 3-aminopropanal is a mediator of the brain damaging sequelae of cerebral ischemia, which can be therapeutically modulated.

Local cerebral blood flow increases during auditory and emotional processing in the conscious rat.

Local cerebral blood flow was measured in rats by the 14C-labeled iodoantipyrine technique with quantitative autoradiography during the processing of environmental stimuli. Presentation of a tone increased blood flow in the auditory but not the visual pathway. When the animal had previously been conditioned to fear the tone, blood flow additionally increased in the hypothalamus and amygdala. Local cerebral blood flow can thus be used to detect patterns of cerebral excitation associated with transient (30- to 40-second) mental events in experimental animals.

SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein.

Peptides derived from proteolytic processing of the beta-amyloid precursor protein (APP), including the amyloid-beta peptide, are important for the pathogenesis of Alzheimer's dementia. We found that transgenic mice overexpressing APP have a profound and selective impairment in endothelium-dependent regulation of the neocortical microcirculation. Such endothelial dysfunction was not found in transgenic mice expressing both APP and superoxide dismutase-1 (SOD1) or in APP transgenics in which SOD was topically applied to the cerebral cortex. These cerebrovascular effects of peptides derived from APP processing may contribute to the alterations in cerebral blood flow and to neuronal dysfunction in Alzheimer's dementia.

Association between Intracranial Atherosclerotic Calcium Burden and Angiographic Luminal Stenosis Measurements.

BACKGROUND AND PURPOSE: Calcification of the intracranial vasculature is an independent risk factor for stroke. The relationship between luminal stenosis and calcium burden in the intracranial circulation is incompletely understood. We evaluated the relationship between atherosclerotic calcification and luminal stenosis in the intracranial ICAs. MATERIALS AND METHODS: Using a prospective stroke registry, we identified patients who had both NCCT and CTA or MRA examinations as part of a diagnostic evaluation for ischemic stroke. We used NCCTs to qualitatively (modified Woodcock Visual Score) and quantitatively (Agatston-Janowitz Calcium Score) measure ICA calcium burden and used angiography to measure arterial stenosis. We calculated correlation coefficients between the degree of narrowing and calcium burden measures. RESULTS: In 470 unique carotid arteries (235 patients), 372 (79.1%) had atherosclerotic calcification detectable on CT compared with 160 (34%) with measurable arterial stenosis on CTA or MRA (P < .001). We found a weak linear correlation between qualitative (R = 0.48) and quantitative (R = 0.42) measures of calcium burden and the degree of luminal stenosis (P < .001 for both). Of 310 ICAs with 0% luminal stenosis, 216 (69.7%) had measurable calcium scores. CONCLUSIONS: There is a weak correlation between intracranial atherosclerotic calcium scores and luminal narrowing, which may be explained by the greater sensitivity of CT than angiography in detecting the presence of measurable atherosclerotic disease. Future studies are warranted to evaluate the relationship between stenosis and calcium burden in predicting stroke risk.

Regulation of the cerebral microcirculation during neural activity: is nitric oxide the missing link?

Although the mechanisms regulating the cerebral microcirculation during neural activity have been the subject of inquiry for a century or more, the mediators responsible for the changes in cerebral blood flow still remain to be clearly identified. The discovery that nitric oxide, a powerful cerebrovasodilator, is produced by active neurons has led to the hypothesis that this agent could be the long-sought mediator 'coupling' brain activity to cerebral blood flow. This hypothesis is supported by recent experimental data suggesting that nitric oxide participates in the maintenance of resting cerebral blood flow and in the cerebrovasodilatation elicited by increased neural activity. In this article, this evidence is critically reviewed and discussed in the context of general principles of cerebrovascular regulation.

Bright and dark sides of nitric oxide in ischemic brain injury.

There is increasing evidence that nitric oxide (NO), a free radical that can act both as a signaling molecule and a neurotoxin, is involved in the mechanisms of cerebral ischemia. Although early investigations yielded conflicting results, the introduction of more-selective pharmacological tools and the use of molecular approaches for deletion of genes encoding for NO synthase have provided a better understanding of the role of NO in the mechanisms of ischemic brain damage. The evidence reviewed in this article suggests that NO is protective or destructive depending on the stage of evolution of the ischemic process and on the cellular source of NO. Defining the role of NO in cerebral ischemia provides the rationale for new neuroprotective strategies based on modulation of NO production in the post-ischemic brain.

Pathobiology of ischaemic stroke: an integrated view.

Brain injury following transient or permanent focal cerebral ischaemia (stroke) develops from a complex series of pathophysiological events that evolve in time and space. In this article, the relevance of excitotoxicity, peri-infarct depolarizations, inflammation and apoptosis to delayed mechanisms of damage within the peri-infarct zone or ischaemic penumbra are discussed. While focusing on potentially new avenues of treatment, the issue of why many clinical stroke trials have so far proved disappointing is addressed. This article provides a framework that can be used to generate testable hypotheses and treatment strategies that are linked to the appearance of specific pathophysiological events within the ischaemic brain.

Subcellular localization of nicotinamide adenine dinucleotide phosphate oxidase subunits in neurons and astroglia of the rat medial nucleus tractus solitarius: relationship with tyrosine hydroxylase immunoreactive neurons.

Superoxide produced by the enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase mediates crucial intracellular signaling cascades in the medial nucleus of the solitary tract (mNTS), a brain region populated by catecholaminergic neurons, as well as astroglia that play an important role in autonomic function. The mechanisms mediating NADPH oxidase (phagocyte oxidase) activity in the neural regulation of cardiovascular processes are incompletely understood, however the subcellular localization of superoxide produced by the enzyme is likely to be an important regulatory factor. We used immunogold electron microscopy to determine the phenotypic and subcellular localization of the NADPH oxidase subunits p47(phox), gp91(phox,) and p22(phox) in the mNTS in rats. The mNTS contains a large population of neurons that synthesize catecholamines. Significantly, catecholaminergic signaling can be modulated by redox reactions. Therefore, the relationship of NADPH oxidase subunit labeled neurons or glia with respect to catecholaminergic neurons was also determined by dual labeling for the superoxide producing enzyme and tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. In the mNTS, NADPH oxidase subunits were present primarily in somatodendritic processes and astrocytes, some of which also contained TH, or were contacted by TH-labeled axons, respectively. Immunogold quantification of NADPH oxidase subunit localization showed that p47(phox) and gp91(phox) were present on the surface membrane, as well as vesicular organelles characteristic of calcium storing smooth endoplasmic reticula in dendritic and astroglial processes. These results indicate that NADPH oxidase assembly and consequent superoxide formation are likely to occur near the plasmalemma, as well as on vesicular organelles associated with intracellular calcium storage within mNTS neurons and glia. Thus, NADPH oxidase-derived superoxide may participate in intracellular signaling pathways linked to calcium regulation in diverse mNTS cell types. Moreover, NADPH oxidase-derived superoxide in neurons and glia may directly or indirectly modulate catecholaminergic neuron activity in the mNTS.

Cyclooxygenase-1 participates in selected vasodilator responses of the cerebral circulation.

Cyclooxygenase (COX) is a prostanoid-synthesizing enzyme present in 2 isoforms: COX-1 and COX-2. Although it has long been hypothesized that prostanoids participate in cerebrovascular regulation, the lack of adequate pharmacological tools has led to conflicting results and has not permitted investigators to define the relative contribution of COX-1 and COX-2. We used the COX-1 inhibitor SC-560 and COX-1-null (COX-1(-/-)) mice to investigate whether COX-1 plays a role in cerebrovascular regulation. Mice were anesthetized (urethane and chloralose) and equipped with a cranial window. Cerebral blood flow (CBF) was measured by laser Doppler flowmetry or by the (14)C-iodoantipyrine technique with quantitative autoradiography. In wild-type mice, SC-560 (25 micromol/L) reduced resting CBF by 21+/-4% and attenuated the CBF increase produced by topical application of bradykinin (-59%) or calcium ionophore A23187 (-49%) and by systemic hypercapnia (-58%) (P<0.05 to 0.01). However, SC-560 did not reduce responses to acetylcholine or the increase in somatosensory cortex blood flow produced by vibrissal stimulation. In COX-1(-/-) mice, resting CBF assessed by (14)C-iodoantipyrine was reduced (-13% to -20%) in cerebral cortex and other telencephalic regions (P<0.05). The CBF increase produced by bradykinin, A23187, and hypercapnia, but not acetylcholine or vibrissal stimulation, were attenuated (P<0.05 to 0.01). The free radical scavenger superoxide dismutase attenuated responses to bradykinin and A23187 in wild-type mice but not in COX-1(-/-) mice, suggesting that COX-1 is the source of the reactive oxygen species known to mediate these responses. The data provide evidence for a critical role of COX-1 in maintaining resting vascular tone and in selected vasodilator responses of the cerebral microcirculation.

OC-02 - Risk of arterial thromboembolism in patients with breast cancer.

INTRODUCTION: Breast cancer is the most common cancer in women and clearly increases the risk of venous thromboembolism. However, its association with arterial thromboembolism is less well defined. AIM: To determine the short-term cumulative incidence and relative hazard of arterial thromboembolism in elderly patients with incident breast cancer. MATERIALS AND METHODS: Using the Surveillance Epidemiology and End Results-Medicare linked database, which includes approximately 28% of all patients diagnosed with cancer in the United States, we identified patients with a new primary diagnosis of breast cancer from 2002 through 2011. These patients were individually matched by age, sex, race, registry, and medical comorbidities to a group of Medicare enrollees without cancer, and each pair was followed through 2012. Validated diagnosis codes were used to identify a primary composite outcome of arterial thromboembolism defined as any ischemic stroke or myocardial infarction. Secondary outcomes included ischemic stroke alone and myocardial infarction alone. Cumulative incidence rates were calculated using competing risk survival statistics. The Gray test was used to compare rates between groups. The proportional hazard assumption was violated for the entirety of patient follow-up; therefore, Cox proportional hazard analysis was performed at discrete time points when the assumption was generally met. RESULTS: We identified 96,666 pairs of breast cancer patients and matched controls. Median age was 75 years and few cancers were advanced at diagnosis (12% stages 3/4). The 3-month cumulative incidence of arterial thromboembolism was 2.1% (95% confidence interval [CI] 2.0-2.2%) in cancer patients compared to 1.4% (95% CI 1.3-1.5%) in controls (hazard ratio [HR] 1.5, 95% CI 1.4-1.6, p<0.01). The short-term risk of each secondary outcome was heightened in the breast cancer group, although the relative hazard for myocardial infarction was higher than for ischemic stroke. The 3-month cumulative incidence of ischemic stroke was 1.3% (95% CI 1.2-1.4%) in cancer patients compared to 1.0% (95% CI 0.9-1.1%) in controls (HR 1.3, 95% CI 1.2-1.4, p<0.01), and the 3-month cumulative incidence of myocardial infarction was 0.9% (95% CI 0.8-0.9%) in cancer patients compared to 0.4% (0.4-0.5%) in controls (HR 2.0, 95% CI 1.8-2.3, p<0.01). Excess risks attenuated over time and were no longer present beyond 1 year. CONCLUSIONS: Patients with incident breast cancer face an increased short-term risk of ischemic stroke and myocardial infarction.

Cyclooxygenase-2 contributes to functional hyperemia in whisker-barrel cortex.

The prostanoid-synthesizing enzyme cyclooxygenase-2 (COX-2) is expressed in selected cerebral cortical neurons and is involved in synaptic signaling. We sought to determine whether COX-2 participates in the increase in cerebral blood flow produced by synaptic activity in the somatosensory cortex. In anesthetized mice, the vibrissae were stimulated mechanically, and cerebral blood flow was recorded in the contralateral somatosensory cortex by a laser-Doppler probe. We found that the COX-2 inhibitor NS-398 attenuates the increase in somatosensory cortex blood flow produced by vibrissal stimulation. Furthermore, the flow response was impaired in mice lacking the COX-2 gene, whereas the associated increase in whisker-barrel cortex glucose use was not affected. The increases in cerebral blood flow produced by hypercapnia, acetylcholine, or bradykinin were not attenuated by NS-398, nor did they differ between wild-type and COX-2 null mice. The findings provide evidence for a previously unrecognized role of COX-2 in the mechanisms coupling synaptic activity to neocortical blood flow and provide an insight into one of the functions of constitutive COX-2 in the CNS.

Angiotensin II AT-1A receptor immunolabeling in rat medial nucleus tractus solitarius neurons: subcellular targeting and relationships with catecholamines.

The angiotensin II AT-1A receptor (AT-1A) is the major mediator of the hypertensive actions of angiotensin II (ANG II) in the medial nucleus of the solitary tract (mNTS). The localization of the AT-1A receptor at surface or intracellular sites is an important determinant of its signaling properties, including intercellular or intracrine communication. However, the spatial localization of this protein, particularly within small distal or intermediate size dendrites of mNTS neurons, is unknown. Within the mNTS, ANG II and catecholamines interact in the regulation of autonomic function; however, it is unknown if AT-1A receptors are present at functional sites in catecholamine containing dendrites, or are contacted by catecholamine containing axon terminals. We compared surface and intracellular distributions of the AT-1A receptor in dendritic processes from the mNTS using immunogold electron microscopy in conjunction with immunoperoxidase labeling for tyrosine hydroxylase (TH) and morphometric analysis. Collapsed across all AT-1A-labeled dendritic profiles, immunogold labeling was more frequent in intracellular sites as compared with the plasma membrane. Small (<0.6 microm) dendritic profiles contained a higher ratio of particles associated with the surface membrane when compared with larger profiles. Approximately 27% of all AT-1A receptor-labeled dendritic profiles also contained labeling for TH. Approximately 12% of dendritic profiles single labeled for the AT-1A receptor were contacted by TH containing axons or axon terminals. The present results provide the first quantitative demonstration of select plasmalemmal and intracellular localizations of AT-1A receptors in dendritic processes of mNTS neurons, including those containing TH, or contacted by catecholaminergic axon terminals. These results suggest that AT-1A receptors are positioned for modulation of catecholamine signaling in the mNTS.

Sex differences in NMDA GluN1 plasticity in rostral ventrolateral medulla neurons containing corticotropin-releasing factor type 1 receptor following slow-pressor angiotensin II hypertension.

There are profound, yet incompletely understood, sex differences in the neurogenic regulation of blood pressure. Both corticotropin signaling and glutamate receptor plasticity, which differ between males and females, are known to play important roles in the neural regulation of blood pressure. However, the relationship between hypertension and glutamate plasticity in corticotropin-releasing factor (CRF)-receptive neurons in brain cardiovascular regulatory areas, including the rostral ventrolateral medulla (RVLM) and paraventricular nucleus of the hypothalamus (PVN), is not understood. In the present study, we used dual-label immuno-electron microscopy to analyze sex differences in slow-pressor angiotensin II (AngII) hypertension with respect to the subcellular distribution of the obligatory NMDA glutamate receptor subunit 1 (GluN1) subunit of the N-methyl-D-aspartate receptor (NMDAR) in the RVLM and PVN. Studies were conducted in mice expressing the enhanced green fluorescence protein (EGFP) under the control of the CRF type 1 receptor (CRF1) promoter (i.e., CRF1-EGFP reporter mice). By light microscopy, GluN1-immunoreactivity (ir) was found in CRF1-EGFP neurons of the RVLM and PVN. Moreover, in both regions tyrosine hydroxylase (TH) was found in CRF1-EGFP neurons. In response to AngII, male mice showed an elevation in blood pressure that was associated with an increase in the proportion of GluN1 on presumably functional areas of the plasma membrane (PM) in CRF1-EGFP dendritic profiles in the RVLM. In female mice, AngII was neither associated with an increase in blood pressure nor an increase in PM GluN1 in the RVLM. Unlike the RVLM, AngII-mediated hypertension had no effect on GluN1 localization in CRF1-EGFP dendrites in the PVN of either male or female mice. These studies provide an anatomical mechanism for sex-differences in the convergent modulation of RVLM catecholaminergic neurons by CRF and glutamate. Moreover, these results suggest that sexual dimorphism in AngII-induced hypertension is reflected by NMDA receptor trafficking in presumptive sympathoexcitatory neurons in the RVLM.

Inflammation and stroke: putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia.

Ischemic stroke is a leading cause of death and disability in developed countries. Yet, in spite of substantial research and development efforts, no specific therapy for stroke is available. Several mechanism for neuroprotection have been explored including ion channels, excitatory amino acids and oxygen radicals yet none has culminated in an effective therapeutic effect. The review article on "inflammation and stroke" summarizes key data in support for the possibility that inflammatory cells and mediators are important contributing and confounding factors in ischemic brain injury. In particular, the role of cytokines, endothelial cells and leukocyte adhesion molecules, nitric oxide and cyclooxygenase (COX-2) products are discussed. Furthermore, the potential role for certain cytokines in modulation of brain vulnerability to ischemia is also reviewed. The data suggest that novel therapeutic strategies may evolve from detailed research on some specific inflammatory factors that act in spatial and temporal relationships with traditionally recognized neurotoxic factors. The dual nature of some mediators in reformatting of brain cells for resistance or sensitivity to injury demonstrate the delicate balance needed in interventions based on anti-inflammatory strategies.

Cyclooxygenase-2 inhibitor ns-398 protects neuronal cultures from lipopolysaccharide-induced neurotoxicity.

BACKGROUND AND PURPOSE: The prostanoid-synthesizing enzyme cyclooxygenase (COX)-2 is markedly upregulated after cerebral ischemia and may participate in the mechanisms by which postischemic inflammation contributes to the late stages of ischemic brain injury. In the present study, we sought to provide additional evidence for a role of COX-2 in the mechanisms of neurotoxicity associated with inflammation. METHODS: Nine-day-old neuronal-glial cultures, prepared from the cerebral cortex of newborn C57BL/6J mice, were exposed to lipopolysaccharide (LPS), a potent proinflammatory agent. The contribution of COX-2 was investigated by using the COX-2 inhibitor NS-398. RESULTS: LPS produced a dose-dependent (0.001 to 10 microg/mL) and selective neuronal death that was well developed 72 hours after treatment. The effect was associated with a marked increase in the concentration of the COX reaction product prostaglandin E(2) (PGE(2)) and of the cytokine tumor necrosis factor-alpha (TNF-alpha). NS-398 (10 micromol/L) blocked the PGE(2) increase, attenuated the TNF-alpha increase, and prevented the neuronal death produced by LPS. TNF-alpha-blocking antibodies attenuated LPS-induced neuronal death, but the protection was less pronounced than that afforded by NS-398. LPS failed to elevate PGE(2) or to produce cell death in neuron-enriched cultures, suggesting that glial cells are required for these effects. CONCLUSIONS: COX-2, in part through TNF-alpha-related mechanisms, contributes to LPS-induced neuronal death. The data support the hypothesis that COX-2, in addition to its role in glutamate excitotoxicity, participates in the cytotoxicity associated with inflammation.

Evidence that disruption of the blood-brain barrier precedes reduction in cerebral blood flow in hypertensive encephalopathy.

Alternative hypotheses concerning the pathogenesis of hypertensive encephalopathy are that vasospasm produces cerebral ischemia and cerebral edema, or that passive dilation of cerebral vessels during severe hypertension produces disruption of the blood-brain barrier and cerebral edema. Stroke-prone spontaneously hypertensive rats (SHRSP) were studied when they developed signs of neurological dysfunction. We measured regional cerebral blood flow (rCBF) with 14C-iodoantipyrine, and permeability of the blood-brain barrier with Evans blue dye. Twelve rats had focal disruption of the barrier without histological evidence of ischemic infarction or cerebral hemorrhage: areas with disruption of the barrier had severe focal edema in seven rats and minimal edema in five rats. In areas with disruption of the barrier and marked focal edema, rCBF was decreased to 38 +/- 8 (mean +/- SE) ml/min/100 g vs 102 +/- 13 (p less than 0.05) in other areas of the ipsilateral hemisphere, and 86 +/- 16 in the homologous area of the contralateral hemisphere (p less than 0.05). In contrast, in areas with disruption of the blood-brain barrier with only minimal edema, rCBF was normal or increased: rCBF was 100 +/- 11 ml/min/100 g vs 85 +/- 12 in other areas of the ipsilateral hemisphere (p greater than 0.05) and 64 +/- 8 in the homologous area contralaterally (p less than 0.05). The findings indicate that edema precedes reduction in rCBF in SHRSP and suggest that the initiating event in hypertensive encephalopathy is disruption of the blood-brain barrier, and not vasospasm.

Reduction of focal cerebral ischemic damage by delayed treatment with nitric oxide donors.

We studied whether delayed posttreatment with the nitric oxide donor 3-morpholinosydnonimine (SIN-1) is effective in reducing the size of the infarct produced by occlusion of the middle cerebral artery (MCA) in spontaneously hypertensive rats (SHRs). SHRs were anesthetized with halothane and intubated transorally. The left MCA was occluded at the level of the inferior cerebral vein. Cerebral blood flow (CBF) was monitored in the ischemic hemisphere by a laser-Doppler flowmeter, and an electroencephalogram (EEG) was recorded. SIN-1 was infused into the left internal carotid artery for 60 min starting 3, 15, 30, 60 or 120 min after MCA occlusion. The hypotension associated with SIN-1 administration was controlled by i.v. administration of phenylephrine. At the end of the infusion, rats were extubated and allowed to recover. Infarct size was measured 24 h later on thionein-stained coronal brain sections by computer-assisted planimetry. SIN-1 infusion 3 min after MCA occlusion enhanced the recovery of CBF and EEG amplitude and reduced the size of the infarct by 30 +/- 11% (p < 0.05, analysis of variance). The reduction in infarct size by SIN-1 was still seen when SIN-1 was administered 15, 30, and 60 min after MCA occlusion (p < 0.05). However, administration of SIN-1 2 h after MCA occlusion did not affect the size of the infarct (p > 0.05). We conclude that posttreatment with SIN-1 is effective in reducing focal ischemic damage if this agent is administered up to 60 min after MCA occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Stimulation of the fastigial nucleus enhances EEG recovery and reduces tissue damage after focal cerebral ischemia.

Stimulation of the cerebellar fastigial nucleus (FN) increases CBF but not metabolism and reduces the tissue damage resulting from focal cerebral ischemia. This effect may result from enhancing CBF in the ischemic tissue without increasing local metabolic demands. To test this hypothesis, we studied whether the reduction in tissue damage is restricted to the neocortex, a region in which the CBF increase is independent of metabolism, and whether stimulation of the dorsal medullary reticular formation (DMRF), a treatment that increases both cerebral metabolism and CBF, also protects the brain from ischemia. In halothane-anesthetized Sprague-Dawley rats, the middle cerebral artery (MCA) was occluded either proximally or distally to the lenticulostriate branches. The FN or DMRF were then stimulated for 1 h (50-100 microA; 50 Hz; 1 s on/l s off). Twenty-four hours later, the infarct volume was determined. FN stimulation substantially reduced the size of the infarct, an effect that was greater with distal (-69 +/- 8%; n = 6; p < 0.001; mean +/- SD) than with proximal (-38 +/- 8%; n = 8; p < 0.001) MCA occlusion. The reduction occurred only in neocortex (-43 +/- 9%; p < 0.001) and not in striatum (-16 +/- 21%; p > 0.05). Stimulation of the FN also enhanced recovery of EEG amplitude in the ischemic cortex (+48%; p < 0.003). DMRF stimulation (n = 7) did not affect the stroke size or EEG recovery (p > 0.05). Thus, stimulation of the FN, but not the DMRF, attenuates the damage resulting from focal ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)