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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both excitotoxicity and apoptosis contribute to neuronal loss in various neurodegenerative diseases such as Alzheimer's disease as well as stroke, and a drug inhibiting both types of cell death may lead to practical treatment for these diseases. Post-treatment with troglitazone, a potent and specific activator of peroxisome proliferator-activated receptor (PPAR)-gamma attenuated the cell death of cerebellar granule neurons, triggered by glutamate exposure. The inhibitory effect of troglitazone against glutamate excitotoxicity, in vitro, was observed even when added 2.5 h after the end of glutamate exposure, a time when glutamate antagonists are no longer neuroprotective. However, troglitazone did not block the glutamate-induced elevation of calcium influx, suggesting that troglitazone interfered with downstream consequences of excitotoxic glutamate receptor overactivation. In addition, troglitazone also suppressed low-potassium-induced apoptosis in cerebellar granule neurons in a phosphatidylinositol 3-kinase independent manner. In conclusion, although the mechanisms of troglitazone's neuroprotective effects are unknown, the post-treatment-neuroprotective effect and the dual-inhibitory-activity against both excitotoxicity and apoptosis may provide a novel therapy for various neurodegenerative diseases.
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PMID:Troglitazone inhibits both post-glutamate neurotoxicity and low-potassium-induced apoptosis in cerebellar granule neurons. 1175 Sep 8

Protein kinase B/Akt possesses prosurvival and antiapoptotic activities and is involved in growth factor-mediated neuronal protection. In this study we establish Akt deactivation as a causal mediator of cell death. Akt deactivation occurs in multiple models of cell death including N-methyl-d-aspartate excitotoxicity, vascular stroke, and nitric oxide (NO)- and hydrogen peroxide (H2O2)-elicited death of HeLa, PC12, and Jurkat T cells. Akt deactivation characterizes both caspase-dependent and -independent cell death. Conditions rescuing cell death, such as treatment with poly(ADP-ribose) polymerase or NO synthase inhibitors and preconditioning with sublethal concentrations of N-methyl-d-aspartate, restore Akt activity. Infection of neurons with adenovirus expressing constitutively active Akt prevents excitotoxicity, whereas phosphatidylinositol 3-kinase inhibitors or infection with dominant negative Akt induce death of untreated neuronal cells.
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PMID:Akt as a mediator of cell death. 1450 98

1. Reactive oxygen species and oxidative state are slowly gaining acceptance in having a physiological relevance rather than just being the culprits in pathophysiological processes. The control of the redox environment of the cell provides for additional regulation in relation to signal transduction pathways. Conversely, aberrant regulation of oxidative state manifesting as oxidative stress can predispose a cell to adverse outcome. 2. The phosphatidylinositol 3-kinase/akt pathway is one such pathway that is partially regulated via oxidative state and, in an oxidative stress paradigm such as ischaemic-reperfusion injury, may be inactivated, which can lead to exacerbation of cell death. 3. Activation of nuclear factor (NF)-kappaB has been associated with oxidative stress. The role of NF-kappaB in neuronal cell death is widely debated, with major studies highlighting both a pro- and anti-apoptotic role for NF-kappaB, with the outcome being region, stimulus, dose and duration specific. 4. Oxidative state plays a key role in the regulation and control of numerous signal transduction pathways in the cell. Elucidating the mechanisms behind oxidative stress-mediated neuronal cell death is important in identifying potential putative targets for the treatment of diseases such as stroke.
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PMID:Impact of oxidative stress on neuronal survival. 1523 24

Cumulative evidence suggests that apoptosis plays a pivotal role in neuronal death after cerebral ischemia in various experimental animal models. The time-dependent molecular and biochemical sequelae that lead to apoptotic cell death after the interruption of cerebral blood flow have been established. Many neuroprotective agents that target cell death pathways have been failures, and alternative strategies need to be considered. One such strategy is to target the neuronal survival signaling pathway, which involves the phosphatidylinositol 3-kinase (PI3-K)/Akt (protein kinase B) pathway. It has been demonstrated that PI3-K/Akt and downstream phosphorylated Bad and proline-rich Akt substrate survival signaling cascades are upregulated in surviving neurons in the ischemic brain that overexpresses copper-zinc superoxide dismutase activity. These studies provide an impetus for novel therapeutic targets in neuroprotective strategies in stroke.
Stroke 2004 Nov
PMID:Future targets and cascades for neuroprotective strategies. 1538 4

Lithium has emerged as a neuroprotective agent efficacious in preventing apoptosis-dependent cellular death. Lithium neuroprotection is provided through multiple, intersecting mechanisms, although how lithium interacts with these mechanisms is still under investigation. Lithium increases cell survival by inducing brain-derived neurotrophic factor and thereby stimulating activity in anti-apoptotic pathways, including the phosphatidylinositol 3-kinase/Akt and the mitogen-activated protein kinase pathways. In addition, lithium reduces pro-apoptotic function by directly and indirectly inhibiting glycogen synthase kinase-3beta activity and indirectly inhibiting N-methyl-D-aspartate (NMDA)-receptor-mediated calcium influx. Lithium-induced regulation of anti- and pro-apoptotic pathways alters a wide variety of downstream effectors, including beta-catenin, heat shock factor 1, activator protein 1, cAMP-response-element-binding protein, and the Bcl-2 protein family. Lithium neuroprotection has a wide variety of clinical implications. Beyond its present use in bipolar mood disorder, lithium's neuroprotective abilities imply that it could be used to treat or prevent brain damage following traumatic injury, such as stroke, and neurodegenerative diseases such as Huntington's and Alzheimer's diseases.
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PMID:Lithium neuroprotection: molecular mechanisms and clinical implications. 1548 56

Rai (Shc C or N-Shc) is a neuron-specific member of the family of Shc-like adaptor proteins. Rai functions in the cytoplasmic propagation of Ret-dependent survival signals and regulates, in vivo, the number of sympathetic neurons. We report here a function of Rai, i.e., the regulation of the neuronal adaptive response to environmental stresses. We demonstrate that (i) primary cultures of cortical neurons from Rai-/- mice are more sensitive to apoptosis induced by hypoxia or oxidative stress; (ii) in Rai-/- mice, ischemia/reperfusion injury induces severe neurological deficits, increased apoptosis and size of the infarct area, and significantly higher mortality; and (iii) Rai functions as a stress-response gene that increases phosphatidylinositol 3-kinase activation and Akt phosphorylation after hypoxic or oxidation insults. These data suggest that Rai has a functional neuroprotective role in brain injury, with possible implications in the treatment of stroke.
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PMID:The Rai (Shc C) adaptor protein regulates the neuronal stress response and protects against cerebral ischemia. 1549 42

The estrogen 17beta-estradiol has profound effects on the brain throughout life, whereas 17alpha-estradiol, the natural optical isomer, is generally considered less active because it binds less avidly to estrogen receptors. On the contrary, recent studies in the brain document that 17alpha-estradiol elicits rapid and sustained activation of the MAPK/ERK and phosphatidylinositol 3-kinase-Akt signaling pathways; is neuroprotective, after an ischemic stroke and oxidative stress, and in transgenic mice with Alzheimer's disease; and influences spatial memory and hippocampal-dependent synaptic plasticity. The present study measured the endogenous content of 17alpha-estradiol in the brain and further clarified its actions and kinetics. Here we report that: 1) endogenous levels of 17alpha-estradiol and its precursor estrone are significantly elevated in the postnatal and adult mouse brain and adrenal gland of both sexes, as determined by liquid chromatography/tandem mass spectrometry; 2) 17alpha-estradiol and 17beta-estradiol bind estrogen receptors with similar binding affinities; 3) 17alpha-estradiol transactivates an estrogen-responsive reporter gene; and 4) unlike 17beta-estradiol, 17alpha-estradiol does not bind alpha-fetoprotein or SHBG, the estrogen-binding plasma proteins of the developing rodent and primate, respectively. 17alpha-Estradiol was also found in the brains of gonadectomized or gonadectomized/adrenalectomized mice, supporting the hypothesis that 17alpha-estradiol is locally synthesized in the brain. These findings challenge the view that 17alpha-estradiol is without biological significance and suggest that 17alpha-estradiol and its selective receptor, ER-X, are not part of a classical hormone/receptor endocrine system but of a system with important autocrine/paracrine functions in the developing and adult brain. 17alpha-Estradiol may have enormous implications for hormone replacement strategies at the menopause and in the treatment of such neurodegenerative disorders as Alzheimer's disease and ischemic stroke.
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PMID:17alpha-estradiol: a brain-active estrogen? 1594 6

Mitochondria are the powerhouse of the cell. Their primary physiological function is to generate ATP through oxidative phosphorylation via the electron transport chain. Reactive oxygen radicals generated from mitochondria have been implicated in acute brain injuries, like stroke and neurodegeneration. Recent studies have shown that mitochondrially formed oxidants are mediators of molecular signaling and have implicated mitochondria-dependent apoptosis involving pro- and antiapoptotic protein binding, the release of cytochrome c and Smac, the activation of downstream caspase-9 and -3, and the fragmentation of DNA. Oxidative stress and the redox state are also implicated in the survival signaling pathway that involves phosphatidylinositol 3-kinase (PI3-K)/Akt and downstream signaling molecular bindings like Bad/Bcl-X(L) and phosphorylated Bad/14-3-3. Genetically modified mice (SOD1, SOD2) or rats that overexpress or are deficient in superoxide dismutase have provided strong evidence in support of the role of mitochondrial dysfunction and oxidative stress as determinants of neuronal death/survival after stroke and neurodegeneration.
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PMID:Mitochondrial dysfunction and oxidative stress as determinants of cell death/survival in stroke. 1596 64

Proneuronal basic helix-loop-helix (bHLH) transcription factor, neurogenin 1 (Ngn1), regulates neuronal differentiation during development of the cerebral cortex. Akt mediates proneuronal bHLH protein function to promote neuronal differentiation. Here, we show that recombinant human erythropoietin (rhEPO) significantly increased Akt activity and Ngn1 mRNA levels in neural progenitor cells derived from the subventricular zone (SVZ) of adult rat, which was coincident with increases of neural progenitor cell proliferation, differentiation, and neurite outgrowth. Inhibition of Akt activity by the phosphatidylinositol 3-kinase/Akt (PI3K/Akt) inhibitor, LY294002, abolished rhEPO-increased Ngn1 mRNA levels and the effects of rhEPO on neural progenitor cells. In addition, reducing expression of endogenous Ngn1 by means of short-interfering RNA (siRNA) blocked rhEPO-enhanced neuronal differentiation and neurite outgrowth but not rhEPO-increased proliferation. Furthermore, treatment of stroke rat with rhEPO significantly increased Ngn1 mRNA levels in SVZ cells. These data suggest that rhEPO acts as an extracellular molecule that activates the PI3K/Akt pathway, which enhances adult neural progenitor cell proliferation, differentiation, and neurite outgrowth, and Ngn1 is required for Akt-mediated neuronal differentiation and neurite outgrowth.
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PMID:Neurogenin 1 mediates erythropoietin enhanced differentiation of adult neural progenitor cells. 1613 56

Cell survival is regulated by the balance between death and survival signals. Previous studies have shown that the N-methyl-d-aspartate receptors (NMDARs) are responsible for the glutamate-induced excitotoxicity in the postischemic brain. Meanwhile, nerve growth factor (NGF) is critically involved in cell survival and neuroprotective effects via the extracellular signal-related kinase (ERK) pathway or the phosphatidylinositol 3-kinase (PI3-K) pathway mediated by the high affinity NGF receptor, tropomyosin-related kinase A (TrkA). Clinically, electroacupuncture (EA) has been shown to produce beneficial effects on stroke patients. However, the detailed mechanisms mediating the beneficial effects of EA on stroke are still unknown. In the present study, we found that EA treatment reversed the high expression of NR1 subunit and up-regulated the level of TrkA in a rat model of middle cerebral artery occlusion. Using protein kinase inhibitors of specific intracellular signaling pathways, we found that the neuroprotective effects of EA appear to be mediated by stimulation of the PI3-K pathway, but not ERK pathway. These findings may provide important experimental evidence for the clinical application of EA treatment for stroke patients.
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PMID:Electroacupuncture regulates NMDA receptor NR1 subunit expression via PI3-K pathway in a rat model of cerebral ischemia-reperfusion. 1628 3


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