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Factors involved in the neuronal death during postischemic reperfusion:experimental study in rabbits

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Chinese Medical Journal 1999年第2期112卷 58-61页

作者：段满林李德馨徐建国王刚傅素娥 Department of Anesthesiology Clin. Sch. Med. Coll. Nanjing Univ. Nanjing General Hospital of PLA Nanjing 210002 China

Objective To explore the main pathogenic factors in the development of neuronal death during normothermic reperfusion in rabbits.Methods Ninety six New Zealand rabbits were randomly allocated into two groups: group Ⅰ served as non ischemic controls; group Ⅱ served as postischemic normothermic reperfusion models. Complete cerebral ischemia was induced by the four vessel model for 30 minutes. After ischemia, rabbits in group Ⅱ were further divided into three subgroups according to the duration of reperfusion: subgroup A, 30 minutes; subgroup B, 180 minutes and subgroup C, 360 minutes. Twenty eight biochemical parameters in the brain were measured, and neuronal changes were observed by histomorphological assessment. Neurons of 12 regions were differentiated into four types: type A (normal), type B (mildly damaged), type C (severely damaged) and type D (necrotic). Bivariate correlate analysis between the levels of biochemical parameters and the percentages of each type of neurons was carried out.Results The main parameters involved in the progressive decrement of type A neurons were VIP, β EP, PGI 2, T 3, T 4 and N + a,K + ATPase; in the increment of type B were β EP and TXB 2; in the increment of type C were GLU and TXB 2/PGI 2 respectively; in the stepwise increment of percentages of type D neurons were T 4, N + a,K + ATPase, GLU, T 3 and VIP (Pneuronal death during postischemic normothermic reperfusion in rabbits include hypermetabolism, deactivation of N + a,K + ATPase, release of excitatory amino acids and disorder of neuropeptides.

关键词： neuronal death reperfusion damage correlate analysis

Proteasome alteration and delayed neuronal death in hippocampal CA1 and dentate gyrus regions following transient cerebral ischemia

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Neural Regeneration Research 2009年第10期4卷 744-748页

作者： Pengfei Ge Tianfei Luo Jizhou Zhang Haifeng Wang Wenchen Li Yongxin Luan Feng Ling Yi'nan Luo Department of Neurosurgery First Hospital Jifin University Changchun 130021 Jilin Province China Department of Biochemistry and Molecular Biology Norman Bethune Medical School Jilin University Changchun 130021 Jilin Province China Department of Neurosurgery Xuanwu Hospital Capital University of Medical Science Beijing 100053 China

BACKGROUND： Proteasome dysfunction has been reported to induce abnormal protein aggregation and cell death. OBJECTIVE： To investigate the effect of proteasome changes on delayed neuronal death in CA1 and dentate gyrus （DG） regions of the rat hippocampus following transient cerebral ischemia. DESIGN, TIME AND SETTING： A randomized, controlled animal experiment. The study was performed at the Department of Biochemistry and Molecular Biology, Norman Bethune Medical College of Jilin University, from September 2006 to May 2008. MATERIALS： Rabbit anti-19S S10B polyclonal antibody was purchased from Bioreagents, USA; propidium iodide and fluorescently-labeled goat anti-rabbit IgG were purchased from Jackson Immunoresearch, USA; hematoxylin and eosin staining solution was purchased from Sigma, USA; LSM 510 confocal microscope was purchased from Zeiss, Germany. METHODS： A total of 40 healthy Wistar rats, male, 4 months old, were randomly divided into sham surgery group （n = 8） and model group （n = 32）. Ischemic models were established in the model group by transient clamping of the bilateral carotid arteries and decreased blood pressure. After 20 minutes of global ischemia, the clamp was removed to allow blood flow for 30 minutes, 4, 24 and 72 hours, respectively, with 8 rats at each time point. The bilateral carotid arteries were not ligated in the sham surgery group. MAIN OUTCOME MEASURES： neuronal death in the CA1 and DG regions was observed by hematoxylin-eosin staining. Proteasome expression in CA1 and DG region neurons was detected by immunohistochemistry. RESULTS： Hematoxylin-eosin staining showed neuronal death in the CA1 region alone at 72 hours of reperfusion following ischemia. In comparison to the sham surgery group, a significant decrease in proteasome expression was observed, by immunohistochemistry, in the CA1 and DG regions in the model group, following 30 minutes, 4, 24, and 72 hours of reperfusion （P 〈 0.01）. After 72 hours of reperfusion following ischemia, proteasome expression had almost completely di

关键词： transient cerebral ischemia neuronal death proteasome

Responses of CDKs and p53 in Delayed Ischemic neuronal death

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Journal of Nanjing Medical University 2002年第2期16卷 49-64页

作者：王伏虎 Neuroscience Research Institute University of Ottawa Ottawa Ontario Canada K1H 8M5

Stroke is a debilitating disease that affects millions each year. While in many cases cerebral ischemic injury can be limited by effective resuscitation or thrombolytic treatment, the injured neurons wither in a process known as delayed neuronal death (DND). Mounting evidence indicates that DND is not simply necrosis played out in slow motion but apoptosis is triggered. Of particular interest are two groups of signal proteins that participate in apoptosis cyclin dependent kinases (CDKs) and p53 among a myriad of signaling events after an ischemic insult. Recent investigations have shown that CDKs, a family of enzymes initially known for their role in cell cycle regulation, are activated in injured neurons in DND. As for p53, new reports suggest that its up regulation may represent a failed attempt to rescue injured neurons, although its up regulation was previously considered an indication of apoptosis. These observations thus rekindle an old quest to identify new neuroprotective targets to minimize the stroke damage. In this review, the author will examine the evidence that indicates the participation of CDKs and p53 in DND and then introduce pre clinical data to explore CDK inhibition as a potential neuroprotective target. Finally, using CDK inhibition as an example, this paper will discuss the pertinent criteria for a viable neuroprotective strategy for ischemic injury.

关键词： stroke cerebral ischemia excitotoxicity cyclin dependent kinases neuronal death apoptosis water maze retinoblastoma

Thinking outside the black box:are the brain endothelial cells the new main target in Alzheimer's disease?

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Neural Regeneration Research 2023年第12期18卷 2592-2598页

作者： Enrique Estudillo Adolfo López-Ornelas Alejandro Rodríguez-Oviedo Neptali Gutiérrez de la Cruz Marco Antonio Vargas-Hernández Adriana Jiménez Laboratorio de Reprogramación Celular Instituto Nacional de Neurología y Neurocirugía Manuel Velasco SuárezMexico CityMexico División de Investigación Hospital Juárez de MéxicoMexico CityMexico Hospital Nacional Homeopático Hospitales Federales de ReferenciaMexico CityMexico Facultad de Ciencias Universidad Nacional Autónoma de MéxicoMexico CityMexico Laboratorio de Morfología Escuela Militar de Graduados de SanidadSecretaría de la Defensa NacionalBatalla de CelayaLomas de SoteloMiguel HidalgoMexico CityMexico Escuela Militar de Graduados de Sanidad Secretaría de la Defensa NacionalBatalla de CelayaLomas de SoteloMiguel HidalgoMexico CityMexico

The blood-brain barrier is the interface through which the brain interacts with the milieu and consists mainly of a sophisticated network of brain endothelial cells that forms blood vessels and selectively moves molecules inside and outside the brain through multiple mechanisms of transport.Although brain endothelial cell function is crucial for brain homeostasis,their role in neurodegenerative diseases has historically not been considered with the same importance as other brain cells such as microglia,astroglia,neurons,or even molecules such as amyloid beta,Tau,or alpha-synuclein.Alzheimer's disease is the most common neurodegenerative disease,and brain endothelial cell dysfunction has been reported by several groups.However,its impairment has barely been considered as a potential therapeutic target.Here we review the most recent advances in the relationship between Alzheimer's disease and brain endothelial cells commitment and analyze the possible mechanisms through which their alterations contribute to this neurodegenerative disease,highlighting their inflammatory phenotype and the possibility of an impaired secretory pattern of brain endothelial cells that could contribute to the progression of this ailment.Finally,we discuss why shall brain endothelial cells be appreciated as a therapeutic target instead of solely an obstacle for delivering treatments to the injured brain in Alzheimer's disease.

关键词： dementia endothelial cells neurodegeneration neuroinflammation neuronal death paracellular transport transcellular transport

Clemastine in remyelination and protection of neurons and skeletal muscle after spinal cord injury

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Neural Regeneration Research 2023年第5期18卷 940-946页

作者： Ali Myatich Azizul Haque Christopher Sole Naren L.Banik Department of Microbiology and Immunology Medical University of South CarolinaCharlestonSCUSA Department of Neurosurgery Medical University of South CarolinaCharlestonSCUSA Ralph H.Johnson Veterans Administration Medical Center CharlestonSCUSA Department of Health and Human Performance The CitadelCharlestonSCUSA

Spinal cord injuries affect nearly five to ten individuals per million every year. Spinal cord injury causes damage to the nerves, muscles, and the tissue surrounding the spinal cord. Depending on the severity, spinal injuries are linked to degeneration of axons and myelin, resulting in neuronal impairment and skeletal muscle weakness and atrophy. The protection of neurons and promotion of myelin regeneration during spinal cord injury is important for recovery of function following spinal cord injury. Current treatments have little to no effect on spinal cord injury and neurogenic muscle loss. Clemastine, an Food and Drug Administration-approved antihistamine drug, reduces inflammation, protects cells, promotes remyelination, and preserves myelin integrity. Recent clinical evidence suggests that clemastine can decrease the loss of axons after spinal cord injury, stimulating the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes that are capable of myelination. While clemastine can aid not only in the remyelination and preservation of myelin sheath integrity, it also protects neurons. However, its role in neurogenic muscle loss remains unclear. This review discusses the pathophysiology of spinal cord injury, and the role of clemastine in the protection of neurons, myelin, and axons as well as attenuation of skeletal muscle loss following spinal cord injury.

关键词： axonal damage clemastine myelination neuronal death oligodendrocytes skeletal muscle spinal cord injury

Role of CDK5 on ATM phosphorylation in neuronal death induced by DNA damage

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Role of CDK5 on ATM phosphorylation in neuronal death induce...

中国神经科学学会第四次会员代表大会暨第八届全国学术会议

作者： Bo TIAN~(1,2),Zi-Xu MAO~(1,*) 1 Department of Pharmacology and Neurology,Emory University School of Medicine,Atlanta,GA 30322 2 Department of Neurology,Tongji Medical college of Huazhong University of Science and Technology,Wuhan,400030, China

＜正＞Objective The phosphatidylinositol-3-kinase-like kinase ATM（Ataxia - telangiectasia mutated） plays a central role in coordinating the DNA damage responses including cell cycle checkpoint control,DNA repair,and apoptosis. Mutations of ATM cause a spectrum of defects ranging from neurodegeneration to cancer predisposition.However,the mechanism by which DNA damage activates ATM is poorly understood.Methods Different analysis by protein determination,kinase assays,real-time PCR,infection with adenoviruses or Antiviruses and survival assays among others,were used to demonstrate that Cdk5 mediates DNA damage signaling through ATM phosphorylation.Results We show that Cdk5（cyclin-dependent kinase 5）,activated by DNA damage,directly phosphorylates ATM at serine 794 in postmitotic neurons.Phosphorylation at serine 794 precedes and is required for ATM autophosphorylation at serine 1981, and activates ATM kinase activity.Cdk5-ATM signal regulates phosphorylation and function of ATM targets p53 and H2AX.Interruption of Cdk5-ATM pathway attenuates DNA damage-induced neuronal cell cycle reentry and expression of p53 targets PUMA and Bax,protecting neurons from DNA damage-induced death.Conclusion This study reveals the role of Cdk5 on ATM phosphorylation after DNA damage.Activation of Cdk5 by DNA damage serves as a critical signal to initiate ATM response and regulate ATM-dependent cellular processes.

关键词： CDK5 ATM DNA damage neuronal death phosphorylation

Characterization of neuronal death in a convulsant model of rats,induced by intrahippocampal injection of BmK I,a sodium channel-specific modulator

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Characterization of neuronal death in a convulsant model of ...

中国神经科学学会第四次会员代表大会暨第七届全国学术会议

作者： Jun YANG~1,Rong ZHAO~2,Chun-Chun WENG~1,Xu-Ying ZHANG~2,Jian-Wei ZHANG~1,Yong-Hua JI~(1,2*) 1 School of Life Sciences,Shanghai University,Shanghai 200444,China 2 Graduate School of the Chinese Academy of Sciences,Institute of Physiology,Shanghai Institutes for Biological Sciences,Chinese Academy of Sciences,Shanghai 200031,China

＜正＞BmK I,anα-like neurotoxin acting on receptor-3 of the voltage-gated sodium channel,has been demonstrated to evoke epileptic seizures in rats.In the present study,we investigated the hippocampus morphological alteration and cell loss during convulsions induced by intrahippocampal injection of BmK I.The nissl staining results showed that high-dose BmK I produced a significant morphological change of hippocampus after BmK I administration into hippocampus CA1.Both 0.5ug/ul and 1ug/ul BmK I strongly reduced the number and density of pyramidal neurons in ipsilateral CA1, CA2,CA3 fields,but granule cells in the hilus of dentate gyrus were only decreased by 1ug/ul BmK I injection.neuronal death was not detected in the contralateral hippocampus.The present study indicated that the epileptic seizures induced by BmK I are associated with loss of focal hippocampal excessive cell.It may provide a potential model to elucidate underlying cellular mechanisms of channel-induced epileptogenesis.

关键词： neuronal death seizures BmK I nissl staining

The Role of Mitochondria Fusion and Fission in neuronal death Induced by Cerebral Ischemia/Reperfusion

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The Role of Mitochondria Fusion and Fission in Neuronal Deat...

第十四届中国医师协会神经外科医师年会

作者： Chen Yike Guo Songxue Ma Feiqiang Luo Jinqi Wu Qun

Mitochondria are highly dynamic organelles which are joined by mitochondrial fusion and divided by mitochondrial fission. The balance of mitochondrial fusion and fission plays a critical role in maintaining the normal function of neurons. These processes are both mediated by several proteins, which could be affected by external stimulation. Cerebral ischemia-reperfusion（I/R） injury could destroy the homeostasis of the intracellular environment and disrupt the balance of mitochondrial fusion and fission through regulating the expression and post-translation modification of fusion and fission related proteins, thereby causing neuronal death. Furthermore human intervention in fusion and fission related proteins could influence the function of neurons and change the outcomes of cerebral I/R injury. In this review, we are aiming to highlight current development to help us understand the regulatory factors and signaling networks of aberrant mitochondrial fusion and fission contributing to neuronal death upon I/R, as well as the potential neuroprotective therapeutics targeting mitochondrial dynamics.

关键词： Ischemia/Reperfusion Mitochondria Fusion/Fission neuronal death

Oxidation of survival factor MEF2D in neuronal death and Parkinson’s disease

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Oxidation of survival factor MEF2D in neuronal death and Par...

中国神经科学学会第十届全国学术会议

作者： Li Gao Hua She Wenming Li Jinqiu Zhu Dean P Jones Zixu Mao Guodong Gao Qian Yang Department of Neurosurgery Tangdu HospitalThe Fourth Military Medical University Department of Pharmacology Emory University School of Medicine Department of Neurology Emory University School of Medicine Department of Medicine Emory University School of Medicine

Dysfunction of transcription factor myocyte enhancer factor 2D（MEF2D）,a key survival factor,underlies the pathogenic loss of dopaminergic neurons in Parkinson’s disease（PD）.Both genetic factors and neurotoxins associated with PD impair MEF2D function in vitro and in animal models of PD.We investigated whether distinct stress conditions may target MEF2D via converging mechanisms.We show that exposure of DA neuronal progenitor cells to 6-hyroxydopamine（6-OHDA）,a neurotoxin associated with PD,caused direct oxidative modifications of MEF2D,including carbonyl formation and oxidization of cysteine residues.Oxidized MEF2D bound to a key regulator for chaperone-mediated autophagy（CMA）,heat-shock cognate protein 70 kDa（Hsc70）,at higher affinity.In addition,oxidative stress also increased the level of lysosomal associated membrane protein 2A（LAMP2A）,a rate limiting receptor for CMA process,and stimulated CMA activity,resulting in accelerated degradation of MEF2D.Furthermore,6-OHDA caused oxidation of MEF2D and increased LAMP2A in the SNc region of mouse brain.More importantly,the levels of oxidized MEF2D were much higher in the postmortem PD brains compared to controls.Functionally,reducing the levels of either MEF2D or LAMP2A exacerbated 6-OHDA-induced death of DA neuronal progenitor cells while increasing the levels of a MEF2D mutant resistant to oxidative modification protected cells from oxidation-induced death.This study establishes survival protein MEF2D as a direct target in oxidative stress-induced DA neuronal death.Oxidation modification of survival factor MEF2D inhibits its function,is part of PD pathogenic process,and underlies neurotoxicity associated with the disease.

关键词： chaperone-mediated autophagy oxidative stress MEF2D Parkinson’s disease neuronal death