脂蛋白(a)与动脉粥样硬化及脑梗死的研究进展

脂蛋白(a)是由载脂蛋白(a)和低密度脂蛋白构成的。脂蛋白(a)不随血浆中同型半胱氨酸、载脂蛋白A、高密度脂蛋白的变化而变化,是一种相对独立的脂蛋白。脂蛋白(a)的合成过程主要是在肝脏中完成的,脂蛋白(a)可以抑制NO介导的血管舒张,破坏血管壁中促凝与抗凝因子的平衡,参与动脉粥样硬化斑块的形成。动脉粥样硬化是脑梗死最基本的病因之一,在临床工作中我们应当重视脂蛋白(a)与脑梗死的关系,我们可以通过测定血清中脂蛋白(a)的水平来预测脑梗死的患病风险,尤其能对病变损害程度重,病变累及范围广的脑梗死的发生提出预警。高水平的血浆脂蛋白(a)是脑梗死及动脉粥样硬化的独立危险因素,本文就脂蛋白(a)与动脉粥样硬化及脑梗死研究中的进展做一综述,为脑梗死的预防提供参考和研究依据。     

Carbon monoxide mediates vasodilator effects of glutamate in isolated pressurized cerebral arterioles of newborn pigs

The excitatory neurotransmitter glutamate causes dilation of newborn pig cerebral arterioles in vivo that is blocked by inhibition of carbon monoxide (CO) production. CO, a potent dilator in cerebral circulation in vivo, is produced endogenously in cerebral microvessels via heme oxygenase (HO). In isolated pressurized cerebral arterioles (approximately 200 microm) from newborn pigs, we investigated the involvement of CO and the endothelium in response to glutamate. A CO-releasing molecule, dimanganese decacarbonyl (10(-8)-10(-6) M), dilated cerebral arterioles. Glutamate (10(-6)-10(-4) M) and 1-aminocyclopentane-cis-1,3-dicarboxylic acid (cis-ACPD; 10(-6)-10(-5) M), a N-methyl-D-aspartate (NMDA) receptor agonist, caused cerebral vascular dilation. Dilation of cerebral arterioles to glutamate and cis-ACPD was abolished by chromium mesoporphyrin (CrMP; 10(-6) M), a HO inhibitor. In contrast, CrMP did not alter dilation to isoproterenol, a -adrenergic receptor agonist. Endothelium-denuded cerebral arterioles did not dilate to glutamate or bradykinin (endothelium-dependent dilator), whereas responses to isoproterenol were preserved. These data indicate that cerebral arterioles from newborn pigs may directly respond to glutamate and the NMDA receptor agonists by endothelium-dependent dilation that involves stimulation of CO production via the HO pathway in the endothelium.     

Twins,triplets, and cerebral palsy in births in Western Australia in the 1980s.

OBJECTIVES--To examine the rate of cerebral palsy in twins and triplets in births from 1980 to 1989 in Western Australia and to identify factors associated with increase in risk. DESIGN--Pluralities for all births in Western Australia were identified through the standardised midwives'' notification system, and cases of cerebral palsy were identified from the Western Australian cerebral palsy register. MAIN OUTCOME MEASURES--Multiple births, cerebral palsy, excluding postneonatal cause. RESULTS--The prevalence of cerebral palsy in triplets, of 28 per 1000 survivors to 1 year (95% confidence interval 11 to 63) exceeded that in twins (7.3; 5.2 to 10) and singletons (1.6; 1.4 to 1.8). Although twins and triples were more likely than singletons to be low in birth weight, their risks of cerebral palsy if low in birth weight were similar. In contrast, in normal birthweight categories twins had a higher rate of cerebral palsy (4.2; 2.2 to 7.7) than singletons (1.1; 1.0 to 1.3). The prevalence of cerebral palsy was similar in twins of unlike sex pairs, all of whom are dizygotic, and in like sex pairs. A twin pair in which one member died in utero was at higher risk of cerebral palsy: 96 per 1000 twin pairs (36 to 218) compared with 12 (8.2 to 17) for twin pregnancies in which both survived. There was a similar but non-significant trend for death of one triplet to be associated with increased risk of cerebral palsy in the survivors of the set. CONCLUSION--Triplet pregnancies produced a child with cerebral palsy 47 times more often than singleton pregnancies did and twin pregnancies eight times more often. Eighty six per cent of cerebral palsy in multiple births was in twins. As multiple births are increasing mainly because of personal and medical decisions the increased risk of cerebral palsy in multiple births is of concern.     

Patient-specific modeling of cardiovascular and respiratory dynamics during hypercapnia

This study develops a lumped cardiovascular–respiratory system-level model that incorporates patient-specific data to predict cardiorespiratory response to hypercapnia (increased CO₂ partial pressure) for a patient with congestive heart failure (CHF). In particular, the study focuses on predicting cerebral CO₂ reactivity, which can be defined as the ability of vessels in the cerebral vasculature to expand or contract in response CO₂ induced challenges. It is difficult to characterize cerebral CO₂ reactivity directly from measurements, since no methods exist to dynamically measure vasomotion of vessels in the cerebral vasculature. In this study we show how mathematical modeling can be combined with available data to predict cerebral CO₂ reactivity via dynamic predictions of cerebral vascular resistance, which can be directly related to vasomotion of vessels in the cerebral vasculature. To this end we have developed a coupled cardiovascular and respiratory model that predicts blood pressure, flow, and concentration of gasses (CO₂ and O₂) in the systemic, cerebral, and pulmonary arteries and veins. Cerebral vascular resistance is incorporated via a model parameter separating cerebral arteries and veins. The model was adapted to a specific patient using parameter estimation combined with sensitivity analysis and subset selection. These techniques allowed estimation of cerebral vascular resistance along with other cardiovascular and respiratory parameters. Parameter estimation was carried out during eucapnia (breathing room air), first for the cardiovascular model and then for the respiratory model. Then, hypercapnia was introduced by increasing inspired CO₂ partial pressure. During eucapnia, seven cardiovascular parameters and four respiratory parameters was be identified and estimated, including cerebral and systemic resistance. During the transition from eucapnia to hypercapnia, the model predicted a drop in cerebral vascular resistance consistent with cerebral vasodilation.     

Evaluating experimental cerebral malaria using oxidative stress indicator OKD48 mice

Cerebral malaria is a fatal complication of malaria. Conventional methods for evaluating experimental cerebral malaria have several drawbacks. Therefore, we aimed to develop an easy-to-use method for evaluating experimental cerebral malaria using OKD48 (Keap1-dependent Oxidative stress Detector, No-48-luciferase) mice to evaluate oxidative stress. OKD48 mice infected with Plasmodium berghei ANKA strain (PbA) suffered from experimental cerebral malaria and oxidative stress was successfully detected in the brains of living OKD48 mice developing experimental cerebral malaria. Oxidative stress in the brain was dependent on the development of experimental cerebral malaria, as prevention of experimental cerebral malaria did not elicit oxidative stress. We provide a novel evaluation method for experimental cerebral malaria using oxidative stress indicator OKD48 mice.     

Hemodilutional anemia is associated with increased cerebral neuronal nitric oxide synthase gene expression.

Severe hemodilutional anemia may reduce cerebral oxygen delivery, resulting in cerebral tissue hypoxia. Increased nitric oxide synthase (NOS) expression has been identified following cerebral hypoxia and may contribute to the compensatory increase in cerebral blood flow (CBF) observed after hypoxia and anemia. However, changes in cerebral NOS gene expression have not been reported after acute anemia. This study tests the hypothesis that acute hemodilutional anemia causes cerebral tissue hypoxia, triggering changes in cerebral NOS gene expression. Anesthetized rats underwent hemodilution when 30 ml/kg of blood were exchanged with pentastarch, resulting in a final hemoglobin concentration of 51.0 +/- 1.2 g/l (n = 7 rats). Caudate tissue oxygen tension (Pbr(O(2))) decreased transiently from 17.3 +/- 4.1 to 14.4 +/- 4.1 Torr (P < 0.05), before returning to baseline after approximately 20 min. An increase in CBF may have contributed to restoring Pbr(O(2)) by improving cerebral tissue oxygen delivery. An increase in neuronal NOS (nNOS) mRNA was detected by RT-PCR in the cerebral cortex of anemic rats after 3 h (P < 0.05, n = 5). A similar response was observed after exposure to hypoxia. By contrast, no increases in mRNA for endothelial NOS or interleukin-1beta were observed after anemia or hypoxia. Hemodilutional anemia caused an acute reduction in Pbr(O(2)) and an increase in cerebral cortical nNOS mRNA, supporting a role for nNOS in the physiological response to acute anemia.     

脑梗死后智能障碍影响因素分析

目的 探讨影响脑梗死后智能障碍的因素。方法 应用长谷川痴呆量表对249例经CT证实的脑梗死患者进行智能测评,评分0～21．5为智能障碍组,22～32．5为正常组,探讨智能障碍的发生与性别、年龄、文化程度、卒中主要危险因素(高血压和糖尿病)、梗死灶数量及体积,以及脑萎缩和脑白质疏松之间的相互关系．结果 249例脑梗死患者中有106例(42．6％)出现智能障碍．并发现年龄、性别、文化程度、高血压病、糖尿病与智能障碍的发生有关;梗死灶的数量越多、体积越大其智能障碍发生率越高;脑萎缩及脑白质疏松与智能障碍关系密切．结论 脑梗死后智能障碍是多因素相互作用的结果,与梗死灶数量、体积、脑萎缩及脑白质疏松等多种因素有关．     

Nucleoside Transporter of Cerebral Micro vessels and Choroid Plexus

The nucleoside transporter of cerebral microvessels and choroid plexus was identified and characterized using [3H]nitrobenzylthioinosine (NBMPR) as a specific probe. [3H]NBMPR bound reversibly and with high affinity to a single specific site in particulate fractions of cerebral microvessels, choroid plexus, and cerebral cortex of the rat and the pig. The dissociation constants (KD 0.1-0.7 nM) were similar in the various tissue preparations from each species, but the maximal binding capacities (Bmax) were about fivefold higher in cerebral microvessels and choroid plexus than in the cerebral cortex. Nitrobenzylthioguanosine and dipyridamole were the most potent competitors for [3H]NBMPR binding. Several naturally occurring nucleosides displaced specific [3H]NBMPR binding to cerebral microvessels in vitro, in a rank order that correlated well with their ability to cross the blood-brain barrier in vivo. Adenosine analogues and theophylline were less effective in displacing [3H]NBMPR binding than in displacing adenosine receptor ligands. Photoactivation of cerebral microvessels and choroid plexus bound with [3H]NBMPR followed by solubilization and polyacrylamide gel electrophoresis labeled a protein(s) with a molecular weight of approximately 60,000. These results indicate that cerebral microvessels and choroid plexus have a much higher density of the nucleoside transporter moiety than the cerebral cortex and that this nucleoside transporter has pharmacological properties and a molecular weight similar to those of erythrocytes and other mammalian tissues.     

The TRIF-dependent signaling pathway is not required for acute cerebral ischemia/reperfusion injury in mice

TIR domain-containing adaptor protein (TRIF) is an adaptor protein in Toll-like receptor (TLR) signaling pathways. Activation of TRIF leads to the activation of interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-κB). While studies have shown that TLRs are implicated in cerebral ischemia/reperfusion (I/R) injury and in neuroprotection against ischemia afforded by preconditioning, little is known about TRIF’s role in the pathological process following cerebral I/R. The present study investigated the role that TRIF may play in acute cerebral I/R injury. In a mouse model of cerebral I/R induced by transient middle cerebral artery occlusion, we examined the activation of NF-κB and IRF3 signaling in ischemic cerebral tissue using ELISA and Western blots. Neurological function and cerebral infarct size were also evaluated 24 h after cerebral I/R. NF-κB activity and phosphorylation of the inhibitor of kappa B (IκBα) increased in ischemic brains, but IRF3, inhibitor of κB kinase complex-ε (IKKε), and TANK-binding kinase1 (TBK1) were not activated after cerebral I/R in wild-type (WT) mice. Interestingly, TRIF deficit did not inhibit NF-κB activity or p-IκBα induced by cerebral I/R. Moreover, although cerebral I/R induced neurological and functional impairments and brain infarction in WT mice, the deficits were not improved and brain infarct size was not reduced in TRIF knockout mice compared to WT mice. Our results demonstrate that the TRIF-dependent signaling pathway is not required for the activation of NF-κB signaling and brain injury after acute cerebral I/R.     

Endogenous heme oxygenase prevents impairment of cerebral vascular functions caused by seizures

In newborn pigs, the mechanism of seizure-induced cerebral hyperemia involves carbon monoxide (CO), the vasodilator product of heme catabolism by heme oxygenase (HO). We hypothesized that seizures cause cerebral vascular dysfunction when HO activity is inhibited. With the use of cranial window techniques, we examined cerebral vascular responses to endothelium-dependent (hypercapnia and bradykinin) and endothelium-independent (isoproterenol and sodium nitroprusside) dilators during the recovery from bicuculline-induced seizures in saline controls and in animals pretreated with a HO inhibitor, tin protoporphyrin (SnPP). SnPP (3 mg/kg iv) blocked dilation to heme and reduced the CO level in cortical periarachnoid cerebrospinal fluid, indicating HO inhibition in the cerebral microcirculation. In saline control piglets, seizures increased the CO level, which correlated with the time-dependent cerebral vasodilation; during the recovery (2 h after seizure induction), responses to all vasodilators were preserved. In SnPP-treated animals, cerebral vasodilation and the CO responses to seizures were greatly reduced, and cerebral vascular reactivity was severely impaired during the recovery. These findings suggest that HO in the cerebral microcirculation is rapidly activated during seizures and provides endogenous protection against seizure-induced vascular injury.     

A Type-II Positive Allosteric Modulator of α7 nAChRs Reduces Brain Injury and Improves Neurological Function after Focal Cerebral Ischemia in Rats

In the absence of clinically-efficacious therapies for ischemic stroke there is a critical need for development of new therapeutic concepts and approaches for prevention of brain injury secondary to cerebral ischemia. This study tests the hypothesis that administration of PNU-120596, a type-II positive allosteric modulator (PAM-II) of α7 nicotinic acetylcholine receptors (nAChRs), as long as 6 hours after the onset of focal cerebral ischemia significantly reduces brain injury and neurological deficits in an animal model of ischemic stroke. Focal cerebral ischemia was induced by a transient (90 min) middle cerebral artery occlusion (MCAO). Animals were then subdivided into two groups and injected intravenously (i.v.) 6 hours post-MCAO with either 1 mg/kg PNU-120596 (treated group) or vehicle only (untreated group). Measurements of cerebral infarct volumes and neurological behavioral tests were performed 24 hrs post-MCAO. PNU-120596 significantly reduced cerebral infarct volume and improved neurological function as evidenced by the results of Bederson, rolling cylinder and ladder rung walking tests. These results forecast a high therapeutic potential for PAMs-II as effective recruiters and activators of endogenous α7 nAChR-dependent cholinergic pathways to reduce brain injury and improve neurological function after cerebral ischemic stroke.     

ET-1神经分布异常与高血压鼠脑动脉神经源性调节的关系

目的探讨ET-1（Endothelin-1,ET-1）能神经纤维分布与高血压鼠脑血管的神经源性调节的关系,探讨ET-1神经是否参与高血压时期脑血流的调节。方法应用免疫组织化学技术观察自发性高血压鼠和Wistar正常血压鼠脑底动脉（包括大脑前动脉、大脑中动脉、大脑后动脉和基底动脉）ET-1能神经纤维的分布密度和走行方式。结果自发性高血压鼠和Wistar正常血压鼠脑底动脉均可见棕褐色的ET-1能免疫反应阳性纤维,似细线状,攀附于血管壁上,自发性高血压鼠脑底动脉各主要分支ET-1能免疫反应阳性纤维密度较Wistar正常血压鼠明显增加,纤维走行大多呈网状。结论实验结果提示自发性高血压鼠脑底动脉增加的ET-1能免疫反应阳性纤维可能与脑血管的神经源性调节有关;高密度的ET-1能神经纤维可能涉及高血压时期脑血流的调节。     

Cerebral blood flow response to isocapnic hypoxia during slow-wave sleep and wakefulness.

Nocturnal hypoxia is a major pathological factor associated with cardiorespiratory disease. During wakefulness, a decrease in arterial O2 tension results in a decrease in cerebral vascular tone and a consequent increase in cerebral blood flow; however, the cerebral vascular response to hypoxia during sleep is unknown. In the present study, we determined the cerebral vascular reactivity to isocapnic hypoxia during wakefulness and during stage 3/4 non-rapid eye movement (NREM) sleep. In 13 healthy individuals, left middle cerebral artery velocity (MCAV) was measured with the use of transcranial Doppler ultrasound as an index of cerebral blood flow. During wakefulness, in response to isocapnic hypoxia (arterial O2 saturation -10%), the mean (+/-SE) MCAV increased by 12.9 +/- 2.2% (P < 0.001); during NREM sleep, isocapnic hypoxia was associated with a -7.4 +/- 1.6% reduction in MCAV (P <0.001). Mean arterial blood pressure was unaffected by isocapnic hypoxia (P >0.05); R-R interval decreased similarly in response to isocapnic hypoxia during wakefulness (-21.9 +/- 10.4%; P <0.001) and sleep (-20.5 +/- 8.5%; P <0.001). The failure of the cerebral vasculature to react to hypoxia during sleep suggests a major state-dependent vulnerability associated with the control of the cerebral circulation and may contribute to the pathophysiologies of stroke and sleep apnea.     

Syncope, cerebral perfusion, and oxygenation.

During standing, both the position of the cerebral circulation and the reductions in mean arterial pressure (MAP) and cardiac output challenge cerebral autoregulatory (CA) mechanisms. Syncope is most often associated with the upright position and can be provoked by any condition that jeopardizes cerebral blood flow (CBF) and regional cerebral tissue oxygenation (cO(2)Hb). Reflex (vasovagal) responses, cardiac arrhythmias, and autonomic failure are common causes. An important defense against a critical reduction in the central blood volume is that of muscle activity ("the muscle pump"), and if it is not applied even normal humans faint. Continuous tracking of CBF by transcranial Doppler-determined cerebral blood velocity (V(mean)) and near-infrared spectroscopy-determined cO(2)Hb contribute to understanding the cerebrovascular adjustments to postural stress; e.g., MAP does not necessarily reflect the cerebrovascular phenomena associated with (pre)syncope. CA may be interpreted as a frequency-dependent phenomenon with attenuated transfer of oscillations in MAP to V(mean) at low frequencies. The clinical implication is that CA does not respond to rapid changes in MAP; e.g., there is a transient fall in V(mean) on standing up and therefore a feeling of lightheadedness that even healthy humans sometimes experience. In subjects with recurrent vasovagal syncope, dynamic CA seems not different from that of healthy controls even during the last minutes before the syncope. Redistribution of cardiac output may affect cerebral perfusion by increased cerebral vascular resistance, supporting the view that cerebral perfusion depends on arterial inflow pressure provided that there is a sufficient cardiac output.     

肢体缺血预处理减轻大鼠海马缺血/再灌注损伤

目的:探讨肢体缺血预处理(LIP)对大鼠全脑缺血/再灌注损伤的影响.方法: 36只大鼠椎动脉凝闭后随机分为假手术(Control)组、脑缺血组、肢体缺血组、LIP 0 d组(LIP后即刻行脑缺血)、LIP 1 d组(LIP后1 d行脑缺血)和LIP 2 d组(LIP后2 d行脑缺血).重复夹闭大鼠双侧股动脉3次(每次10 min,间隔10 min)作为LIP,夹闭颈总动脉进行全脑缺血8 min后再灌注.硫堇染色观察海马CA1区组织学分级及锥体神经元密度以判断海马损伤程度.结果:脑缺血组海马CA1区锥体神经元损伤严重,与Control组比较,组织学分级明显升高,神经元密度明显降低(P<0.01).LIP 0 d组海马CA1区神经元损伤较脑缺血组明显减轻,组织学分级明显降低,神经元密度明显升高(P<0.01).而LIP 1 d组和LIP 2 d组大鼠海马CA1区锥体细胞缺失较多,仍有明显的组织损伤.结论:LIP可减轻随后立即发生的脑缺血/再灌注损伤,但对间隔1 d后的脑缺血/再灌注损伤无显著对抗作用.     

神经途径在肢体缺血预处理抗脑缺血/再灌注损伤中的作用

目的：探讨神经途径在肢体缺血预处理（limbi schemic preconditioning,LIP）抗脑缺血／再灌注损伤中的作用。方法：脑缺血采用四血管闭塞模型,重复短暂夹闭放松大鼠双侧股动脉3次作为LIP。将凝闭椎动脉的大鼠随机分为sham组、脑缺血组、股神经切断＋脑缺血组、LIP＋脑缺血组、股神经切断＋LIP＋脑缺血组。于Sham手术和脑缺血后7d处死大鼠,硫堇染色观察海马CA1区锥体神经元迟发性死亡的变化。于Sham手术和脑缺血后6h心脏灌注固定大鼠,免疫组化法测定海马CAI区c-Fos表达的变化。结果：硫堇染色结果显示,与sham组比较。脑缺血组和股神经切断＋脑缺血组大鼠海马CAI区均有明显组织损伤。LIP＋脑缺血组CAI区无明显细胞缺失,神经元密度明显高于脑缺血组（P〈0．01）。而股神经切断＋LIP＋脑缺血组大鼠海马CA1区明显损伤,锥体细胞缺失较多,与LIP＋脑缺血组组比较,神经元密度显著降低（P〈O．01）,提示LIP前切断双侧股神经取消了LIP抗脑缺血／再灌注损伤作用。c—Fos免疫组化染色结果显示,Sham组海马CAI区未见明显的c-Fos蛋白表达。脑缺血组海马CAI区偶见c—Fm的阳性表达。LIP＋脑缺血组c—Fos表达增强,数量增加,与Sham组和脑缺血组比较。c-Fos阳性细胞数和光密度均明显升高（P〈0．01）。而股神经切断＋LIP＋脑缺血组c-Fos表达明显减少,仅见少量弱阳性e-Fos表达。结论：LIP可通过神经途径发挥抗脑缺血／再灌注损伤作用,而LIP诱导c—Fos表达增加可能是LIP诱导脑缺血耐受神经途径的一个环节。     

Association between Apolipoprotein E genotype and cerebral palsy is not confirmed in a Caucasian population

Apolipoprotein E (APOE) plays a significant role in lipid metabolism and has been implicated in the growth and repair of injured neurons. Two small studies have suggested an association between APOE genotype and cerebral palsy. We investigated if APOE genotype is associated with an increased risk for cerebral palsy, influences the type of cerebral palsy or interacts with prenatal viral infection to influence risk of cerebral palsy. The population-based case-control study comprised newborn screening cards of 443 Caucasian patients with cerebral palsy and 883 Caucasian matched controls. APOE genotyping was performed on DNA extracted from dried blood spots. Allelic and genotypic frequencies did not differ between cases and controls and combined frequencies were 0.10 (ε2), 0.76 (ε3), 0.14 (ε4), 0.03 (ε2/ε2), 0.10 (ε2/ε3), 0.03 (ε2/ε4), 0.02 (ε4/ε4), 0.21 (ε3/ε4), 0.61 (ε3/ε3). APOE genotype was correlated with cerebral palsy, type of cerebral palsy, gestation at birth and the presence of viral nucleic acids detected in previous work. Analysis by gestational age (all gestational ages, ≥37, 32–36 and <32 weeks) and type of cerebral palsy (all types, diplegia, hemiplegia and quadriplegia) showed no association between APOE genotype and cerebral palsy in this Caucasian population. An association between prenatal viral infection, APOE genotype and cerebral palsy was not demonstrated. These results did not confirm an association between APOE genotype, cerebral palsy, type of cerebral palsy and prenatal infection in a Caucasian population. Given the low frequency of APOE ε2 and some of the heterozygote and homozygote combinations in this study, a larger study is assessing this further.     

A multiscale 0-D/3-D approach to patient-specific adaptation of a cerebral autoregulation model for computational fluid dynamics studies of cardiopulmonary bypass

Neurological complication often occurs during cardiopulmonary bypass (CPB). One of the main causes is hypoperfusion of the cerebral tissue affected by the position of the cannula tip and diminished cerebral autoregulation (CA). Recently, a lumped parameter approach could describe the baroreflex, one of the main mechanisms of cerebral autoregulation, in a computational fluid dynamics (CFD) study of CPB. However, the cerebral blood flow (CBF) was overestimated and the physiological meaning of the variables and their impact on the model was unknown. In this study, we use a 0-D control circuit representation of the Baroreflex mechanism, to assess the parameters with respect to their physiological meaning and their influence on CBF. Afterwards the parameters are transferred to 3D-CFD and the static and dynamic behavior of cerebral autoregulation is investigated.     

Trefoil Factor 3 as an Endocrine Neuroprotective Factor from the Liver in Experimental Cerebral Ischemia/Reperfusion Injury

Cerebral ischemia, while causing neuronal injury, can activate innate neuroprotective mechanisms, minimizing neuronal death. In this report, we demonstrate that experimental cerebral ischemia/reperfusion injury in the mouse causes upregulation of the secretory protein trefoil factor 3 (TFF3) in the hepatocyte in association with an increase in serum TFF3. Partial hepatectomy (~60% liver resection) immediately following cerebral injury significantly lowered the serum level of TFF3, suggesting a contribution of the liver to the elevation of serum TFF3. Compared to wild-type mice, TFF3^-/- mice exhibited a significantly higher activity of caspase 3 and level of cell death in the ischemic cerebral lesion, a larger fraction of cerebral infarcts, and a smaller fraction of the injured cerebral hemisphere, accompanied by severer forelimb motor deficits. Intravenous administration of recombinant TFF3 reversed changes in cerebral injury and forelimb motor function due to TFF3 deficiency. These observations suggest an endocrine neuroprotective mechanism involving TFF3 from the liver in experimental cerebral ischemia/reperfusion injury.     

Reactivity in human cerebral artery: species variation

It is becoming obvious that the reactivity of vascular smooth muscle to vasoactive agents is not homogeneous in different arteries (cerebral vs. other arteries) from the same animal species or in cerebral arteries from different species. In this communication, the reactivity of human cerebral arteries to norepinephrine (NE), dopamine (DA), small amounts of K+ and ouabain and their mechanisms of action are compared with those in monkey and dog cerebral arteries. NE produces moderate contractions in the primate arteries, mediated by alpha 1 adrenoceptors, and slight contractions in the dog arteries, possibly mediated by alpha 2 receptors. DA relaxes human and monkey cerebral arteries but contracts the dog arteries. The primate artery relaxation mediated by dopaminergic receptors is large enough to predominate over the alpha 1 receptor-mediated contraction. Minute amounts of K+ preferentially relax cerebral arteries from humans, monkeys, and dogs, possibly activating the electrogenic Na+ pump. Ouabain, a Na+ pump inhibitor, contracts these cerebral arteries with low concentrations. Human and monkey cerebral arteries respond similarly to vasoactive agents presented so far, and appear to share the same mechanisms of action; however, the responsiveness of dog cerebral arteries differs.