Inducible nitric oxide synthase expression in the ischemic core and penumbra after transient focal cerebral ischemia in mice

Zhu, Dawei; Deng, Qiang; Yao, Honghong; Wang, Dongchun; Deng, Ying; Liu, Guoqing

doi:10.1016/s0024-3205(02)01970-7

Cited by 76 publications

(61 citation statements)

References 45 publications

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“…Our observation that microglia activated by the mGluRII agonist, DCG-IV, secreted TNF-␣ (but not nitric oxide), and that TNF-␣ was required for neuron killing, is consistent with earlier studies using the same stimulus (Taylor et al, 2002(Taylor et al, , 2005. Some studies found that inhibiting iNOS was neuroprotective (Galea et al, 1998;Zhang and Stanimirovic, 2002) and reduced infarct size in vivo after focal ischemia (Zhu et al, 2002). We found that iNOS and peroxynitrite were not re- A higher-magnification image shows a typical microglial cell with processes abutting the neuronal cell body (near top) and wrapping around the axonal processes.…”

Section: Discussionsupporting

confidence: 91%

Mechanisms of Microglia-Mediated Neurotoxicity in a New Model of the Stroke Penumbra

Kaushal¹,

Schlichter²

2008

J. Neurosci.

297

225

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After an ischemic stroke, neurons in the core are rapidly committed to die, whereas neuron death in the slowly developing penumbra is more amenable to therapeutic intervention. Microglia activation contributes to delayed inflammation, but because neurotoxic mechanisms in the penumbra are not well understood, we developed an in vitro model of microglia activation and propagated neuron killing. To recapitulate inflammatory triggers in the core, microglia were exposed to oxygen glucose-deprived neurons and astrocytes. To model the developing penumbra, the microglia were washed and allowed to interact with healthy naive neurons and astrocytes. We found that oxygen-glucose deprivation (OGD)-stressed neurons released glutamate, which activated microglia through their group II metabotropic glutamate receptors (mGluRs). Microglia activation involved nuclear factor B (NF-B), a transcription factor that promotes their proinflammatory functions. The activated microglia became neurotoxic, killing naive neurons through an apoptotic mechanism that was mediated by tumor necrosis factor-␣ (TNF-␣), and involved activation of both caspase-8 and caspase-3. In contrast to some earlier models (e.g., microglia activation by lipopolysaccharide), neurotoxicity was not decreased by an inducible nitric oxide synthase (iNOS) inhibitor (S-methylisothiourea) or a peroxynitrite scavenger [5,10,15,20-tetrakis(N-methyl-4Ј-pyridyl)porphinato iron (III) chloride], and did not require p38 mitogen-activated protein kinase (MAPK) activation. The same microglia neurotoxic behavior was evoked without exposure to OGD-stressed neurons, by directly activating microglial group II mGluRs with (2S,2ЈR,3ЈR)-2-(2Ј3Ј-dicarboxycyclopropyl) glycine or glutamate, which stimulated production of TNF-␣ (not nitric oxide) and mediated TNF-␣-dependent neurotoxicity through activation of NF-B (not p38 MAPK). Together, these results support potential therapeutic strategies that target microglial group II mGluRs, TNF␣ overproduction, and NF-B activation to reduce neuron death in the ischemic penumbra.

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Section: Discussionsupporting

confidence: 91%

Mechanisms of Microglia-Mediated Neurotoxicity in a New Model of the Stroke Penumbra

Kaushal¹,

Schlichter²

2008

J. Neurosci.

297

225

View full text Add to dashboard Cite

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“…The generation of new neurons in the adult mammalian hippocampus is thought to play a role in repairing the brain after injury. There is a study indicated that expression of iNOS is necessary for ischemia-stimulated cell birth in the dentate gyrus and that activation of iNOS may provide a possible strategy for functional recovery from cerebral ischemic insult (Zhu et al, 2002). In the present study, a significant increase of expression of iNOS mRNA was observed by using RT-PCR method, the result is in agreement with above reports.…”

supporting

confidence: 93%

Protective Effect of Pharmacological Preconditioning of Total Flavones of Abelmoschl Manihot on Cerebral Ischemic Reperfusion Injury in Rats

Wen

Chen

2007

Am. J. Chin. Med.

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The present study was to investigate the effect of pharmacological preconditioning of total flavones of Abelmoschl Manihot (TFA) on cerebral ischemic reperfusion injury in rats. Rat cerebral ischemia/reperfusion injury was induced by occluding the right middle cerebral artery (MCA). The infarct size was determined by staining with 2,3,5-triphenyl tetrazalium chloride (TTC). The serum malonaldehyde (MDA), nitric oxide (NO) and lactate dehydrogenase (LDH) levels were measured by using spectrophotometry; Inducible NO synthase (iNOS) mRNA expression was detected by RT-PCR method. The percentage of cerebral infarction volume was 28.1 ± 0.8 in the model group, while TFA or nimodipine (Nim) pretreatment 36 hours prior to the ischemic insult significantly decreased the infarction volume. Increases of serum LDH activity and MDA level were observed after ischemia/reperfusion, but these changes were inhibited in rats pretreated with either TFA (20, 40, 80, 160 mg/kg) or Nim, indicating a delayed protective effect of TFA preconditioning on cerebral ischemic reperfusion injury. In addition, the serum NO level and the cerebral iNOS mRNA were up-regulated, suggesting a possible mechanism for the protective effect of TFA pretreatment on cerebral ischemic reperfusion injury.

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“…[57][58][59][60] The onset of the ischemic insult induces a progressive increase in iNOS expression that peaks 24 to 48 hours later. 61 Moreover, inhibition of iNOS results in a significant decrease in the volume of the ischemic lesion 48 hours after MCAO. 21,35 The increase in the expression of iNOS after MCAO is originated in infiltrating cells, astrocytes, and microglia.…”

Section: Discussionmentioning

confidence: 99%

Tissue-Type Plasminogen Activator and the Low-Density Lipoprotein Receptor-Related Protein Mediate Cerebral Ischemia-Induced Nuclear Factor-κB Pathway Activation

Zhang

Polavarapu

She

et al. 2007

The American Journal of Pathology

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Tissue-type plasminogen activator (tPA) is a serine proteinase found in the intravascular space and the central nervous system. The low-density lipoprotein receptor-related protein (LRP) is a member of the low-density lipoprotein receptor gene family found in neurons and astrocytes. Cerebral ischemia induces activation of the nuclear factor (NF)-B pathway. The present study investigated the role that the interaction between tPA and LRP plays on middle cerebral artery occlusion (MCAO)-induced NF-B-mediated inflammatory response. We found that MCAO increased LRP expression primarily in astrocytes and that this effect was significantly decreased in the absence of tPA. The onset of the ischemic insult induced activation of the NF-B pathway in wild-type and plasminogen (Plg ؊/؊ )-deficient mice, and this effect was attenuated after inhibition of LRP or genetic deficiency of tPA. Moreover, administration of tPA to tPA ؊/؊ mice resulted in activation of the NF-B pathway comparable with that observed in wild-type and Plg ؊/؊ mice. We also report that inhibition of either tPA activity or LRP or genetic deficiency of tPA resulted in a significant decrease in MCAO-induced nitric oxide production and inducible nitric-oxide synthase expression. In conclusion, our results demonstrate that after MCAO the interaction between tPA and LRP results in NF-B activation in astrocytes and induction of inducible nitric-oxide synthase expression in the ischemic tissue , suggesting a cytokine-like plasminogen-independent role for tPA during cerebral ischemia.

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Inducible nitric oxide synthase expression in the ischemic core and penumbra after transient focal cerebral ischemia in mice

Cited by 76 publications

References 45 publications

Mechanisms of Microglia-Mediated Neurotoxicity in a New Model of the Stroke Penumbra

Mechanisms of Microglia-Mediated Neurotoxicity in a New Model of the Stroke Penumbra

Protective Effect of Pharmacological Preconditioning of Total Flavones of Abelmoschl Manihot on Cerebral Ischemic Reperfusion Injury in Rats

Tissue-Type Plasminogen Activator and the Low-Density Lipoprotein Receptor-Related Protein Mediate Cerebral Ischemia-Induced Nuclear Factor-κB Pathway Activation

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