Molecular mechanisms of cerebral ischemia-induced neuronal death

Hou, Sheng T.; MacManus, J. P.

doi:10.1016/s0074-7696(02)21011-6

Cited by 172 publications

(126 citation statements)

References 332 publications

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“…NMDA receptor antagonists, such as MK-801, primarily protect against ischemic cell death, whereas antioxidants, such as those found in extracts of GT, block only hypoxic cell death. These results indicate that neuronal cell death is controlled by several different signaling pathways (18). Intracellular Ca 2ϩ is a key mediator of H͞H-induced cell death predominantly via necrosis (19).…”

Section: Discussionmentioning

confidence: 99%

A multifunctional cytoprotective agent that reduces neurodegeneration after ischemia

Jiang

Lu²,

Nelson³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Section: Discussionmentioning

confidence: 99%

A multifunctional cytoprotective agent that reduces neurodegeneration after ischemia

Jiang

Lu²,

Nelson³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Release and metabolism of AA through the phospholipase A 2 (PLA 2 )/ PTGS pathway is increased during excitotoxicity [12], a process that involves the over activation of brain excitatory neurotransmission. Kainic acid (KA), the prototypic excitotoxin, binds to the KA receptors in the brain and induces seizures that result in inflammation, oxidative damage and neuronal death, processes that have been implicated in neurological, neurodegenerative and psychiatric diseases [16,20,40,49,52,66,68,71,72]. Although it has been demonstrated that PTGS plays a role in excitotoxicity, the distinct role of the two PTGS isoforms has not been fully established.…”

Section: Introductionmentioning

confidence: 99%

Altered GABAergic neurotransmission is associated with increased kainate-induced seizure in prostaglandin-endoperoxide synthase-2 deficient mice

Toscano

Ueda

Tomita

et al. 2008

Brain Research Bulletin

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Excitotoxicity involves over activation of brain excitatory glutamate receptors and has been implicated in neurological, neurodegenerative and neuropsychiatric diseases. Metabolism of arachidonic acid (AA) through the phospholipase A 2 (PLA 2 )/ prostaglandin-endoperoxide synthase (PTGS) pathway is increased after excitotoxic stimulation. However, the individual roles of the PTGS isoforms in this process are not well established. We assessed the role of the PTGS isoforms in the process of excitotoxicity by exposing mice deficient in either PTGS-1 (PTGS-1 -/-) or PTGS-2 (PTGS-2 -/-) to the rototypic excitotoxin, kainic acid (KA). Seizure intensity and neuronal damage were significantly elevated in KA-exposed PTGS-2 -/-, but not in PTGS-1 -/-, mice. The increased susceptibility was not associated with an alteration in KA receptor binding activity or mediated through the CB1 endocannabinoid receptor. The frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) was decreased in the CA1 pyramidal neurons of PTGS-2 -/-mice, suggesting an alteration of GABAergic function. In wild-type mice, six weeks treatment with the PTGS-2 selective inhibitor celecoxib recapitulated the increased susceptibility to KA-induced excitotoxicity observed in PTGS-2 -/-mice, further supporting the role of PTGS-2 in the excitotoxic process. The increased susceptibility to KA was also associated with decreased brain levels of PGE 2 , a biomarker of PTGS-2 activity. Our results suggest that PTGS-2 activity and its specific products may modulate neuronal excitability by affecting GABAergic neurotransmission. Further, inhibition of PTGS-2 but not PTGS-1, may increase the susceptibility to seizures.

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“…It has been shown that KYNA is an antagonist of the glycine site of NMDA and of the α-7 nicotinic acetylcholine receptors [19,20] as well as a ligand for the orphan G-protein coupled receptor, GPR 35 [21] . Excessive or persistent activation of glutamate receptors in the mammalian central nervous system results in neuronal death, contributing to brain damage in stroke, trauma, epilepsy [22] or other neurodegenerative disorders [23] .…”

Section: Discussionmentioning

confidence: 99%

Kynurenic acid attenuates multiorgan dysfunction in rats after heatstroke

Hsieh

Chen

Yeh³

et al. 2011

Acta Pharmacol Sin

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IntroductionHeatstroke is defined as a form of excessive hyperthermia (>40 °C) associated with a systemic inflammatory response that leads to multi-organ dysfunction in which central nervous system (CNS) disorders such as delusion, convulsion and coma predominate [1] . Our recent results have demonstrated that heatstroke rodents display hypotension, systemic inflammatory responses, hypothalamic ischemia and neuronal damage, and multi-organ dysfunction [2][3][4] .Kynurenic acid (KYNA) or its metabolic precursor L-kynurenine may be of therapeutic value in neurodegenerative diseased models [5,6] . For example, systemically administered high doses of KYNA had a neuroprotective effect in the gerbil model of global ischemia [7] . Both the homocysteine-induced impairment of endothelial cells [8] and the motility and inflammatory activation in the early phase of acute experimental colitis in the rat [9] were significantly reduced by administration of KYNA. The aim of this study was to investigate whether the heatstroke induced hypotension, systemic inflammatory responses, hypothalamic ischemia and damage, and multiorgan dysfunction could be attenuated by KYNA preconditioning. Accordingly, the temporal profiles of the apoptotic cell numbers of spleen, kidney, liver, lung, and hypothalamus, Kynurenic acid attenuates multiorgan dysfunction in rats after heatstroke Aim: To assess whether systemic delivery of kynurenic acid improves the outcomes of heatstroke in rats. Methods: Anesthetized rats were divided into 2 major groups and given vehicle solution (isotonic saline 0.3 mL/kg rat weight) or kynurenic acid (30-100 mg in 0.3 mL saline/kg) 4 h before the start of thermal experiments. They were exposed to an ambient temperature of 43 ºC for 68 min to induce heatstroke. Another group of rats were exposed to room temperature (26 ºC) and used as normothermic controls. Their core temperatures, mean arterial pressures, serum levels of systemic inflammatory response molecules, hypothalamic values of apoptotic cells and neuronal damage scores, and spleen, liver, kidney and lung values of apoptotic cells were determined. Results: The survival time values during heatstroke for vehicle-treated rats were decreased from the control values of 475-485 min to new values of 83-95 min. Treatment with KYNA (30-100 mg/kg, iv) 4 h before the start of heat stress significantly and dose-dependently decreased the survival time to new values of 152-356 min (P<0.05). Vehicle-treated heatstroke rats displayed hypotension, hypothalamic neuronal degeneration and apoptosis, increased serum levels of tunor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and interleukin-10 (IL-10), and spleen, liver, kidney, and lung apoptosis. KYNA preconditioning protected against hypotension but not hyperthermia and attenuated hypothalamic neuronal degeneration and apoptosis during heatstroke. KYNA preconditioning attenuated spleen, kidney, liver, and lung apoptosis and up-regulated serum IL-10 levels but down-regulated serum TNF-α and ICAM-1 lev...

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Molecular mechanisms of cerebral ischemia-induced neuronal death

Cited by 172 publications

References 332 publications

A multifunctional cytoprotective agent that reduces neurodegeneration after ischemia

A multifunctional cytoprotective agent that reduces neurodegeneration after ischemia

Altered GABAergic neurotransmission is associated with increased kainate-induced seizure in prostaglandin-endoperoxide synthase-2 deficient mice

Kynurenic acid attenuates multiorgan dysfunction in rats after heatstroke

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