Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Excitotoxicity contributes to neuronal degeneration in many acute CNS diseases, including ischemia, trauma, and epilepsy, and may also play a role in chronic diseases, such as amyotrophic lateral sclerosis (ALS). Key mediators of excitotoxic damage are Ca ions (Ca(2+)), which under physiological conditions govern a multitude of cellular processes, including cell growth, differentiation, and synaptic activity. Consequently, homeostatic mechanisms exist to maintain a low intracellular Ca(2+) ion concentration so that Ca(2+) signals remain spatially and temporally localized. This permits multiple independent Ca-mediated signaling pathways to occur in the same cell. In excitotoxicity, excessive synaptic release of glutamate can lead to the disregulation of Ca(2+) homeostasis. Glutamate activates postsynaptic receptors, including the ionotropic N-methyl-D-aspartate (NMDA), 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) proprionate (AMPA), and kainate receptors. Upon their activation, these open their associated ion channel to allow the influx of Ca(2+) and Na(+) ions. Although physiological elevations in intracellular Ca(2+) are salient to normal cell functioning, the excessive influx of Ca(2+) together with any Ca(2+) release from intracellular compartments can overwhelm Ca(2+)-regulatory mechanisms and lead to cell death. Although Ca(2+) disregulation is paramount to neurodegeneration, the exact mechanism by which Ca(2+) ions actually mediate excitotoxicity is less clear. One hypothesis outlined in this review suggests that Ca(2+)-dependent neurotoxicity occurs following the activation of distinct signaling cascades downstream from key points of Ca(2+) entry at synapses, and that triggers of these cascades are physically co-localized with specific glutamate receptors. Thus, we summarize the importance of Ca(2+) regulation in mammalian neurons and the excitotoxicity hypothesis, and focus on the molecular determinants of glutamate receptor-mediated excitotoxic mechanisms.
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PMID:Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity. 1290 79

Almost all injurious stimuli, when applied below the threshold of producing injury, activate endogenous protective mechanisms that significantly decrease the degree of injury after subsequent injurious stimuli. For example, a short duration of ischemia (i.e., ischemic preconditioning [PC]) can provide significant brain protection to subsequent long-duration ischemia (i.e., ischemic tolerance [IT]). PC/IT has recently been shown in human brain, suggesting that learning more about these endogenous neuroprotective mechanisms could help identify new approaches to treat patients with stroke and other central nervous system disorders/injury. This chapter provides a brief overview of PC/IT research, illustrates the types of data that can be generated from in vivo and in vitro models to help us understand gene and protein expression related to induced neuroprotective mechanisms, and emphasizes the importance of future research on this phenomenon to help discover new mechanisms and targets for the medical treatment of brain and other end-organ injuries.
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PMID:Endogenous brain protection: models, gene expression, and mechanisms. 1545 67

Oncologic patients may suffer from acute central nervous system disorders either related to the disease itself or to its therapy. These disorders may present as a disturbance of consciousness, as mental changes, as focal neurological signs, as epileptic seizures or as a combination of these. Symptoms may be caused by cerebral metastases, hemorrhage, ischemia or infectious complication, by metabolic changes or by treatment sequealae. This article will focus on clinical presentation, diagnostic workup and possible therapy or prophylaxis of these complications.
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PMID:[Acute central nervous symptoms in oncologic patients]. 1558 Apr 62

Orexins are neuropeptides that have a range of physiological effects including the regulation of feeding behavior and the sleep-wakefulness cycle. Recently, we reported that level of orexin A in spinal fluid was decreased in the patients of some neurodegenerative diseases and it is considered that orexin A and the receptors might be related to central nervous system disorders. However, the expression and localization of orexin receptors is not elicited well. Therefore, the purpose of this study is to investigate the time-dependent changes and the cellular localization of orexin receptor focusing on orexin-1 receptor (OX1R) in the mouse brain after transient common carotid artery occlusion (tCCAO) model by using immunohistochemical techniques. OX1R immunoreactivity dramatically increased and peaked in the hippocampus and cortex 2 days after tCCAO, but remained unchanged in the hypothalamus. Using double-immunohistochemistry, the OX1R immunopositive cells at 2 days after tCCAO were co-localized not only with neuronal marker, NeuN-immunoreactivity but also with astroglial and oligodendroglial markers, GFAP- and CNPase-immunoreactivities, respectively. These results suggested that OX1R is induced other cells in addition to the neurons during stress such as ischemia and orexins and its receptor might play an important role for ischemic insult.
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PMID:Orexin-1 receptor expression after global ischemia in mice. 1562 Apr 13

Treatment with statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) reduces the risk of ischemic stroke among patients with increased risk of vascular disease. Recent experimental data point to neuroprotective properties of statins in acute cerebral ischemia. There is a proven link between bioavailability of nitric oxide and the activity of statins and ischemic stroke. Due to their ability to up-regulate nitric oxide synthase, statins have been considered in the therapy of a number of the central nervous system disorders, including cerebral ischemia, Alzheimer's disease, Parkinson's disease, tumors, and trauma. It has been claimed that they suppress inflammatory response and secondary injury after acute ischemia.
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PMID:Neuroprotective properties of statins. 1622 38

Historically, the use of regional anesthetic techniques in patients with preexisting central nervous system (CNS) disorders has been considered relatively contraindicated. The fear of worsening neurologic outcome secondary to mechanical trauma, local anesthetic toxicity, or neural ischemia is commonly reported. We examined the frequency of new or progressive neurologic complications in patients with preexisting CNS disorders who subsequently underwent neuraxial blockade. The medical records of all patients at the Mayo Clinic from the period 1988 to 2000 with a history of a CNS disorder who subsequently received neuraxial anesthesia or analgesia were retrospectively reviewed. One-hundred-thirty-nine (n = 139) patients were identified for study inclusion. Mean patient age was 60 +/- 17 yr. Gender distribution was 86 (62%) males and 53 (38%) females. An established CNS disorder diagnosis was present a mean of 23 +/- 23 yr at the time of surgical anesthesia, with 74 (53%) patients reporting active neurologic symptoms. Spinal anesthesia was performed in 75 (54%) patients, epidural anesthesia or analgesia in 58 (42%) patients, continuous spinal anesthesia in 4 (3%) patients, and a combined spinal-epidural technique in 2 (1%) patients. Bupivacaine was the local anesthetic most commonly used in all techniques. Epinephrine was added to the injectate in 72 (52%) patients. There were 15 (11%) technical complications, with the unintentional elicitation of a paresthesia and traumatic needle placement occurring most frequently. A satisfactory block was reported in 136 (98%) patients. No new or worsening postoperative neurologic deficits occurred when compared to preoperative findings (0.0%; 95% confidence interval, 0.0%-0.3%). We conclude that the risks commonly associated with neuraxial anesthesia and analgesia in patients with preexisting CNS disorders may not be as frequent as once thought and that neuraxial blockade should not be considered an absolute contraindication within this patient population.
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PMID:Neuraxial anesthesia and analgesia in patients with preexisting central nervous system disorders. 1679 Jun 57

Local environmental conditions contribute to the activation state of cells. Extracellular matrix glycoproteins participate in cell-cell boundaries within the microvascular and extravascular tissues of the central nervous system and provide a scaffold for the local environment. These conditions are altered during focal cerebral ischemia (and other central nervous system disorders) when extracellular matrix boundaries are degraded or when matrix proteins in the vascular circulation enter the neuropil as the microvascular permeability barrier is degraded. Microglia in the resting state become activated after the onset of ischemia. During activation these cells can express a number of factors and proteases, including latent matrix metalloproteinase-9 (pro-MMP-9). Whereas MMP-9 and MMP-2 are generated early during focal ischemia in select models, their cellular sources in vivo are still under study. In vitro microglia cells activate and respond to exposure to specific matrix proteins (eg, vitronectin, fibronectin) that circulate. Certain MMP inhibitors, specifically tetracycline derivatives, can modulate microglial activation and reduce injury volume in limited studies. But, the injury reduction relies on preinjury exposure to the tetracycline. Other studies underway suggest the hypothesis that microglial cell activation and pro-MMP-9 generation during focal cerebral ischemia is promoted in part by matrix proteins in the circulation that extravasate into the neuropil when the blood-brain barrier is compromised. These matrix proteins are known to activate microglia through their specific cell surface matrix receptors.
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PMID:Microglial activation and matrix protease generation during focal cerebral ischemia. 1726 8

Cumulative evidence has indicated a critical role of poly(ADP-ribose) polymerase-1 activation in ischemic brain damage. Poly(ADP-ribose) glycohydrolase (PARG) is a key enzyme in poly(ADP-ribose) catabolism. Our previous studies showed that PARG inhibitors, gallotannin (GT) and nobotanin B, can profoundly decrease oxidative cell death in vitro. Here, we tested the hypothesis that intranasal delivery of GT can decrease ischemic brain damage by inhibiting PARG. Intranasal delivery of 25 mg / kg GT within 5 hours after a 2-hour focal brain ischemia markedly decreased the infarct formation and neurological deficits of rats. The GT administration also increased poly(ADP-ribose) in the ischemic brains, suggesting that GT acts as a PARG inhibitor in vivo. Furthermore, the GT treatment abolished nuclear translocation of apoptosis-inducing factor (AIF) in the ischemic brains, suggesting that prevention of AIF translocation may contribute to the protective effects of GT. In contrast, intravenous injection of GT, at 2 hours after ischemic onset, did not reduce ischemic brain damage. Collectively, our findings suggest that PARG inhibition can significantly decrease ischemic brain injury, possibly by blocking AIF translocation. This study also highlights distinct merits of intranasal drug delivery for treating CNS diseases.
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PMID:Intranasal administration of a PARG inhibitor profoundly decreases ischemic brain injury. 1756 25

In neurotrauma, brain ischemia or neurodegenerative diseases, astrocytes become reactive (which is known as reactive gliosis) and this is accompanied by an altered expression of many genes. Two cellular hallmarks of reactive gliosis are hypertrophy of astrocyte processes and the upregulation of the part of the cytoskeleton known as intermediate filaments, which are composed of nestin, vimentin, and GFAP. Our aim has been to better understand the function of reactive astrocytes in CNS diseases. Using mice deficient for astrocyte intermediate filaments (GFAP(-/-)Vim(-/-)), we were able to attenuate reactive gliosis and slow down the healing process after neurotrauma. We demonstrated the key role of reactive astrocytes in neurotrauma-at an early stage after neurotrauma, reactive astrocytes have a neuroprotective effect; at a later stage, they facilitate the formation of posttraumatic glial scars and inhibit CNS regeneration, specifically, they seem to compromise neural graft survival and integration, reduce the extent of synaptic regeneration, inhibit neurogenesis in the old age, and inhibit regeneration of severed CNS axons. We propose that reactive astrocytes are the future target for the therapeutic strategies promoting regeneration and plasticity in the brain and spinal cord in various disease conditions. Through its involvement in inflammation, opsonization, and cytolysis, complement protects against infectious agents. Although most of the complement proteins are synthesized in CNS, the role of the complement system in the normal or ischemic CNS remains unclear. Complement activiation in the CNS has been generally considered as contributing to tissue damage. However, growing body of evidence suggests that complement may be a physiological neuroprotective mechanism as well as it may participate in maintenance and repair of the adult brain.
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PMID:The role of astrocytes and complement system in neural plasticity. 1767 57

Many central nervous system (CNS) diseases display sexual dimorphism, specifically a predilection for one gender or a gender-dependent response to treatment. Exposure to circulating sex steroids is felt to be a chief contributor to this phenomenon. However, CNS diseases of childhood and of the elderly also demonstrate gender predominance and/or sexual dimorphism response to therapies. In this short update, we provide information concerning one of the most interesting new emerging concepts related to the influence of the sex in the pathogenesis of developmental brain injuries leading to different levels of neuroprotection between genders after cerebral hypoxia-ischemia or ischemia.
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PMID:Gender-related differences in apoptotic pathways after neonatal cerebral ischemia. 1797 6


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