Heat shock protein 72 overexpression protects against hyperthermia, circulatory shock, and cerebral ischemia during heatstroke.

This study extends our earlier studies in rats by applying our heatstroke model to a new species. Additionally, transgenic mice are used to examine the role of heat shock protein (HSP) 72 in experimental heatstroke. Transgenic mice that were heterozygous for a porcine HSP70i gene ([+]HSP72), transgene-negative littermate controls ([-]HSP72), and normal Institute of Cancer Research strain mice (ICR) under pentobarbital sodium anesthesia were subjected to heat stress (40 degrees C) to induce heatstroke. In [-]HSP72 or ICR, the values for mean arterial pressure, the striatal blood flow, and the striatal PO2 after the onset of heatstroke were significantly lower than those in preheat controls. The core and brain temperatures, the extracellular concentrations of ischemic and injury markers in the striatum, and the striatal neuronal damage scores were significantly greater than those in the preheat controls. In [-]HSP72 or ICR, the body temperatures, cell ischemia content, and injury marker in the striatum were significantly higher, and the mean arterial pressure, striatal blood flow, and striatal PO2 concentration were significantly lower during heatstroke than in [+]HSP72. Accordingly, the latency and the survival times for [+]HSP72 significantly exceeded those of [-]HSP72 or ICR. These results demonstrate that the overexpression of HSP72 in multiple organs improves survival during heatstroke by reducing hyperthermia, circulatory shock, and cerebral ischemia and damage in mice.     

C-fos expression in rat brain during heat stress

Rats, under urethane anesthesia, 0, 20, 40 or 80 min after the start of heat stress (42°C) were sacrificed for determination of c-fos expression in different brain regions. In situ hybridization and immunocytochemistry methods were used, respectively, for determination of c-fos mRNA and protein, respectively. In general, either colon temperature (T_CO), mean arterial pressure (MAP), local cerebral blood flow (CBF) or c-fos expression in different brain regions (including the preoptic area, supraoptic nuclei, paraventricular nuclei, thalamus, amygdala, nucleus tract solitarii, area postrema and ventrolateral medulla) increased at 20–40 min after the start of heat exposure. However, the heatstroke, which appears as profound decreases in both MAP and local CBF and increases in T_CO, was produced 80 min after heat stress. The c-fos expression was heavily induced in all these brain regions after the onset of heatstroke. The data suggest that c-fos expression in rat brain during heatstroke is associated with hyperthermia, arterial hypotension or cerebral ischemia.     

Hyperthermia-induced vasoconstriction of the carotid artery, a possible causative factor of heatstroke.

Clinical and experimental studies indicate that hyperthermia can cause heatstroke with cerebral ischemia and brain damage. However, no study has examined the direct effects of heating carotid artery smooth muscle and tested the hypothesis that hyperthermia induces arterial vasoconstriction and, thereby, decreases cerebral blood flow. We recorded isometric tension of rabbit carotid artery strips in organ baths during stepwise temperature elevation. The heating responses were tested at basal tone, in norepinephrine- and KCl-precontracted vessels, and after electrical field stimulation. Stepwise heating from 37 degrees C to 47 degrees C induced reproducible graded contraction proportional to temperature. The responses could be elicited at basal tone and in precontracted vessels. Heating decreased the contractile responses to norepinephrine and electrical field stimulation but increased contraction to KCl. These responses were not eliminated by pretreatment with the neuronal blocker tetrodotoxin. Our results demonstrate that heating carotid artery preparations above 37 degrees C (normothermia) induced a reversible graded vasoconstriction proportional to temperature. In vivo this reaction may lead to a decrease in cerebral blood flow and cerebral ischemia with brain damage as in heatstroke. The heating-induced contraction is not mediated by a neurogenic process but is due to altered transcellular Ca2+ transport. Cooling, in particular of the neck area, therefore, should be used in the treatment of heatstroke.     

Proteomic analysis of hypothalamic injury in heatstroke rats

Ischemic and oxidative damage to the hypothalamus may be associated with decreased heat tolerance as well as heatstroke formation. The present study explores the hypothalamic proteome mechanisms associated with heatstroke‐mediated hypothalamic ischemia, and oxidative damage. Heatstroke rats had hypotension, hypothalamic ischemia, and lethality. In addition, they had hyperthermia and hypothalamic blood–brain–barrier disruption, oxidative stress, activated inflammation, and neuronal apoptosis and degeneration. 2DE combined LC‐MS/MS revealed that heatstroke‐induced ischemic injury and apoptosis were associated with upregulation of L‐lactate dehydrogenase but downregulation of both dihydropyriminase‐related protein and 14‐3‐3 Zeta isoform protein. Heat‐induced blood–brain–barrier disruption might be related to upregulation of glial fibrillary acidic protein. Oxidative stress caused by heatstroke might be related to upregulation of cytosolic dehydrogenase‐1. Also, heat‐induced overproduction of proinflammatory cytokines might be associated with downregulation of stathmin 1. Heat‐induced hypothalamic ischemia, apoptosis, injury (or upregulation of L‐lactate dehydrogenase), blood–brain–barrier disruption (or upregulation of glial fibrillary acidic protein), oxidative stress (or upregulation of cytosolic dehydrogenase‐1), and activated inflammation (or downregulation of stathmin 1) were all significantly reversed by whole body cooling. Our data indicate that cooling therapy improves outcomes of heatstroke by modulating hypothalamic proteome mechanisms.     

Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging

Pericytes play a key role in the development of cerebral microcirculation. The exact role of pericytes in the neurovascular unit in the adult brain and during brain aging remains, however, elusive. Using adult viable pericyte-deficient mice, we show that pericyte loss leads to brain vascular damage by two parallel pathways: (1) reduction in brain microcirculation causing diminished brain capillary perfusion, cerebral blood flow, and cerebral blood flow responses to brain activation that ultimately mediates chronic perfusion stress and hypoxia, and (2) blood-brain barrier breakdown associated with brain accumulation of serum proteins and several vasculotoxic and/or neurotoxic macromolecules ultimately leading to secondary neuronal degenerative changes. We show that age-dependent vascular damage in pericyte-deficient mice precedes neuronal degenerative changes, learning and memory impairment, and the neuroinflammatory response. Thus, pericytes control key neurovascular functions that are necessary for proper neuronal structure and function, and pericyte loss results in a progressive age-dependent vascular-mediated neurodegeneration.     

Heatstroke induces a reduction of natural killer cell activity in rats

Experiments were carried out to determine the changes of natural killer (NK) cell activity that occurred during heatstroke in rats pretreated with or without interleukin-1 (IL-1) receptor antagonist (IL-1ra). After the onset of heatstroke, all the splenic NK cell activity, the effector-target cell conjugation, and the NK cell numbers were decreased in rats. Additionally, an increase in the plasma IL-1 level was associated with arterial hypotension, cerebral ischemia and hyperthermia during rat heatstroke. Pretreatment with an IL-1ra reversed in part the heatstroke-induced inhibition of NK cell activity. Thus it appears that the inhibition of NK cell activity produced by activation of IL-1 receptor mechanism is associated with the increased susceptibility to infection that is well described in heatstroke.     

Contribution of arterial Windkessel in low-frequency cerebral hemodynamics during transient changes in blood pressure

The Windkessel properties of the vasculature are known to play a significant role in buffering arterial pulsations, but their potential importance in dampening low-frequency fluctuations in cerebral blood flow has not been clearly examined. In this study, we quantitatively assessed the contribution of arterial Windkessel (peripheral compliance and resistance) in the dynamic cerebral blood flow response to relatively large and acute changes in blood pressure. Middle cerebral artery flow velocity (MCA(V); transcranial Doppler) and arterial blood pressure were recorded from 14 healthy subjects. Low-pass-filtered pressure-flow responses (<0.15 Hz) during transient hypertension (intravenous phenylephrine) and hypotension (intravenous sodium nitroprusside) were fitted to a two-element Windkessel model. The Windkessel model was found to provide a superior goodness of fit to the MCA(V) responses during both hypertension and hypotension (R2 = 0.89 ± 0.03 and 0.85 ± 0.05, respectively), with a significant improvement in adjusted coefficients of determination (P < 0.005) compared with the single-resistance model (R2 = 0.62 ± 0.06 and 0.61 ± 0.08, respectively). No differences were found between the two interventions in the Windkessel capacitive and resistive gains, suggesting similar vascular properties during pressure rise and fall episodes. The results highlight that low-frequency cerebral hemodynamic responses to transient hypertension and hypotension may include a significant contribution from the mechanical properties of vasculature and, thus, cannot solely be attributed to the active control of vascular tone by cerebral autoregulation. The arterial Windkessel should be regarded as an important element of dynamic cerebral blood flow modulation during large and acute blood pressure perturbation.     

A simple mathematical model of the interaction between intracranial pressure and cerebral hemodynamics

Ursino, Mauro, and Carlo Alberto Lodi. A simplemathematical model of the interaction between intracranial pressure andcerebral hemodynamics. J. Appl.Physiol. 82(4): 1256-1269, 1997.A simplemathematical model of intracranial pressure (ICP) dynamics oriented toclinical practice is presented. It includes the hemodynamics of thearterial-arteriolar cerebrovascular bed, cerebrospinal fluid (CSF)production and reabsorption processes, the nonlinear pressure-volumerelationship of the craniospinal compartment, and a Starling resistormechanism for the cerebral veins. Moreover, arterioles are controlledby cerebral autoregulation mechanisms, which are simulated by means ofa time constant and a sigmoidal static characteristic. The model isused to simulate interactions between ICP, cerebral blood volume, andautoregulation. Three different related phenomena are analyzed: thegeneration of plateau waves, the effect of acute arterial hypotensionon ICP, and the role of cerebral hemodynamics during pressure-volume index (PVI) tests. Simulation results suggest the following:1) ICP dynamics may become unstablein patients with elevated CSF outflow resistance and decreasedintracranial compliance, provided cerebral autoregulation is efficient.Instability manifests itself with the occurrence of self-sustainedplateau waves. 2) Moderate acutearterial hypotension may have completely different effects on ICP,depending on the value of model parameters. If physiological compensatory mechanisms (CSF circulation and intracranial storage capacity) are efficient, acute hypotension has only negligible effectson ICP and cerebral blood flow (CBF). If these compensatory mechanismsare poor, even modest hypotension may induce a large transient increasein ICP and a significant transient reduction in CBF, with risks ofsecondary brain damage. 3) The ICPresponse to a bolus injection (PVI test) is sharply affected, viacerebral blood volume changes, by cerebral hemodynamics andautoregulation. We suggest that PVI tests may be used to extractinformation not only on intracranial compliance and CSF circulation,but also on the status of mechanisms controlling CBF.

     

Failure of cerebral autoregulation as a cause of brain dysfunction in the elderly.

Cerebral blood flow in relation to change in arterial pressure was measured in 11 elderly patients with postural hypotension. Seven patients with symptoms showed bilateral or unilateral failure of cerebral autoregulation, while the four asymptomatic patients did not. Variations in cerebral autoregulation would explain why some elderly people with minor falls of systemic arterial pressure develop clinical signs of cerebral ischaemia whereas others with greater falls in blood pressure remain asymptomatic. Elderly patients with impaired autoregulation may be at risk of brain damage from minor falls in blood pressure.     

Nitric oxide does not contribute to the hypotension of heatstroke.

The purpose of this study was to determine whether nitric oxide (NO) contributes to the hypotensive state induced by prolonged environmental heat (EH) stress. Ketamine-anesthetized rats were instrumented for the measurement of arterial blood pressure, electrocardiogram, and temperature at four sites. Rats were exposed to EH (ambient temperature, 40 +/- 1 degrees C) until mean arterial blood pressure (MAP) decreased to 75 mmHg, which was arbitrarily defined as the induction of heatstroke. In addition to cardiovascular and temperature measurements, the time required to reach this MAP end point and the subsequent survival time were measured. In three separate experimental series, the competitive NO synthesis inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) was administered (0, 10, or 100 mg/kg) either before, during (30 min after initiation of EH), or immediately after EH. L-NAME administered at any of these times transiently increased MAP. L-NAME infusion either before or during EH did not alter the EH time required to decrease MAP to 75 mmHg, but L-NAME pretreatment did decrease the colonic temperature at which this MAP end point was reached. L-NAME infusion before or after EH did not affect subsequent survival time, but L-NAME administered during EH significantly decreased survival time. The administration of L-NAME at any time point, therefore, did not prove beneficial in either preventing or reversing heatstroke. Taken together, these data suggest that NO does not mediate the hypotension associated with heatstroke.     

炎症相关因子在血管性痴呆发病机制中的作用

血管性痴呆（vascular dementia,VD）是指由各种脑血管病,包括缺血性脑血管病、出血性脑血管病及急性与慢性缺氧性脑血管病引起的脑功能障碍,进而产生认知功能障碍的临床综合征。血管性痴呆是一种慢性进行性疾病,被认为是仅次于阿尔兹海默症,导致痴呆的第2位原因。目前,血管性痴呆的发病机制尚不明确,有可能与炎症、神经元损伤、胆碱能系统功能障碍、脑白质病变及氧化应激等有关。其中,炎症反应在急性与慢性脑缺血继发性脑损伤中起主要作用。抑制炎症能改善血管性痴呆动物模型的症状,显示炎症可能在血管性痴呆发病机制中发挥重要作用。参与炎症反应的相关因子,如细胞因子等可对中枢神经系统造成损伤。同时,炎症相关因子会触发炎症级联反应,加重脑损伤。本文总结了有关炎症相关因子参与导致血管性痴呆的各种病理损害和促进其发生发展的分子机制的最新研究进展,这些都有助于了解炎症相关因子在血管性痴呆发病机制中的作用。     

Thiopental Inhibits Global Protein Synthesis by Repression of Eukaryotic Elongation Factor 2 and Protects from Hypoxic Neuronal Cell Death

Ischemic and traumatic brain injury is associated with increased risk for death and disability. The inhibition of penumbral tissue damage has been recognized as a target for therapeutic intervention, because cellular injury evolves progressively upon ATP-depletion and loss of ion homeostasis. In patients, thiopental is used to treat refractory intracranial hypertension by reducing intracranial pressure and cerebral metabolic demands; however, therapeutic benefits of thiopental-treatment are controversially discussed. In the present study we identified fundamental neuroprotective molecular mechanisms mediated by thiopental. Here we show that thiopental inhibits global protein synthesis, which preserves the intracellular energy metabolite content in oxygen-deprived human neuronal SK-N-SH cells or primary mouse cortical neurons and thus ameliorates hypoxic cell damage. Sensitivity to hypoxic damage was restored by pharmacologic repression of eukaryotic elongation factor 2 kinase. Translational inhibition was mediated by calcium influx, activation of the AMP-activated protein kinase, and inhibitory phosphorylation of eukaryotic elongation factor 2. Our results explain the reduction of cerebral metabolic demands during thiopental treatment. Cycloheximide also protected neurons from hypoxic cell death, indicating that translational inhibitors may generally reduce secondary brain injury. In conclusion our study demonstrates that therapeutic inhibition of global protein synthesis protects neurons from hypoxic damage by preserving energy balance in oxygen-deprived cells. Molecular evidence for thiopental-mediated neuroprotection favours a positive clinical evaluation of barbiturate treatment. The chemical structure of thiopental could represent a pharmacologically relevant scaffold for the development of new organ-protective compounds to ameliorate tissue damage when oxygen availability is limited.     

Quintessential Risk Factors: Their Role in Promoting Cognitive Dysfunction and Alzheimer’s Disease

Alzheimer??s disease (AD) is a progressive neurodegenerative disorder. The human brain is extremely sensitive to hypoxia, ischemia, and glucose depletion. Impaired delivery of oxygen in obstructive sleep apnea (OSA) alters neuronal homeostasis, induces pathology, and triggers neuronal degeneration/death. This article systematically delineates the steps in the complex cascade leading to AD, focusing on pathology caused by chronic intermittent hypoxia, hypertension, brain hypoperfusion, glucose dysmetabolism, and endothelial dysfunction. Hypoxia/hypoxemia underpins several pathological processes including sympathetic activation, chemoreflex activity, neuroinflammation, oxidative stress, and a host of perturbations leading to neurodegeneration. The arterial blood flow reduction in OSA is profound, being about 76?% in obstructive hypopneas and 80?% in obstructive apneas; this leads to cerebral ischemia promoting neuronal apoptosis in neocortex and brainstem. OSA pathology also includes gray matter loss in the frontal, parietal, temporal, and occipital cortices, the thalamus, hippocampus, and key brainstem nuclei including the nucleus tractus solitarius. (18)F-FDG PET studies on OSA and AD patients, and animal models of AD, have shown reduced cerebral glucose metabolism in the above mentioned brain regions. Owing to the pathological impact of hypoxia, hypertension, hypoperfusion and impaired glucose metabolism, the adverse cardiovascular, neurocirculatory and metabolic consequences upregulate amyloid beta generation and tau phosphorylation, and lead to memory/cognitive impairment??culminating in AD. The framework encompassing these factors provides a pragmatic neuropathological approach to explain onset of Alzheimer??s dementia. The basic tenets of the current paradigm should influence the design of therapeutic strategies to ameliorate AD.     

Analysis of the timing parameters of blood flow in the carotid basin arteries of hypertensive patients

Vascular duplex ultrasound study with simultaneous ECG recording was performed to estimate the timing parameters of blood flow in the common carotid, internal carotid, and middle cerebral arteries in patients with grades 1 and 2 arterial hypertension. There was an increase in the blood flow acceleration phase index in the common carotid and middle cerebral arteries and a reduction in the systolic phase index in the internal carotid arteries. There were correlations of phasic blood flow parameters in the extra- and intracranial arteries with age and lipidogram readings.     

中暑致肝损伤机制的研究进展

中暑是常发生在夏季高温环境或大量运动时的急危重症,可导致包括肝脏在内的多器官功能损害。中暑的发生及发展过程经历了代偿期、急性反应期和失代偿期。近年来国内外关于中暑致肝损伤机制方面的研究表明,中暑致肝脏功能损伤可能与热的直接作用、肝细胞内线粒体功能障碍和级联放大的炎症反应有关,各环节相互促进,最终导致肝脏的损伤。而且,在肝窦内的级联放大炎症反应在中暑致肝损伤中可能起主要作用。因此,本文对近年来中暑的病理生理和中暑致肝损伤机制方面的研究及进展作一综述,为中暑致肝损伤的临床防治提供思路。     

Hsp-72, a candidate prognostic indicator of heatstroke

Exposure of rats to environmental heat enhances the expression of heat shock protein-72 (Hsp-72) in most of their organs proportionally to heat stress severity. Pre-induction or over-expression of Hsp-72 prevents organ damage and lethality, suggesting that heat shock proteins (Hsps) may have a pathogenic role in this condition. We investigated the expression profile of Hsps in baboons subjected to environmental heat stress until the core temperature attained 42.5°C (moderate heatstroke) or occurrence of hypotension associated with core temperature ≥43.5°C (severe heatstroke). Western blot analysis demonstrated a differential induction of Hsp-72 among organs of heat-stressed animals with the highest induction in the liver and the lowest in lung. Hsp-60 and Hsc-70 expression was similar between control and heat-stressed animals. ELISA studies indicated a marked release of Hsp-72 into the circulation of baboons with severe heatstroke with a peak at 24 h post-heatstroke onset and remained sustained up to 72 h. Hsp-72 release was not associated with core temperature or systolic blood pressure, but correlated with markers of liver, myocardium, and skeletal muscle tissue necrosis. Non-survivors displayed significantly higher Hsp-72 levels than survivors. No Hsp-60 was detected in the circulation. These findings add further evidence that increased expression of Hsp-72 may be an important component of the host response to severe heatstroke. They also suggest that extracellular Hsp-72 is a marker of multiple organs tissue damage. Whether extracellular Hsp-72 plays a role in the host immune response to heat stress merits further studies.     

老年急性脑梗死患者脑动脉狭窄的分布及其危险因素研究

目的:探讨老年急性脑梗死患者脑动脉狭窄的分布及其危险因素。方法:对150例老年急性脑梗死患者及144例对照组人群进行经颅多普勒超声和血压、血脂、血糖、吸烟饮酒史、心脑血管病家族史进行收集。结果:研究组颅内动脉狭窄检出率(42.0%)高于对照组(13.9%)(P0.05),颅内动脉狭窄分布为MCA 41.3%、TICA 31.7%、VA 14.3%、ACA 9.5%、BA 6.3%、PCA4.8%。血脂异常、长期吸烟、长期饮酒、高血压、糖尿病、心脑血管病家族史、胆红素、尿酸以及C反应蛋白与颅内动脉狭窄相关。结论:关注颅内动脉狭窄及其危险因素对老年急性脑梗死患者非常重要,控制危险因素是医务工作者的重要工作。     

Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders

The neurovascular unit (NVU) comprises brain endothelial cells, pericytes or vascular smooth muscle cells, glia and neurons. The NVU controls blood-brain barrier (BBB) permeability and cerebral blood flow, and maintains the chemical composition of the neuronal 'milieu', which is required for proper functioning of neuronal circuits. Recent evidence indicates that BBB dysfunction is associated with the accumulation of several vasculotoxic and neurotoxic molecules within brain parenchyma, a reduction in cerebral blood flow, and hypoxia. Together, these vascular-derived insults might initiate and/or contribute to neuronal degeneration. This article examines mechanisms of BBB dysfunction in neurodegenerative disorders, notably Alzheimer's disease, and highlights therapeutic opportunities relating to these neurovascular deficits.     

神经性肺水肿之神经与血流动力学机制

临床分析及动物实验均报告颅内病变、头部受作或颅内压增加会导致急性肺水肿;在麻木麻醉鼠,严重脑部压迫产生急性、猛暴及致死性肺水肿,此种神经性肺病变乃由于激发脑干交感神经机构产生体循环高血压及一连串的血流动力学变化,导致主动脉血流急剧下降,引发肺部血量及血压严重增加,最终结果为血管破裂形成出务性肺水肿。     

Vinpocetine prevents ischemic cell damage in rat hippocampus

The effects of vinpocetine on hippocampal cell damage and local cerebral blood flow (LCBF) were measured in a rat model of forebrain ischemia (2-vessel occlusion and hypotension). Duration of ischemia was 10 min. LCBF was determined after 2 min of recirculation using the 14C-iodoantipyrine technique. Hippocampal cell loss was quantified histologically 7 days post-ischemia. Intraperitoneal application of vinpocetine (10 mg/kg) 15 min prior to ischemia significantly reduced neuronal cell loss in hippocampal CA 1 sector from 60% to 28%. The drug led to a marked increase in blood flow in cortical areas, whereas LCBF remained unchanged in hippocampus and all other structures measured. It is suggested that the protective effect of vinpocetine does not depend on increased postischemic blood flow.