Involvement of Aquaporin 4 in Astrocyte Function and Neuropsychiatric Disorders

Aquaporin 4 (AQP4) is the main water channel in the central nervous system (CNS) and specifically localized to astrocyte processes. Recent studies indicate that AQP4 regulates various biological functions of astrocytes, including maintaining CNS water balance, spatial buffering of extracellular potassium, calcium signal transduction, regulation of neurotransmission, synaptic plasticity, and adult neurogenesis, while under neuropathological conditions, AQP4 has a role in astrogliosis and proinflammatory cytokine secretion. In addition, accumulating evidence suggests that, besides cerebral edema, neuromyelitis optica and epilepsy, AQP4 participates in the onset and progression of Alzheimer disease, Parkinson disease, depression, and drug addiction. This review summarizes recent findings and highlights the involvement of AQP4 in astrocyte function and neuropsychiatric disorders.     

Changes in Lipid-Sensitive Two-Pore Domain Potassium Channel TREK-1 Expression and Its Involvement in Astrogliosis Following Cerebral Ischemia in Rats

Astrocytes play an active and important role in the pathophysiology of cerebral ischemia. We have previously shown that mature hipppocampal astrocytes functionally express two-pore domain K⁺ channel TREK-1, which significantly contributes to the passive conductance and help to set the negative resting membrane potential essential for the optimal operation of some astrocytic homeostatic functions. However, its expression under ischemic conditions remains to be determined. In this study, we examined the expression of TREK-1 in rat brain under physiological and focal ischemia conditions. The results show that TREK-1 was broadly expressed on astrocytes and neurons in the cortex, CA1 region of hippocampus. After middle cerebral artery occlusion induced focal ischemia, the TREK-1 expression was significantly increased at days 3, 7 and 30 following reperfusion, which correlated with reactive astrogliosis in the cortex and hippocampus. Cultured cortical astrocytes also express TREK-1. TREK-1 inhibitor quinine inhibited the proliferation of astrocytes exposed to hypoxia condition. These data provide evidence showing the astrocytic TREK-1 involvement in ischemia pathology.     

植物多酚神经保护作用的研究进展

植物多酚为植物体内的复杂酚类次生代谢物,具有多元酚结构,表现出多种生物化学活 性及药理学活性。近年来关于植物多酚的研究主于集中于抗氧化、抗炎、抗细胞增殖活性等功能。 脑缺血过程中会有过量氧自由基的产生,活性氧自由基损伤脂质体、蛋白和核酸,从而引起凋亡或坏 死。越来越多的研究表明,植物多酚可以对抗脑缺血造成的相关神经损伤。本文主要对植物多酚的 神经保护作用以及在脑缺血模型中的应用展开综述,并提出植物多酚在卒中治疗的建议。     

亚低温用于缺血性脑卒中的神经保护研究进展

低温治疗一直是医学研究的热点,早在古罗马时代希波克拉底就知道将受伤的士兵包裹后放入雪中以减少出血量。上个世纪30～40年代,Fay[1]首次报道了低温用于脑外伤的治疗,第一次将低温应用于神经系统的     

SEPS1 Gene is Activated during Astrocyte Ischemia and Shows Prominent Antiapoptotic Effects

Contrarily to neurons, astrocytes can survive short periods of ischemia. We have searched for genes implicated in astrocyte resistance to ischemia using oxygen and glucose deprivation (OGD) as a stroke model. A RNA differential display approach uncovered the OGD induction of selenoprotein-S-encoding gene SEPS1. This endoplasmic reticulum (ER) resident protein is known to promote cell survival regulating the ER stress as well as inflammation. We found that suppression of SEPS1 by small interfering RNA severely increases astrocyte injure caused by OGD, suggesting that selenoprotein S protects astrocytes against ischemia. Our data also support that modulation of ER stress is implicated in this effect.     

缺血性脑损伤的神经保护治疗的困惑与展望

缺血性脑血管病以其发病率高、致残率高、病死率高及神经损伤的难治性等因素倍受神经科学者关注。目前,对脑卒中的治疗除超早期溶栓、一级和二级预防外缺乏有效的治疗方法。但是脑卒中病人能够得到溶栓治疗的仅占3%左右,其余病人只     

Physical Activity and Neuroprotection in Amyotrophic Lateral Sclerosis

Physical exercise exerts a wide range of benefits on an organism's overall health and well-being. Exercise contributes positively toward an individual's healthy weight, muscle strength, immune system, and cardiovascular health. Indeed, exercise has been demonstrated to reduce life-threatening conditions such as high blood pressure, heart disease, obesity, and diabetes. Of particular interest to this review, exercise has also been shown to be neuroprotective in both the central and peripheral nervous systems. Naturally, such findings apply broadly to the study of neurodegenerative disease with numerous reports demonstrating that exercise has beneficial effects on disease progression. One of the most devastating neurodegenerative diseases is amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease in the United States, or motor neuron disease in the United Kingdom, resulting from the progressive loss of brain and spinal cord motor neurons. Several human studies show that moderate exercise regimens improve ALS patients' scoring on functionality tests and ameliorate disease symptoms. Other promising recent works using transgenic mouse models of familial ALS have shown markedly slowed disease progression, improved function, and extension of survival in moderately exercised animals. Possible explanations for these findings include the exercise-induced changes in motor neuron morphology, muscle-nerve interaction, glial activation, and altering levels of gene expression of anti-apoptotic proteins and neurotrophic factors in the active tissue. Here we review the current literature on exercise and motor neuron disease, focusing on rodent and human studies to define the proper type, intensity, and duration of exercise necessary to enhance neuron survival as well discuss current mechanistic studies to further define the exercise-mediated pathways of neuroprotection.     

慢性脑缺血神经保护的实验研究进展

慢性脑缺血是神经系统的一种常见病理状态,伴发于多种脑血管病的病理过程中。目前对慢性脑缺血神经保护的实验研究包括抗神经元损伤、减轻脑白质损害、纠正神经递质系统紊乱及改善认知功能。     

Inhibition of Astrocyte Connexin 43 Channels Facilitates the Differentiation of Oligodendrocyte Precursor Cells Under Hypoxic Conditions In Vitro

Oligodendrocyte precursor cells (OPCs) proliferation and differentiation are essential for remyelination after white matter injury. Astrocytes could promote oligodendrogenesis after white matter damage whereas the underlying mechanisms are unknown. In this study, the role of astrocytic connexin43 (Cx43) hemichannels involved in OPC proliferation and differentiation in chronic hypoxia was evaluated. In an astrocyte-OPC co-culture chronic hypoxia model, OPCs became proliferative but failed to mature into oligodendrocytes. Application of astrocytic Cx43 blockers attenuated astrocyte activation, suppressed Cx43 hemichannel uptake activity and glutamate release induced by hypoxia, as well as improved OPC differentiation. Moreover, AMPA but not NMDA glutamate receptor antagonist rescued OPC differentiation in hypoxia. In conclusion, these findings suggested that astrocytic Cx43 hemichannel inhibition could potentially improve OPC maturation by attenuating AMPAR-mediated glutamate signaling. Astrocytic Cx43 hemichannels could serve as a potential therapeutic target for remyelination after chronic hypoxia.     

Postischemic Hypothermia and IL-10 Treatment Provide Long-Lasting Neuroprotection of CA1 Hippocampus Following Transient Global Ischemia in Rats

Experimental studies have demonstrated that postischemic therapeutic interventions may delay rather than provide long-lasting neuroprotection. The purpose of this study was to determine whether mild hypothermia (33-34 degrees C) combined with the anti-inflammatory cytokine interleukin-10 (IL-10) would protect the CA1 hippocampus 2 months after ischemia. Rats were subjected to 12.5 min of normothermic (37 degrees C) forebrain ischemia by two-vessel occlusion followed immediately by: (a) 4 h of normothermic (37 degrees C) reperfusion (n = 5); (b) 4 h of postischemic hypothermia (33-34 degrees C) (n = 5); (c) 4 h of normothermia plus IL-10 (5 micrograms) treatment 30 min after ischemia and at 3 days (n = 5); or (d) 4 h of hypothermia plus IL-10 treatment (n = 5). Rats survived for 2 months and were perfusion fixed for quantitative histopathological assessment of CA1 hippocampus. Postischemic normothermia and hypothermia, as well as normothermia plus IL-10 treatment led to severe damage of the CA1 hippocampus. In contrast, the combined treatment of hypothermia with IL-10 treatment improved overall neuronal survival by 49% compared to normothermic ischemia (P < 0.01). These data emphasize the detrimental consequences of secondary inflammatory responses on ischemic neuronal damage after transient global ischemia. In postinjury settings where restricted durations of mild hypothermia can be induced, anti-inflammatory treatments, including IL-10, may promote chronic neuroprotection.     

Involvement of ERK1/2 Pathway in Neuroprotection by Salidroside Against Hydrogen Peroxide-Induced Apoptotic Cell Death

Salidroside is isolated from Rhodiola rosea L., a traditional Chinese medicinal plant, and has a potent antioxidant property. The aim of this study was to investigate the effects of salidroside on hydrogen peroxide (H₂O₂)-induced cell apoptosis in nerve growth factor (NGF)-differentiated PC12 cells and the possible involvement of the extracellular signal-related protein kinase 1/2 (ERK1/2) signaling pathway. MTT assay, Hoechst 33342 staining, and TdT-mediated dUTP-biotin nick end labeling assay collectively showed that pretreatment with salidroside alleviated, in a dose-dependent manner, cell viability loss and apoptotic cell death induced by H₂O₂ stimulation in cultured NGF-differentiated PC12 cells. According to Western blot analysis, pretreatment with salidroside transiently caused the activation of ERK1/2 pathway; a selective inhibitor of the mitogen-activated protein kinase kinase (MAPKK, MEK) blocked salidroside-activated ERK pathway and thus attenuated the influences of salidroside on H₂O₂-induced increase in the level of cleaved caspase-3, a chief executant of apoptosis cascades. Morphological analysis further indicated that in the presence of the MEK inhibitor, the neuroprotective effect of salidroside against H₂O₂-evoked cell apoptosis was significantly abrogated. Taken together, the results suggest that the neuroprotective effects of salidroside might be modulated by ERK signaling pathway, especially at the level or upstream of the caspase-3 activation.     

葛根素对小鼠脑缺血再灌注损伤的神经保护作用及机制研究

目的 观察葛根素对脑缺血再灌注小鼠的神经保护作用并探讨其对雌激素受体（estrogen receptor, ER）及缺氧诱导因子-1（hypoxia inducible factor-1,HI F-1）表达及相关炎症因子释放的影响。 方法 C57BL小鼠随机分为假手术组、溶剂对照组以及葛根素低剂量组（100 mg·kg-1）、中剂量 组（250 mg·kg-1）和高剂量组（500 mg·kg-1）,采用线栓法制备小鼠大脑中动脉栓塞模型（middle cerebral artery occlusion,MCAO）,缺血2 h,再灌注24 h后观察葛根素对损伤后脑梗死体积、含水 量、神经功能评分等指标的影响。根据再灌注不同时间点,溶剂对照组又分为2 h、6 h、12 h、24 h共 4个亚组,分别在相应时间点采用蛋白质免疫印迹技术测定脑组织中ER-α及HIF-1α的变化情况。取 变化最显著的缺血2 h再灌注12 h这一时间点测定葛根素对ER-α及HIF-1α表达的影响,并通过酶联 免疫吸附技术测定葛根素在这一时间点对下游炎症因子如肿瘤坏死因子α（tumor necrosis factor-α, TNF-α）、白细胞介素1β（interleukin-1β,IL-1β）和白细胞介素6（interleukin-6,IL-6）的调节作用。 结果 相比溶剂对照组,低、中和高剂量组葛根素均能降低缺血2 h再灌注24 h小鼠的脑梗死体 积[低剂量（29.6±3.6）%,中剂量（15.2±3.9）%,高剂量（8.2±2.1）% vs 对照组（39.3±5.0）%] 和脑含水量[低剂量（84.9±8.8）%,中剂量（83.7±8.2）%,高剂量（80.9±8.7）% vs 对照组 （85.3±10.2）%],差异有统计学意义。对于脑缺血2 h再灌注12 h小鼠,中、高剂量葛根素组较溶剂对 照组ER-α水平升高,HI F-1α水平降低,差异有统计学意义;中、高剂量葛根素组TNF-α（[ 420.7±27.2） μg·g-1,（379.6±23.9）μg·g -1] 、I L-1β[（211.8±19.2）μg·g-1,（182.4±13.5）μg·g -1]和I L- 6（[ 111.2±9.1）μg·g-1,（104.1±12.4）μg·g -1]水平较溶剂对照组[TNF-α（505.8±36.7）μg·g-1;IL-1β （291.6±21.8）μg·g-1;IL-6（138.4±11.7）μg·g-1] 下降,差异有统计学意义。 结论 葛根素在一定剂量范围内可降低脑缺血再灌注小鼠病变脑组织的含水量,减小梗死体积,其 作用机制可能与激活ER-α、抑制HI F-1α表达并抑制相关炎症因子TNF-α、IL-1β和IL-6的释放有关。     

3-CP对大鼠局灶性脑缺血再灌注损伤的脑保护作用

目的探讨3-CP对大鼠局灶性脑缺血再灌注损伤的脑保护作用。方法采用血管内尼龙线栓塞法建立大鼠局灶性脑缺血模型,脑缺血和再灌注通过激光多普勒监测局部脑血流来证实。所有动物均缺血1h再灌注24h,动物分为4组:实验一组(3-CP100m g/kg;n=6),实验二组(3-CP10m g/kg;n=6),实验三组(3-CP1m g/kg;n=6)和对照组(0.9%生理盐水,n=5)。3-CP和生理盐水均在再灌注开始1m in内注射入血管。脑梗塞体积用TTC染色法显示,用图象分析软件计算梗塞体积。结果实验一、二、三组和对照组脑梗塞体积分别为(44.4±16.5)m m3、(39.5±20.3)m m3、(107.0±18.3)m m3和(146.0±63.6)m m3,实验一、二组和对照组相比,相差显著(P<0.01)。结论100m g/kg3-CP和10m g/kg3-CP剂量的3-CP对大鼠局灶性脑缺血模型中再灌注损伤有神经保护作用。     

Postnatal changes in TASK-1 and TREK-1 expression in rat brain stem and cerebellum

Developmental changes in expression of two-pore domain K+ channels, TASK-1 and TREK-1, were investigated in the juvenile (postnatal day 13; P13) and adult (P105) rat brain stem and cerebellum using immunohistochemistry. In the juvenile, extensive TASK-1-like immunoreactivity (TASK-1-LIR) was seen among glial cells in the white matter (e.g., radial glia), which showed marked reduction in the adult. In contrast, TASK-1-LIR in neurons including cerebellar Purkinje and granule cells, hypoglossal and facial motoneurons, and ventrolateral medulla neurons was increased in the adult. TASK-1-LIR in neuroglia surrounding peripheral axons of cranial nerves was persistent. TREK-1-LIR was similar between ages, although TREK-1-LIR was neuronal and present only in juvenile cerebellar external germinal layer. Present results suggest roles for TASK-1 and K+ homeostasis in neuro-glial interaction, neurogenesis, differentiation, migration, axon guidance, synaptogenesis and myelination.     

Inhibition of human TREK-1 channels by caffeine and theophylline

Caffeine (1,3,7-trimethylxanthine) and theophylline (1,3-dimethylxanthine) are used for therapeutic purposes and can cause life-threatening convulsive seizures due to systemic toxicity. The mechanisms for the epileptogenicity of caffeine and theophylline are not clear. TWIK-related K(+) channels (TREK-1) are highly expressed in the human central nervous system and have a major role in the control of neuronal excitability by regulating the resting membrane potential. In view of their physiological significance, inhibition of TREK-1 channels may be implicated in caffeine- and theophylline-induced seizures. We thus investigated, using whole-cell patch-clamp technique, modulation of hTREK-1 channels expressed in Chinese hamster ovary (CHO) cells by caffeine and theophylline. Caffeine and theophylline produced reversible inhibition of TREK-1 channels in a concentration-dependent manner. The half-maximal inhibitory concentrations (IC(50)) for caffeine and theophylline were 377+/-54microM and 486+/-76microM, respectively. Caffeine and theophylline depolarized the membrane potential of CHO(TREK-1) cells in a reversible and concentration-dependent manner. Inhibition by caffeine (5mM) and theophylline (2mM) was attenuated in TREK-1 channels with mutation of the PKA consensus sequence at serine 348, suggesting the involvement of cAMP/PKA pathway in the inhibitory process. Inhibition of TREK-1 channels and consequent membrane depolarization may contribute to the convulsive seizures induced by toxic levels of caffeine and theophylline.     

Recent Developments in the Understanding of Astrocyte Function in the Cerebellum In Vivo

Several studies have contributed to our understanding of astrocytes, especially Bergmann glia, in the cerebellum; but, until recently, none has looked at their function in vivo. Multicell bolus loading of fluorescent calcium indicators in combination with the astrocytic marker SR101 has allowed imaging of up to hundreds of astrocytes at once in the intact cerebellum. In addition, the selective targeting of astrocytes with fluorescent calcium indicator proteins has enabled the study of their function in vivo without the confounding effects of other neuropil signals and with a resolution that surpasses multicell bolus loading and SR101 staining. The two astrocyte types of the cerebellar cortex, Bergmann glia, and velate protoplasmic astrocytes display a diverse signaling repertoire in vivo, which ranges from localized calcium elevations in subcellular processes to waves, triggered by the release of purines and mediated by purinergic receptors that span multiple processes and can involve tens of astrocytes. During locomotor behavior, even larger numbers of astrocytes display calcium increases that are driven by neuronal activity and correlate with global changes in blood flow. In this review, we give an overview of our current understanding of the function of Bergmann glia and velate protoplasmic astrocytes and the promise of the tools used to study their calcium dynamics and function in vivo.     

MicroRNAs Expression and Function in Cerebral Ischemia Reperfusion Injury

MicroRNAs (miRNAs) are small (18?~?25 nt) noncoding single-stranded RNA molecules that act as negative regulators of gene expression and modulating the stability and/or the translational efficiency of target messenger RNAs. Studies have shown that miRNAs control diverse aspects of brain disease. Recently, several studies have suggested that miRNAs alter the response to ischemia reperfusion injury and regulate the expression of various key elements in cell survival and apoptosis. This review article gives a brief overview of some miRNAs (miR-15a/b, miR-21, miR-29b/c, miR-124, miR-145, miR-181, miR-200 family, miR-338, miR-422a, miR-497, and miR let 7 family) in cerebral ischemia reperfusion injury. Although miRNAs could be potential therapeutic targets for the treatment of ischemia reperfusion injury, their safety and other limitations need further confirmation.     

Pattern of Cortex and White Matter Involvement in Severe Middle Cerebral Artery Ischemia

BACKGROUND AND PURPOSE: In middle cerebral artery (MCA) stroke, ischemia usually is unevenly distributed within the MCA territory. We sought to investigate which brain structures are critical for the acute neurological deficit in severe MCA stroke. METHODS: We used magnetic resonance (MR) imaging and statistical parametric mapping in 64 consecutive stroke patients (64 +/-13 years) to study the pattern of the initial perfusion abnormality. RESULTS: Patients with lesion progression had more severe time-to-peak (TTP) abnormalities (P < .0001) in the inferior frontal gyrus, superior temporal gyrus, insula, and underlying hemispheric white matter than those with lesion regression. Also, patients with lesion progression had more severe T2 abnormalities on day 8 than those with lesion regression. In contrast, the changes of water diffusion were similar among the two groups resulting in a perfusion-diffusion mismatch in lesion progression. TTP-lesions were related to the neurological deficit score (r(s)=-0.563, P < .0001), T2-lesions (r= 0.686, P < .0001), and cerebral artery abnormalities assessed on MR-angiography (r(s)= 0.399, P < .01). CONCLUSIONS: In major MCA, stroke ischemia was most severe in the central portion of the MCA territory. It is suggested that involvement of hemispheric white matter accentuated the neurological deficit probably by affecting cortico-cortical and cortico-subcortical fibers.