The regulatory role of Pin1 in neuronal death

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.

Pre-B-cell colony-enhancing factor as a target for protecting against apoptotic neuronal death and mitochondrial damage in ischemia

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,

Reactive changes in astrocytes, and delayed neuronal death, in the rat hippocampal CA1 region following cerebral ischemia/reperfusion

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.

Role of P2X_7 receptors in neuronal death in the retina

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.

Delayed hippocampal neuronal death in young gerbil following transient global cerebral ischemia is related to higher and longer-term expression of p63 in the ischemic hippocampus

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.

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

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.

Responses of CDKs and p53 in Delayed Ischemic Neuronal Death

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.

Relation of phospholipase A2-Ⅴ and indoxam to hippocampal neuronal death

BACKGROUND: Ⅴ secretory phospholipase A2 (sPLA2-Ⅴ) is abundant in many mammal tissues. However, it remains unknown whether sPLA2-Ⅴ causes biological or pathological response in central nervous system. OBJECTIVE: To observe the effect of phospholipase A2-Ⅴ (PLA2-Ⅴ) and its inhibitor (indoxam) on hippocampal neuron survival. DESIGN: A repetitive measurement. SETTING: The Animal Center of South Carolina University. MATERIALS: Sprague-Dawley pregnancy day-7, 14, 21 female rats were selected; Reagents: sPLA2- Ⅴ and indoxam were obtained from the Dennis Research Laboratories METHODS: The experiment was finished at the animal center in South Carolina University from January to December, 2004. 0, 12.5, 25, 50 and 100 μg/L sPLA2-Ⅴ were added to neuron with none-MgCl2 Eagle’s medium at 37 ℃, then changed to normal neuron culture medium after 3 hours. 1, 2.5, 5 and 10 μmol/L indoxam was added at 6 hours after 100 μg/L sPLA2-Ⅴwas put to Day-21 SD rat hippocampal embryonic neurons with none-MgCl2 Eagle’s medium at 37 ℃. After 3 hours in the inhibition experiment, it was changed to normal neuron culture medium. The embryonic hippocampal neurons were primarily cultured, and the neuron survival ratio was detected with morphological method. MAIN OUTCOME MEASURES: Survival ratio of hippocampal neurons. RESULTS: ① Effects of sPLA2-Ⅴon neuron survival: When sPLA2-Ⅴ was 0, 12.5, 25, 50 and 100 μg/L, the neuron survival ratios in embryonic neurons of day-7 SD rats were (95.3±1.1)%, (81.4±3.1)%, (74.2±2.2)%, (62.4±1.7)% and (48.9±1.6)%, those in embryonic neurons of day-14 rats were (93.2±1.4)%, (74.3±1.9)%, (68.1±1.7)%, (56.1±1.4)% and (42.5±1.1)%, and those in embryonic neurons of day-21 rats were (91.2±1.2)%, (69.4±2.1)%, (60.3±2.2)%, (49.1±1.2)% and (35.5±1.9)%. There were significant differences among different concentrations (P < 0.05). ② Effects of indoxam on neuron survival: In case of sPLA2-Ⅴ 100 μg/L, the neuron survival ratios were (58.65±1.4)%, (69.34±1.1)%, (82.11±1.2)% and (95.28±0.9)% when indoxam was 1, 2.5, 5 and 10 μmol/L, respectively. There were significant differences among different concentrations (P < 0.05). CONCLUSION: ① The of neuronal death ratio is in a concentration-dependent manner with sPLA2-Ⅴ, and increases as the embryonic aging. ② Indoxam inhibits the proapoptotic effect of sPLA2-Ⅴ.

Neuronal Death Mechanisms and Therapeutic Strategy in Ischemic Stroke

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.

Anisodamine protects against neuronal death following cerebral ischemia in gerbils

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

Relevance and therapeutic potential of Cyp A targeting to block apoptosis inducing factor-mediated neuronal cell death

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

Protein aggregation in association with delayed neuronal death in rat model of brain ischemia

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.

Regulation of neuronal survival by DNA methyltransferases

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.

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

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.

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

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.

A candidate protective factor in amyotrophic lateral sclerosis:heterogenous nuclear ribonucleoprotein G

Heterogenous nuclear ribonucleoprotein G is down-regulated in the spinal cord of the Tg(SOD1*G93A)1Gur(TG)amyotrophic lateral sclerosis mouse model.However,most studies have only examined heterogenous nuclear ribonucleoprotein G expression in the amyotrophic lateral sclerosis model and heterogenous nuclear ribonucleoprotein G effects in amyotrophic lateral sclerosis pathogenesis such as in apoptosis are unknown.In this study,we studied the potential mechanism of heterogenous nuclear ribonucleoprotein G in neuronal death in the spinal cord of TG and wild-type mice and examined the mechanism by which heterogenous nuclear ribonucleoprotein G induces apoptosis.Heterogenous nuclear ribonucleoprotein G in spinal cord was analyzed using immunohistochemistry and western blotting,and cell proliferation and proteins(TAR DNA binding protein 43,superoxide dismutase 1,and Bax)were detected by the Cell Counting Kit-8 and western blot analysis in heterogenous nuclear ribonucleoprotein G siRNA-transfected PC12 cells.We analyzed heterogenous nuclear ribonucleoprotein G distribution in spinal cord in the amyotrophic lateral sclerosis model at various time points and the expressions of apoptosis and proliferation-related proteins.Heterogenous nuclear ribonucleoprotein G was mainly localized in neurons.Amyotrophic lateral sclerosis mice were examined at three stages:preonset(60-70 days),onset(90-100 days)and progression(120-130 days).The number of heterogenous nuclear ribonucleoprotein G-positive cells was significantly higher in the anterior horn of the lumbar spinal cord segment of TG mice at the preonset stage than that of control group but lower than that of the control group at the onset stage.The number of heterogenous nuclear ribonucleoprotein G-positive cells in both central canal and surrounding gray matter of the whole spinal cord of TG mice at the onset stage was significantly lower than that in the control group,whereas that of the lumbar spinal cord segment of TG mice was significantly higher than that in the control group at preonset stage and significantly lower than that in the control group at the progression stage.The numbers of heterogenous nuclear ribonucleoprotein G-positive cells in the posterior horn of cervical and thoracic segments of TG mice at preonset and progression stages were significantly lower than those in the control group.The expression of heterogenous nuclear ribonucleoprotein G in the cervical spinal cord segment of TG mice was significantly higher than that in the control group at the preonset stage but significantly lower at the progression stage.The expression of heterogenous nuclear ribonucleoprotein G in the thoracic spinal cord segment of TG mice was significantly increased at the preonset stage,significantly decreased at the onset stage,and significantly increased at the progression stage compared with the control group.heterogenous nuclear ribonucleoprotein G expression in the lumbar spinal cord segment of TG mice was significantly lower than that of the control group at the progression stage.After heterogenous nuclear ribonucleoprotein G gene silencing,PC12 cell survival was lower than that of control cells.Both TAR DNA binding protein 43 and Bax expressions were significantly increased in heterogenous nuclear ribonucleoprotein G-silenced cells compared with control cells.Our study suggests that abnormal distribution and expression of heterogenous nuclear ribonucleoprotein G might play a protective effect in amyotrophic lateral sclerosis development via preventing neuronal death by reducing abnormal TAR DNA binding protein 43 generation in the spinal cord.

Mechanisms of neuroplasticity and brain degeneration: strategies for protection during the aging process

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.

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

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 (P<0.05).Conclusion The main factors involved in the development of neuronal death during postischemic normothermic reperfusion in rabbits include hypermetabolism, deactivation of N + a,K + ATPase, release of excitatory amino acids and disorder of neuropeptides.

Neuroprotection of Chrysanthemum indicum Linne against cerebral ischemia/reperfusion injury by anti-inflammatory effect in gerbils

In this study, we tried to verify the neuroprotective effect of Chrysanthemum indicum Linne（CIL） extract, which has been used as a botanical drug in East Asia, against ischemic damage and to explore the underlying mechanism involving the anti-inflammatory approach. A gerbil was given CIL extract for 7 consecutive days followed by bilateral carotid artery occlusion to make a cerebral ischemia/reperfusion model. Then, we found that CIL extracts protected pyramidal neurons in the hippocampal CA1 region（CA1） from ischemic damage using neuronal nucleus immunohistochemistry and Fluoro-Jade B histofluorescence. Accordingly, interleukin-13 immunoreactivities in the CA1 pyramidal neurons of CIL-pretreated animals were maintained or increased after cerebral ischemia/reperfusion. These findings indicate that the pre-treatment of CIL can attenuate neuronal damage/death in the brain after cerebral ischemia/reperfusion via an anti-inflammatory approach.

Implications of enolase in the RANKL-mediated osteoclast activity following spinal cord injury

Spinal Cord Injury(SCI)is a debilitating condition characterized by damage to the spinal cord,resulting in loss of function,mobility,and sensation.Although increasingly prevalent in the US,no FDA-approved therapy exists due to the unfortunate complexity of the condition,and the difficulties of SCI may be furthered by the development of SCI-related complications,such as osteoporosis.SCI demonstrates two crucial stages for consideration:the primary stage and the secondary stage.While the primary stage is suggested to be immediate and irreversible,the secondary stage is proposed as a promising window of opportunity for therapeutic intervention.Enolase,a metabolic enzyme upregulated after SCI,performs non-glycolytic functions,promoting inflammatory events via extracellular degradative actions and increased production of inflammatory cytokines and chemokines.Neuron-specific enolase(NSE)serves as a biomarker of functional damage to neurons following SCI,and the inhibition of NSE has been demonstrated to reduce signs of secondary injury of SCI and to ameliorate dysfunction.This Viewpoint article involves enolase activation in the regulation of RANK-RANKL pathway and summarizes succinctly the mechanisms influencing osteoclast-mediated resorption of bone in SCI.Our laboratory proposes that inhibition of enolase activation may reduce SCI-induced inflammatory response and decrease osteoclast activity,limiting the chances of skeletal tissue loss in SCI.