Ischemic stroke caused by intracranial vascular occlusion has become increasingly prevalent with considerable mortality and disability,which gravely burdens the global economy.Current relatively effective clinical tre...Ischemic stroke caused by intracranial vascular occlusion has become increasingly prevalent with considerable mortality and disability,which gravely burdens the global economy.Current relatively effective clinical treatments are limited to intravenous alteplase and thrombectomy.Even so,patients still benefit little due to the short therapeutic window and the risk of ischemia/reperfusion injury.It is therefore urgent to figure out the neuronal death mechanisms following ischemic stroke in order to develop new neuroprotective strategies.Regarding the pathogenesis,multiple pathological events trigger the activation of cell death pathways.Particular attention should be devoted to excitotoxicity,oxidative stress,and inflammatory responses.Thus,in this article,we first review the principal mechanisms underlying neuronal death mediated by these significant events,such as intrinsic and extrinsic apoptosis,ferroptosis,parthanatos,pyroptosis,necroptosis,and autophagic cell death.Then,we further discuss the possibility of interventions targeting these pathological events and summarize the present pharmacological achievements.展开更多
Focal ischemic stroke（FIS）results from the lack of blood flow in a particular region of the brain and accounts for about 80%of all human strokes.Although tremendous efforts have been made in translational research,t...Focal ischemic stroke（FIS）results from the lack of blood flow in a particular region of the brain and accounts for about 80%of all human strokes.Although tremendous efforts have been made in translational research,the treatment strategies are still limited.Tissue plasminogen activator is the only FDA-approved drug currently available for acute stroke treatment,展开更多
BACKGROUND： Blood supply to the hippocampus is not provided by the middle cerebral artery. However, previous studies have shown that delayed neuronal death in the hippocampus may occur following focal cerebral ischem...BACKGROUND： Blood supply to the hippocampus is not provided by the middle cerebral artery. However, previous studies have shown that delayed neuronal death in the hippocampus may occur following focal cerebral ischemia induced by middle cerebral artery occlusion. OBJECTIVE： To observe the relationship between reactive changes in hippocampal astrocytes and delayed neuronal death in the hippocampal CA1 region following middle cerebral artery occlusion. DESIGN, TIME AND SETTING： The immunohistochemical, randomized, controlled animal study was performed at the Laboratory of Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, from July to November 2007. MATERIALS： Rabbit anti-glial fibrillary acidic protein （GFAP） （Neomarkers, USA）, goat anti-rabbit IgG （Sigma, USA） and ApoAlert apoptosis detection kit （Biosciences Clontech, USA） were used in this study. METHODS： A total of 42 healthy adult male Wistar rats, aged 3–5 months, were randomly divided into a sham operation group （n = 6） and a cerebral ischemia/reperfusion group （n = 36）. In the cerebral ischemia/reperfusion group, cerebral ischemia/reperfusion models were created by middle cerebral artery occlusion. In the sham operation group, the thread was only inserted into the initial region of the internal carotid artery, and middle cerebral artery occlusion was not induced. Rats in the cerebral ischemia/reperfusion group were assigned to a delayed neuronal death （＋） subgroup and a delayed neuronal death （–） subgroup, according to the occurrence of delayed neuronal death in the ischemic side of the hippocampal CA1 region following cerebral ischemia. MAIN OUTCOME MEASURES： Delayed neuronal death in the hippocampal CA1 region was measured by Nissl staining. GFAP expression and delayed neuronal death changes were measured in the rat hippocampal CA1 region at the ischemic hemisphere by double staining for GFAP and TUNEL. RESULTS： After 3 days of ischemia/reperfusion, astrocytes with abnormal morphology were detected in the rat hippocampal CA1 region in the delayed neuronal death （＋） subgroup. No significant difference in GFAP expression was found in the rat hippocampal CA1 region at the ischemic hemisphere in the sham operation group, delayed neuronal death （＋） subgroup and delayed neuronal death （–） subgroup （P 〉 0.05）. After 7 days of ischemia/reperfusion, many GFAP-positive cells, which possessed a large cell body and an increased number of processes, were activated in the rat hippocampal CA1 region at the ischemic hemisphere. GFAP expression in the hippocampal CA1 region was greater in the delayed neuronal death （＋） subgroup and delayed neuronal death （–） subgroup compared with the sham operation group （P 〈 0.01）. Moreover, GFAP expression was significantly greater in the delayed neuronal death （–） subgroup than in the delayed neuronal death （＋） subgroup （P 〈 0.01）. After 30 days of ischemia/reperfusion, GFAP-positive cells were present in scar-like structures in the rat hippocampal CA1 region at the ischemic hemisphere. GFAP expression was significantly greater in the delayed neuronal death （＋） subgroup and delayed neuronal death （–） subgroup compared with the sham operation group （P 〈 0.05）. GFAP expression was significantly lower in the delayed neuronal death （–） subgroup than in the delayed neuronal death （＋） subgroup （P 〈 0.05）. The delayed neuronal death rates were 42% （5/12）, 33% （4/12） and 33% （4/12） at 3, 7 and 30 days, respectively, followingischemia/reperfusion. No significant differences were detected at various time points （χ2 = 0.341, P 〉 0.05）. CONCLUSION： The activation of astrocytes was poor in the hippocampal CA1 region during the early stages of ischemia, which is an important reason for delayed neuronal death. Glial scar formation aggravated delayed neuronal death during the advanced ischemic stage.展开更多
Acknowledgments： I would like to express my appreciation to Professor Puro DG for leading me to this research topic during my stay as a research fellow in his laboratory at the University of Michigan in 2001, and als...Acknowledgments： I would like to express my appreciation to Professor Puro DG for leading me to this research topic during my stay as a research fellow in his laboratory at the University of Michigan in 2001, and also to Professor Ikeda T forgiving me the opportunity to study abroad and then to continue to investigate this topic in the Department of Ophthalmology at Osaka Medical College, lapan.展开更多
Regulated cell death predominantly involves apoptosis,autophagy,and regulated necrosis.It is vital that we understand how key regulatory signals can control the process of cell death.Pin1 is a cis-trans isomerase that...Regulated cell death predominantly involves apoptosis,autophagy,and regulated necrosis.It is vital that we understand how key regulatory signals can control the process of cell death.Pin1 is a cis-trans isomerase that catalyzes the isomerization of phosphorylated serine or threonine-proline motifs of a protein,thereby acting as a crucial molecular switch and regulating the protein functionality and the signaling pathways involved.However,we know very little about how Pin1-associated pathways might play a role in regulated cell death.In this paper,we review the role of Pin1 in regulated cell death and related research progress and summarize Pin1-related pathways in regulated cell death.Aside from the involvement of Pin1 in the apoptosis that accompanies neurodegenerative diseases,accumulating evidence suggests that Pin1 also plays a role in regulated necrosis and autophagy,thereby exhibiting distinct effects,including both neurotoxic and neuroprotective effects.Gaining an enhanced understanding of Pin1 in neuronal death may provide us with new options for the development of therapeutic target for neurodegenerative disorders.展开更多
The tumor suppressor p63 is one of p53 family members and plays a vital role as a regulator of neuronal apoptosis in the development of the nervous system. However, the role of p63 in mature neuronal death has not bee...The tumor suppressor p63 is one of p53 family members and plays a vital role as a regulator of neuronal apoptosis in the development of the nervous system. However, the role of p63 in mature neuronal death has not been addressed yet. In this study, we first compared ischemia-induced effects on p63 expression in the hippocampal regions （CA1-3） between the young and adult gerbils subjected to 5 minutes of transient global cerebral ischemia. Neuronal death in the hippocampal CA1 region of young gerbils was significantly slow compared with that in the adult gerbils after transient global cerebral ischemia, p63 immunoreactivity in the hippocampal CA1 pyramidal neurons in the sham-operated young group was significantly low compared with that in the sham-operated adult group, p63 immunoreactivity was apparently changed in ischemic hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. In the ischemia-operated adult groups, p63 immunoreactivity in the hippocampal CA1 pyramidal neurons was significantly decreased at 4 days post-ischemia; however, p63 immunoreactivity in the ischemia-operated young group was significantly higher than that in the ischemia-operated adult group. At 7 days post-ischemia, p63 immunoreactivity was decreased in the hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. Change patterns of p63 level in the hippocampal CA1 region of adult and young gerbils after ischemic damage were similar to those observed in the immunohistochemical results. These findings indicate that higher and longer-term expression of p63 in the hippocampal CA1 region of the young gerbils after ischemia/reperfusion may be related to more delayed neuronal death compared to that in the adults.展开更多
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 gyr...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 disappeared in the CA1 region. In contrast, neurons of the DG region showed minimized proteasome expression at 24 hours, with a slight increase at 72 hours （P 〈 0.01）. CONCLUSION： The alteration of proteasome following ischemia/reperfusion in the neurons of hippocampal CA1 and DG regions reduces the ability of cells to degrade abnormal protein, which may be an important factor resulting in delayed neuronal death following transient cerebral ischemia.展开更多
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 proce...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.展开更多
Introduction.Ischemic stroke,spinal cord injury(SCI),and acute primary angle-closure glaucoma constitute three major clinically prevalent and highly disabling central nervous system(CNS)disorders.Their core pathogenes...Introduction.Ischemic stroke,spinal cord injury(SCI),and acute primary angle-closure glaucoma constitute three major clinically prevalent and highly disabling central nervous system(CNS)disorders.Their core pathogenesis universally originates from ischemia/reperfusion(I/R)injury affecting the cerebral,spinal cord,and/or retina.展开更多
To study the effect of anisodamine on neuronal death and hydroxyl radical (OH·) production during forebrain ischemia reperfusion in gerbils Methods The tested gerbils were divided into 3 groups, including sham...To study the effect of anisodamine on neuronal death and hydroxyl radical (OH·) production during forebrain ischemia reperfusion in gerbils Methods The tested gerbils were divided into 3 groups, including sham operated, control and anisodamine groups. In each group, there were 8 animals for biochemical examination and 6 animals for histologic study. Forebrain ischemia was induced by occlusion the bilateral common carotid arteries for 10 min in gerbils. 2,3 and 2,5 DHBA outputs were determined by high performance hiquid chromatography coupled with electrochemical detection. Behavioral change was tested by open field test and neuronal death was assessed by histological examination.Results The exploratory activities of gerbils in the control group were significantly higher than those in the anisodamine group on all test days The amount of viable looking neurons in the medial, middle and lateral CA1 sectors in anisodamine group were 41%±12%, 50%±21% and 67%±15% of the sham operated gerbils, respectively, being significantly higher than those in the control group (3%±2%, 4%±3% and 7%±4% of sham, P <0 01) The 2,3 DHBA outputs in the control group increased by 5 fold of the sham operated gerbils after reperfusion for 60 min, but the 2,3 DHBA outputs in the anisodamine group were only 2 4 fold of sham operated gerbils, being significantly lower than that in the control group ( P <0 01) The 2,5 DHBA outputs in the control group were significantly higher than those in the sham operated group ( P <0 05) Conclusion Anisodamine has inhibitory effects on neuronal death and OH·production during cerebral ischemia reperfusion in gerbils展开更多
Clusterin, a protein associated with multiple functions, is expressed in a wide variety of mammalian tissues. Although clusterin is known to be involved in neurodegenerative diseases, ageing, and tumorigenesis, a deta...Clusterin, a protein associated with multiple functions, is expressed in a wide variety of mammalian tissues. Although clusterin is known to be involved in neurodegenerative diseases, ageing, and tumorigenesis, a detailed analysis of the consequences of gain- or loss-of- function approaches has yet to be performed to understand the underlying mechanisms of clusterin functions. Since clusterin levels change in neurological diseases, it is likely that clusterin contributes to cell death and degeneration in general. Zebrafish was investigated as a model system to study human diseases. During development, zebrafish clusterin was expressed in the notochord and nervous system. Embryonic overexpression of clusterin by mRNA microinjection did not affect axis formation, whereas its knock-down by anti-sense morpholino treatment resulted in neuronal cell death. To analyze the function of clusterin in neurodegeneration, a transgenic zebrafish was investigated, in which nitroreductase expression is regulated under the control of a neuron-specifc huC promoter which is active between the stages of early neuronal precursors and mature neurons. Nitroreductase turns metronidazole into a cytotoxic agent that induces cell death within 12 h. After metronidazole treatment, transgenic zebrafish showed neuron-specific cell death. Interestingly, we also observed a dramatic induction of clusterin expression in the brain and spinal cord in these fish, suggesting a direct or indirect role of clusterin in neuronal cell death and thus, more generally, in neurodegeneration.展开更多
Programmed cell death （PCD） signaling pathways are import- ant contributors to acute neurological insults such as hypox- ic-ischemic brain damage, traumatic brain injury, stroke etc. The pathogenesis of all these di...Programmed cell death （PCD） signaling pathways are import- ant contributors to acute neurological insults such as hypox- ic-ischemic brain damage, traumatic brain injury, stroke etc. The pathogenesis of all these diseases is closely linked with ab- erration of apoptotic cell death pathways. Mitochondria play a crucial role during PCD, acting as both sensors of death signals, and as initiators of biochemical path- ways, which cause cell death （Bras et al., 2005）. Cytochrome c was the firstly identified apoptogenic factor released from mitochondria into the cytosol, where it induces apoptosome formation through the activation of caspases. Other proteins, such as apoptosis inducing factor （AIF）, have been subsequently identified as mitochondrial released factors. AIF contributes to apoptotic nuclear DNA damage （Bras et al., 2005）. in a caspase-independent way展开更多
To investigate the relationship between protein aggregation and delayed neuronal death,we adopted rat models of 20 min ischemia.Brain ischemia was produced using the 2-vessel occlusion(2VO)model in rats Light microsco...To investigate the relationship between protein aggregation and delayed neuronal death,we adopted rat models of 20 min ischemia.Brain ischemia was produced using the 2-vessel occlusion(2VO)model in rats Light microscopy,transmission electronic microscopy and Western blot analysis were performed for morphological analysis of neurons,and protein detection.The results showed delayed neuronal death took place at 72 h after ischemia-reperfusion,protein aggregates formed at 4 h after reperfusion and reached the peak at 24 h after reper-fusion,and Western blot analysis was consistent with transmission electronic microscopy.We conclude that protein aggregation is one of the important factors leading to delayed neuronal death.展开更多
Oxidative stress influences cell survival and homeostasis,but the mechanisms underlying the biological effects of oxidative stress remain to be elucidated.We have defined that the protein kinase MST1 mediates oxidativ...Oxidative stress influences cell survival and homeostasis,but the mechanisms underlying the biological effects of oxidative stress remain to be elucidated.We have defined that the protein kinase MST1 mediates oxidative stress-induced cell death in primary mammalian neurons by directly activating the FOXO transcription factors.However,the upstream regulator of MST1 is largely unknown.Here,we demonstarte the c-Abl-MST1-FOXO signaling cascade mediates oxidative stress-induced neuronal cell death.C-Abl phosphorylates MST1 at a conserve site,Tyrosine 433,that leads to stabilization and activation of MST1.展开更多
The limited regenerative capacity of neuronal cells requires tight orchestration of cell death and survival regulation in the context of longevity, age-associated diseases as well as during the development of the nerv...The limited regenerative capacity of neuronal cells requires tight orchestration of cell death and survival regulation in the context of longevity, age-associated diseases as well as during the development of the nervous system. Subordinate to genetic networks epigenetic mechanisms like DNA methylation and histone modifications are involved in the regulation of neuronal development, function and aging. DNA methylation by DNA methyltransferases （DNMTs）, mostly correlated with gene silencing, is a dynamic and reversible process. In addition to their canonical actions performing cytosine methylation, DNMTs influence gene expression by interactions with histone modifying enzymes or complexes increasing the complexity of epigenetic transcriptional networks. DNMTs are expressed in neuronal progenitors, post-mi- totic as well as adult neurons. In this review, we discuss the role and mode of actions of DNMTs including downstream networks in the regulation of neuronal survival in the developing and aging nervous system and its relevance for associated disorders.展开更多
Calcium (Ca^(2+)) is a key intracellular messenger involved in a variety of cellular functions.Intracellular Ca^(2+)dysregulation drives neuron cell death in multiple degenerative diseases and traumatic conditions.Ret...Calcium (Ca^(2+)) is a key intracellular messenger involved in a variety of cellular functions.Intracellular Ca^(2+)dysregulation drives neuron cell death in multiple degenerative diseases and traumatic conditions.Retinal ganglion cell(RGC) degeneration occurs in blinding diseases such as glaucoma and other optic neuropathies.展开更多
With the gradual advancement of research methods and technologies,various biological processes have been identified as playing roles in the pathogenesis of neurodegenerative diseases.However,current descriptions of th...With the gradual advancement of research methods and technologies,various biological processes have been identified as playing roles in the pathogenesis of neurodegenerative diseases.However,current descriptions of these biological processes do not fully explain the onset,progression,and development of these conditions.Therefore,exploration of the pathogenesis of neurodegenerative diseases remains a valuable area of research.This review summarizes the potential common pathogeneses of Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,Huntington’s disease,frontotemporal lobar dementia,and Lewy body disease.Research findings have indicated that several common biological processes,including aging,genetic factors,progressive neuronal dysfunction,neuronal death and apoptosis,protein misfolding and aggregation,neuroinflammation,mitochondrial dysfunction,axonal transport defects,and gut microbiota dysbiosis,are involved in the pathogenesis of these six neurodegenerative diseases.Based on current information derived from diverse areas of research,these biological processes may form complex pathogenic networks that lead to distinctive types of neuronal death in neurodegenerative diseases.Furthermore,promoting the regeneration of damaged neurons may be achievable through the repair of affected neural cells if the underlying pathogenesis can be prevented or reversed.Hence,these potential common biological processes may represent only very small,limited elements within numerous intricate pathogenic networks associated with neurodegenerative diseases.In clinical treatment,interfering with any single biological process has proven insufficient to completely halt the progression of neurodegenerative diseases.Therefore,future research on the pathogenesis of neurodegenerative diseases should focus on uncovering the complex pathogenic networks,rather than isolating individual biological processes.Based on this,therapies that aim to block or reverse various targets involved in the potential pathogenic mechanisms of neurodegenerative diseases may be promising directions,as current treatment methods that focus on halting a single pathogenic factor have not achieved satisfactory efficacy.展开更多
Parkinson＇s disease （PD） is a neurodegenerative disease with a long preclinical phase. The continuous loss of dopaminergic （DA） neurons is one of the pathogenic hallmarks of PD. Diagnosis largely depends on clini...Parkinson＇s disease （PD） is a neurodegenerative disease with a long preclinical phase. The continuous loss of dopaminergic （DA） neurons is one of the pathogenic hallmarks of PD. Diagnosis largely depends on clinical observation, but motor dysfunctions do not emerge until 70%-80% of the nigrostriatal nerve terminals have been destroyed. Therefore, a biomarker that indicates the degeneration of DA neurons is urgently needed. Transcrip- tion factors are sequence-specific DNA-binding proteins that regulate RNA synthesis from a DNA template. The precise control of gene expression plays a critical role in the development, maintenance, and survival of cells, including DA neurons. Deficiency of certain transcription factors has been associated with DA neuron loss and PD. In this review, we focus on some transcription factors and discuss their structure, function, mechanisms of neuropro- tection, and their potential for use as biomarkers indicating the degeneration of DA neurons.展开更多
Ischemia-reperfusion(I/R)injury induces region-specific neuronal vulnerability within the hippocampus,with the cornu ammonis 1(CA1)subfield particularly prone to delayed neuronal death.While intrinsic neuronal factors...Ischemia-reperfusion(I/R)injury induces region-specific neuronal vulnerability within the hippocampus,with the cornu ammonis 1(CA1)subfield particularly prone to delayed neuronal death.While intrinsic neuronal factors have been implicated,emerging evidence highlights the decisive contribution of astrocyte endfeet(AEF)—specialized perivascular structures that regulate ion and water homeostasis,glutamate clearance,and blood–brain barrier(BBB)stability.This review synthesizes structural and molecular alterations of AEF across the CA1-CA3 subfields following I/R and their correlation with neuronal fate.In CA1,AEF undergo early-onset swelling and detachment from the vascular basal lamina due to dysfunction of critical proteins such as aquaporin-4(AQP4)and Kir4.1.These changes impair glutamate uptake,metabolic support,and potassium buffering,contributing to neuronal hyperexcitability and degeneration.In contrast,AEF in CA3 preserves polarity and functional coupling of AQP4 and Kir4.1,conferring regional resilience.At the signaling level,AEF disruption activates mitogen-activated protein kinase(MAPK)/c-Jun N-terminal kinase(JNK)pathways,promotes reactive oxygen species(ROS)accumulation,and induces inducible nitric oxide synthase(iNOS)-mediated inflammation,amplifying neurotoxicity.Furthermore,subfield-specific astrocytic transcriptional profiles modulate inflammatory responses and gliovascular interactions.By reframing AEF not as passive scaffolds but as active regulators of neuronal survival,this review provides novel insight into the astrocyte-dependent mechanisms of hippocampal vulnerability.Therapeutic strategies that preserve AEF structure and function may offer targeted protection against delayed neuronal death in ischemic brain injury.展开更多
Aging is a dynamic and progressive process that begins at conception and continues until death.This process leads to a decrease in homeostasis and morphological,biochemical and psychological changes,increasing the ind...Aging is a dynamic and progressive process that begins at conception and continues until death.This process leads to a decrease in homeostasis and morphological,biochemical and psychological changes,increasing the individual’s vulnerability to various diseases.The growth in the number of aging populations has increased the prevalence of chronic degenerative diseases,impairment of the central nervous system and dementias,such as Alzheimer’s disease,whose main risk factor is age,leading to an increase of the number of individuals who need daily support for life activities.Some theories about aging suggest it is caused by an increase of cellular senescence and reactive oxygen species,which leads to inflammation,oxidation,cell membrane damage and consequently neuronal death.Also,mitochondrial mutations,which are generated throughout the aging process,can lead to changes in energy production,deficiencies in electron transport and apoptosis induction that can result in decreased function.Additionally,increasing cellular senescence and the release of proinflammatory cytokines can cause irreversible damage to neuronal cells.Recent reports point to the importance of changing lifestyle by increasing physical exercise,improving nutrition and environmental enrichment to activate neuroprotective defense mechanisms.Therefore,this review aims to address the latest information about the different mechanisms related to neuroplasticity and neuronal death and to provide strategies that can improve neuroprotection and decrease the neurodegeneration caused by aging and environmental stressors.展开更多
基金This review was supported by the National Natural Science Foundation of China(81920108017,82130036,and 81630028)the Key Research and Development Program of Jiangsu Province of China(BE2020620)Jiangsu Province Key Medical Discipline(ZDXKA2016020).
文摘Ischemic stroke caused by intracranial vascular occlusion has become increasingly prevalent with considerable mortality and disability,which gravely burdens the global economy.Current relatively effective clinical treatments are limited to intravenous alteplase and thrombectomy.Even so,patients still benefit little due to the short therapeutic window and the risk of ischemia/reperfusion injury.It is therefore urgent to figure out the neuronal death mechanisms following ischemic stroke in order to develop new neuroprotective strategies.Regarding the pathogenesis,multiple pathological events trigger the activation of cell death pathways.Particular attention should be devoted to excitotoxicity,oxidative stress,and inflammatory responses.Thus,in this article,we first review the principal mechanisms underlying neuronal death mediated by these significant events,such as intrinsic and extrinsic apoptosis,ferroptosis,parthanatos,pyroptosis,necroptosis,and autophagic cell death.Then,we further discuss the possibility of interventions targeting these pathological events and summarize the present pharmacological achievements.
基金supported by NIH NS069726 and NS094539America Heart Association 13GRANT17020004(to SD)
文摘Focal ischemic stroke（FIS）results from the lack of blood flow in a particular region of the brain and accounts for about 80%of all human strokes.Although tremendous efforts have been made in translational research,the treatment strategies are still limited.Tissue plasminogen activator is the only FDA-approved drug currently available for acute stroke treatment,
基金the National Outstanding Youth Foundation Program, No. 30725019 the Natural Science Foundation of Hubei Province, No. 2007ABA174
文摘BACKGROUND： Blood supply to the hippocampus is not provided by the middle cerebral artery. However, previous studies have shown that delayed neuronal death in the hippocampus may occur following focal cerebral ischemia induced by middle cerebral artery occlusion. OBJECTIVE： To observe the relationship between reactive changes in hippocampal astrocytes and delayed neuronal death in the hippocampal CA1 region following middle cerebral artery occlusion. DESIGN, TIME AND SETTING： The immunohistochemical, randomized, controlled animal study was performed at the Laboratory of Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, from July to November 2007. MATERIALS： Rabbit anti-glial fibrillary acidic protein （GFAP） （Neomarkers, USA）, goat anti-rabbit IgG （Sigma, USA） and ApoAlert apoptosis detection kit （Biosciences Clontech, USA） were used in this study. METHODS： A total of 42 healthy adult male Wistar rats, aged 3–5 months, were randomly divided into a sham operation group （n = 6） and a cerebral ischemia/reperfusion group （n = 36）. In the cerebral ischemia/reperfusion group, cerebral ischemia/reperfusion models were created by middle cerebral artery occlusion. In the sham operation group, the thread was only inserted into the initial region of the internal carotid artery, and middle cerebral artery occlusion was not induced. Rats in the cerebral ischemia/reperfusion group were assigned to a delayed neuronal death （＋） subgroup and a delayed neuronal death （–） subgroup, according to the occurrence of delayed neuronal death in the ischemic side of the hippocampal CA1 region following cerebral ischemia. MAIN OUTCOME MEASURES： Delayed neuronal death in the hippocampal CA1 region was measured by Nissl staining. GFAP expression and delayed neuronal death changes were measured in the rat hippocampal CA1 region at the ischemic hemisphere by double staining for GFAP and TUNEL. RESULTS： After 3 days of ischemia/reperfusion, astrocytes with abnormal morphology were detected in the rat hippocampal CA1 region in the delayed neuronal death （＋） subgroup. No significant difference in GFAP expression was found in the rat hippocampal CA1 region at the ischemic hemisphere in the sham operation group, delayed neuronal death （＋） subgroup and delayed neuronal death （–） subgroup （P 〉 0.05）. After 7 days of ischemia/reperfusion, many GFAP-positive cells, which possessed a large cell body and an increased number of processes, were activated in the rat hippocampal CA1 region at the ischemic hemisphere. GFAP expression in the hippocampal CA1 region was greater in the delayed neuronal death （＋） subgroup and delayed neuronal death （–） subgroup compared with the sham operation group （P 〈 0.01）. Moreover, GFAP expression was significantly greater in the delayed neuronal death （–） subgroup than in the delayed neuronal death （＋） subgroup （P 〈 0.01）. After 30 days of ischemia/reperfusion, GFAP-positive cells were present in scar-like structures in the rat hippocampal CA1 region at the ischemic hemisphere. GFAP expression was significantly greater in the delayed neuronal death （＋） subgroup and delayed neuronal death （–） subgroup compared with the sham operation group （P 〈 0.05）. GFAP expression was significantly lower in the delayed neuronal death （–） subgroup than in the delayed neuronal death （＋） subgroup （P 〈 0.05）. The delayed neuronal death rates were 42% （5/12）, 33% （4/12） and 33% （4/12） at 3, 7 and 30 days, respectively, followingischemia/reperfusion. No significant differences were detected at various time points （χ2 = 0.341, P 〉 0.05）. CONCLUSION： The activation of astrocytes was poor in the hippocampal CA1 region during the early stages of ischemia, which is an important reason for delayed neuronal death. Glial scar formation aggravated delayed neuronal death during the advanced ischemic stage.
文摘Acknowledgments： I would like to express my appreciation to Professor Puro DG for leading me to this research topic during my stay as a research fellow in his laboratory at the University of Michigan in 2001, and also to Professor Ikeda T forgiving me the opportunity to study abroad and then to continue to investigate this topic in the Department of Ophthalmology at Osaka Medical College, lapan.
基金supported by the National Natural Science Foundation of China, Nos. 81971891 (to KX), 82101126 (to SCW), 81772134 (to KX), 82172196 (to KX)the Natural Science Foundation of Hunan Province of China, No. 2021JJ40873 (to SCW)
文摘Regulated cell death predominantly involves apoptosis,autophagy,and regulated necrosis.It is vital that we understand how key regulatory signals can control the process of cell death.Pin1 is a cis-trans isomerase that catalyzes the isomerization of phosphorylated serine or threonine-proline motifs of a protein,thereby acting as a crucial molecular switch and regulating the protein functionality and the signaling pathways involved.However,we know very little about how Pin1-associated pathways might play a role in regulated cell death.In this paper,we review the role of Pin1 in regulated cell death and related research progress and summarize Pin1-related pathways in regulated cell death.Aside from the involvement of Pin1 in the apoptosis that accompanies neurodegenerative diseases,accumulating evidence suggests that Pin1 also plays a role in regulated necrosis and autophagy,thereby exhibiting distinct effects,including both neurotoxic and neuroprotective effects.Gaining an enhanced understanding of Pin1 in neuronal death may provide us with new options for the development of therapeutic target for neurodegenerative disorders.
基金supported by 2013 Research Grant from Kangwon National University(120131480)Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Education(NRF-2014R1A6A3A01056005)
文摘The tumor suppressor p63 is one of p53 family members and plays a vital role as a regulator of neuronal apoptosis in the development of the nervous system. However, the role of p63 in mature neuronal death has not been addressed yet. In this study, we first compared ischemia-induced effects on p63 expression in the hippocampal regions （CA1-3） between the young and adult gerbils subjected to 5 minutes of transient global cerebral ischemia. Neuronal death in the hippocampal CA1 region of young gerbils was significantly slow compared with that in the adult gerbils after transient global cerebral ischemia, p63 immunoreactivity in the hippocampal CA1 pyramidal neurons in the sham-operated young group was significantly low compared with that in the sham-operated adult group, p63 immunoreactivity was apparently changed in ischemic hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. In the ischemia-operated adult groups, p63 immunoreactivity in the hippocampal CA1 pyramidal neurons was significantly decreased at 4 days post-ischemia; however, p63 immunoreactivity in the ischemia-operated young group was significantly higher than that in the ischemia-operated adult group. At 7 days post-ischemia, p63 immunoreactivity was decreased in the hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. Change patterns of p63 level in the hippocampal CA1 region of adult and young gerbils after ischemic damage were similar to those observed in the immunohistochemical results. These findings indicate that higher and longer-term expression of p63 in the hippocampal CA1 region of the young gerbils after ischemia/reperfusion may be related to more delayed neuronal death compared to that in the adults.
基金Supported by:the Postdoctoral Foundation of China,No.20080440422International Cooperation G rant,No.20070721+1 种基金Outstanding Youth Grant of the Science and Technology Department of Jilin Province, No.20080139a grant from the Science and Technology Department of Changchun City,No.2007128
文摘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 disappeared in the CA1 region. In contrast, neurons of the DG region showed minimized proteasome expression at 24 hours, with a slight increase at 72 hours （P 〈 0.01）. CONCLUSION： The alteration of proteasome following ischemia/reperfusion in the neurons of hippocampal CA1 and DG regions reduces the ability of cells to degrade abnormal protein, which may be an important factor resulting in delayed neuronal death following transient cerebral ischemia.
文摘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.
基金supported by the National Natural Science Foundation of China(Grant nos.62576136 to Yan Huang82372507,82572869 to Kun Xiongthe National Natural Science Foundation of Hunan Province(Grant no.2026JJ30177).
文摘Introduction.Ischemic stroke,spinal cord injury(SCI),and acute primary angle-closure glaucoma constitute three major clinically prevalent and highly disabling central nervous system(CNS)disorders.Their core pathogenesis universally originates from ischemia/reperfusion(I/R)injury affecting the cerebral,spinal cord,and/or retina.
基金ThisstudywassupportedbygrantsfromtheJiangsuProvincialHealthDepartment (No Z9717) JiangsuProvinceCommitteeofScienceandTechn
文摘To study the effect of anisodamine on neuronal death and hydroxyl radical (OH·) production during forebrain ischemia reperfusion in gerbils Methods The tested gerbils were divided into 3 groups, including sham operated, control and anisodamine groups. In each group, there were 8 animals for biochemical examination and 6 animals for histologic study. Forebrain ischemia was induced by occlusion the bilateral common carotid arteries for 10 min in gerbils. 2,3 and 2,5 DHBA outputs were determined by high performance hiquid chromatography coupled with electrochemical detection. Behavioral change was tested by open field test and neuronal death was assessed by histological examination.Results The exploratory activities of gerbils in the control group were significantly higher than those in the anisodamine group on all test days The amount of viable looking neurons in the medial, middle and lateral CA1 sectors in anisodamine group were 41%±12%, 50%±21% and 67%±15% of the sham operated gerbils, respectively, being significantly higher than those in the control group (3%±2%, 4%±3% and 7%±4% of sham, P <0 01) The 2,3 DHBA outputs in the control group increased by 5 fold of the sham operated gerbils after reperfusion for 60 min, but the 2,3 DHBA outputs in the anisodamine group were only 2 4 fold of sham operated gerbils, being significantly lower than that in the control group ( P <0 01) The 2,5 DHBA outputs in the control group were significantly higher than those in the sham operated group ( P <0 05) Conclusion Anisodamine has inhibitory effects on neuronal death and OH·production during cerebral ischemia reperfusion in gerbils
基金supported by the research fund of Chungnam National University,Republic of Koreasupported by the Li Kashing Foundation at Shantou University Medical College,China
文摘Clusterin, a protein associated with multiple functions, is expressed in a wide variety of mammalian tissues. Although clusterin is known to be involved in neurodegenerative diseases, ageing, and tumorigenesis, a detailed analysis of the consequences of gain- or loss-of- function approaches has yet to be performed to understand the underlying mechanisms of clusterin functions. Since clusterin levels change in neurological diseases, it is likely that clusterin contributes to cell death and degeneration in general. Zebrafish was investigated as a model system to study human diseases. During development, zebrafish clusterin was expressed in the notochord and nervous system. Embryonic overexpression of clusterin by mRNA microinjection did not affect axis formation, whereas its knock-down by anti-sense morpholino treatment resulted in neuronal cell death. To analyze the function of clusterin in neurodegeneration, a transgenic zebrafish was investigated, in which nitroreductase expression is regulated under the control of a neuron-specifc huC promoter which is active between the stages of early neuronal precursors and mature neurons. Nitroreductase turns metronidazole into a cytotoxic agent that induces cell death within 12 h. After metronidazole treatment, transgenic zebrafish showed neuron-specific cell death. Interestingly, we also observed a dramatic induction of clusterin expression in the brain and spinal cord in these fish, suggesting a direct or indirect role of clusterin in neuronal cell death and thus, more generally, in neurodegeneration.
文摘Programmed cell death （PCD） signaling pathways are import- ant contributors to acute neurological insults such as hypox- ic-ischemic brain damage, traumatic brain injury, stroke etc. The pathogenesis of all these diseases is closely linked with ab- erration of apoptotic cell death pathways. Mitochondria play a crucial role during PCD, acting as both sensors of death signals, and as initiators of biochemical path- ways, which cause cell death （Bras et al., 2005）. Cytochrome c was the firstly identified apoptogenic factor released from mitochondria into the cytosol, where it induces apoptosome formation through the activation of caspases. Other proteins, such as apoptosis inducing factor （AIF）, have been subsequently identified as mitochondrial released factors. AIF contributes to apoptotic nuclear DNA damage （Bras et al., 2005）. in a caspase-independent way
基金This project was supported by International Cooperation Fund of the Science and Technology Department of Jilin Province(No.20040707-1).
文摘To investigate the relationship between protein aggregation and delayed neuronal death,we adopted rat models of 20 min ischemia.Brain ischemia was produced using the 2-vessel occlusion(2VO)model in rats Light microscopy,transmission electronic microscopy and Western blot analysis were performed for morphological analysis of neurons,and protein detection.The results showed delayed neuronal death took place at 72 h after ischemia-reperfusion,protein aggregates formed at 4 h after reperfusion and reached the peak at 24 h after reper-fusion,and Western blot analysis was consistent with transmission electronic microscopy.We conclude that protein aggregation is one of the important factors leading to delayed neuronal death.
文摘Oxidative stress influences cell survival and homeostasis,but the mechanisms underlying the biological effects of oxidative stress remain to be elucidated.We have defined that the protein kinase MST1 mediates oxidative stress-induced cell death in primary mammalian neurons by directly activating the FOXO transcription factors.However,the upstream regulator of MST1 is largely unknown.Here,we demonstarte the c-Abl-MST1-FOXO signaling cascade mediates oxidative stress-induced neuronal cell death.C-Abl phosphorylates MST1 at a conserve site,Tyrosine 433,that leads to stabilization and activation of MST1.
文摘The limited regenerative capacity of neuronal cells requires tight orchestration of cell death and survival regulation in the context of longevity, age-associated diseases as well as during the development of the nervous system. Subordinate to genetic networks epigenetic mechanisms like DNA methylation and histone modifications are involved in the regulation of neuronal development, function and aging. DNA methylation by DNA methyltransferases （DNMTs）, mostly correlated with gene silencing, is a dynamic and reversible process. In addition to their canonical actions performing cytosine methylation, DNMTs influence gene expression by interactions with histone modifying enzymes or complexes increasing the complexity of epigenetic transcriptional networks. DNMTs are expressed in neuronal progenitors, post-mi- totic as well as adult neurons. In this review, we discuss the role and mode of actions of DNMTs including downstream networks in the regulation of neuronal survival in the developing and aging nervous system and its relevance for associated disorders.
文摘Calcium (Ca^(2+)) is a key intracellular messenger involved in a variety of cellular functions.Intracellular Ca^(2+)dysregulation drives neuron cell death in multiple degenerative diseases and traumatic conditions.Retinal ganglion cell(RGC) degeneration occurs in blinding diseases such as glaucoma and other optic neuropathies.
基金supported by the National Natural Science Foundation of China,No.82160255(to RX)the Natural Science Foundation of Jiangxi Province,No.20212BAB216026(to HL)+2 种基金Science and Technology Plan Project of Health Commission of Jiangxi Province,No.202110016(to HL)Science and Technology Plan Project of Jiangxi Provincial Administration of Traditional Chinese Medicine,No.2022B975(to HL)a grant from Jiangxi Province Key Laboratory of Neurology,No.2024SSY06081(to RX).
文摘With the gradual advancement of research methods and technologies,various biological processes have been identified as playing roles in the pathogenesis of neurodegenerative diseases.However,current descriptions of these biological processes do not fully explain the onset,progression,and development of these conditions.Therefore,exploration of the pathogenesis of neurodegenerative diseases remains a valuable area of research.This review summarizes the potential common pathogeneses of Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,Huntington’s disease,frontotemporal lobar dementia,and Lewy body disease.Research findings have indicated that several common biological processes,including aging,genetic factors,progressive neuronal dysfunction,neuronal death and apoptosis,protein misfolding and aggregation,neuroinflammation,mitochondrial dysfunction,axonal transport defects,and gut microbiota dysbiosis,are involved in the pathogenesis of these six neurodegenerative diseases.Based on current information derived from diverse areas of research,these biological processes may form complex pathogenic networks that lead to distinctive types of neuronal death in neurodegenerative diseases.Furthermore,promoting the regeneration of damaged neurons may be achievable through the repair of affected neural cells if the underlying pathogenesis can be prevented or reversed.Hence,these potential common biological processes may represent only very small,limited elements within numerous intricate pathogenic networks associated with neurodegenerative diseases.In clinical treatment,interfering with any single biological process has proven insufficient to completely halt the progression of neurodegenerative diseases.Therefore,future research on the pathogenesis of neurodegenerative diseases should focus on uncovering the complex pathogenic networks,rather than isolating individual biological processes.Based on this,therapies that aim to block or reverse various targets involved in the potential pathogenic mechanisms of neurodegenerative diseases may be promising directions,as current treatment methods that focus on halting a single pathogenic factor have not achieved satisfactory efficacy.
基金supported by the National Key Research and Development Program of China (2016YFC1306603)the National Natural Science Foundation of China (31671060)
文摘Parkinson＇s disease （PD） is a neurodegenerative disease with a long preclinical phase. The continuous loss of dopaminergic （DA） neurons is one of the pathogenic hallmarks of PD. Diagnosis largely depends on clinical observation, but motor dysfunctions do not emerge until 70%-80% of the nigrostriatal nerve terminals have been destroyed. Therefore, a biomarker that indicates the degeneration of DA neurons is urgently needed. Transcrip- tion factors are sequence-specific DNA-binding proteins that regulate RNA synthesis from a DNA template. The precise control of gene expression plays a critical role in the development, maintenance, and survival of cells, including DA neurons. Deficiency of certain transcription factors has been associated with DA neuron loss and PD. In this review, we focus on some transcription factors and discuss their structure, function, mechanisms of neuropro- tection, and their potential for use as biomarkers indicating the degeneration of DA neurons.
文摘Ischemia-reperfusion(I/R)injury induces region-specific neuronal vulnerability within the hippocampus,with the cornu ammonis 1(CA1)subfield particularly prone to delayed neuronal death.While intrinsic neuronal factors have been implicated,emerging evidence highlights the decisive contribution of astrocyte endfeet(AEF)—specialized perivascular structures that regulate ion and water homeostasis,glutamate clearance,and blood–brain barrier(BBB)stability.This review synthesizes structural and molecular alterations of AEF across the CA1-CA3 subfields following I/R and their correlation with neuronal fate.In CA1,AEF undergo early-onset swelling and detachment from the vascular basal lamina due to dysfunction of critical proteins such as aquaporin-4(AQP4)and Kir4.1.These changes impair glutamate uptake,metabolic support,and potassium buffering,contributing to neuronal hyperexcitability and degeneration.In contrast,AEF in CA3 preserves polarity and functional coupling of AQP4 and Kir4.1,conferring regional resilience.At the signaling level,AEF disruption activates mitogen-activated protein kinase(MAPK)/c-Jun N-terminal kinase(JNK)pathways,promotes reactive oxygen species(ROS)accumulation,and induces inducible nitric oxide synthase(iNOS)-mediated inflammation,amplifying neurotoxicity.Furthermore,subfield-specific astrocytic transcriptional profiles modulate inflammatory responses and gliovascular interactions.By reframing AEF not as passive scaffolds but as active regulators of neuronal survival,this review provides novel insight into the astrocyte-dependent mechanisms of hippocampal vulnerability.Therapeutic strategies that preserve AEF structure and function may offer targeted protection against delayed neuronal death in ischemic brain injury.
基金MT received studentship from Sao Paulo Research Foundation(2017/21655-6)HSB was a Brazilian National Council for Scientific and Technological Development researcher(425838/2016-1,307252/2017-5)This work was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior–Brasil(CAPES)–Finance Code 001 and FAPESP(2016/07115-6).
文摘Aging is a dynamic and progressive process that begins at conception and continues until death.This process leads to a decrease in homeostasis and morphological,biochemical and psychological changes,increasing the individual’s vulnerability to various diseases.The growth in the number of aging populations has increased the prevalence of chronic degenerative diseases,impairment of the central nervous system and dementias,such as Alzheimer’s disease,whose main risk factor is age,leading to an increase of the number of individuals who need daily support for life activities.Some theories about aging suggest it is caused by an increase of cellular senescence and reactive oxygen species,which leads to inflammation,oxidation,cell membrane damage and consequently neuronal death.Also,mitochondrial mutations,which are generated throughout the aging process,can lead to changes in energy production,deficiencies in electron transport and apoptosis induction that can result in decreased function.Additionally,increasing cellular senescence and the release of proinflammatory cytokines can cause irreversible damage to neuronal cells.Recent reports point to the importance of changing lifestyle by increasing physical exercise,improving nutrition and environmental enrichment to activate neuroprotective defense mechanisms.Therefore,this review aims to address the latest information about the different mechanisms related to neuroplasticity and neuronal death and to provide strategies that can improve neuroprotection and decrease the neurodegeneration caused by aging and environmental stressors.
