Inhibition of iNOS activity by 1400W decreases glutamate release and ameliorates stroke outcome after experimental ischemia

Pérez-Asensio, Fernando J.; Hurtado, Olivia; Burguete, Marı́a C.; Moro, Marı́a A.; Salom, Juan B.; Lizasoaín, Ignacio; Torregrosa, Germán; Leza, Juan C.; Alborch, Enrique; Castillo, José; Knowles, Richard G.; Lorenzo, Pedro

doi:10.1016/j.nbd.2004.10.018

Cited by 91 publications

(60 citation statements)

References 57 publications

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“…Inhibiting iNOS activity decreases glutamate release and improves stroke outcomes after experimental ischemia (Perez-Asensio et al, 2005). Similarly, we found that blockade of NO production from iNOS either with a specific inhibitor, aminoguanidine, or in an iNOS gene knockout significantly attenuated KA-induced neuronal death.…”

Section: Discussionsupporting

confidence: 63%

Kainic Acid-induced Neuronal Death is Attenuated by Aminoguanidine but Aggravated by L-NAME in Mouse Hippocampus

Byun

Lee

Jeon

et al. 2009

Korean J Physiol Pharmacol

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Nitric oxide (NO) has both neuroprotective and neurotoxic effects depending on its concentration and the experimental model. W e tested the effects of NG-nitro-L-arginine methyl ester (L-NAME), a nonselective nitric oxide synthase (NOS) inhibitor, and aminoguanidine, a selective inducible NOS (iNOS) inhibitor, on kainic acid (KA)-induced seizures and hippocampal CA3 neuronal death. L-NAME (50 mg/kg, i.p.) and/or aminoguanidine (200 mg/kg, i.p.) were administered 1 h prior to the intracerebroventricular (i.c.v.) injection of KA. Pretreatment with L-NAME significantly increased KA-induced CA3 neuronal death, iNOS expression, and activation of microglia. However, pretreatment with aminoguanidine significantly suppressed both the KA-induced and L-NAME-aggravated hippocampal CA3 neuronal death with concomitant decreases in iNOS expression and microglial activation. The protective effect of aminoguanidine was maintained for up to 2 weeks. Furthermore, iNOS knockout mice (iNOS − /− ) were resistant to KA-induced neuronal death. The present study demonstrates that aminoguanidine attenuates KA-induced neuronal death, whereas L-NAME aggravates neuronal death, in the CA3 region of the hippocampus, suggesting that NOS isoforms play different roles in KA-induced excitotoxicity.

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Section: Discussionsupporting

confidence: 63%

Kainic Acid-induced Neuronal Death is Attenuated by Aminoguanidine but Aggravated by L-NAME in Mouse Hippocampus

Byun

Lee

Jeon

et al. 2009

Korean J Physiol Pharmacol

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“…It has been reported that pathologic amount of NO from iNOS contributes to detrimental neuronal damages such as neurological disorder (Koprowski et al, 1993;Sugimoto and Iadecola, 2002) and apoptotic cell death . It has been also reported that inhibition of iNOS activity decreases glutamate release and improves stroke outcome after experimental ischemia (Perez-Asensio et al, 2005). In accordance with previous reports, the present study demonstrated that celecoxib attenuated KA-induced iNOS expression, which was proportional to the degree of neuronal cell death in CA3 region.…”

Section: Discussionsupporting

confidence: 93%

Celecoxib Attenuates Kainic Acid-induced Neuronal Cell Death Through Suppression of Microglial c-Jun N-terminal Kinase Phosphorylation

et al. 2009

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In the present study, neuroprotective property of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, and its underlying mechanism were examined in the animal model of kainic acid (KA)-induced excitotoxicity. KA, administered intracerebroventricularly (i.c.v.), induced marked neuronal cell death with concurrent microglial activation and subsequent induction of inducible nitric oxide synthase (iNOS) in the hippocampus. Histopathological analysis demonstrated that celecoxib (100 mg/kg), pre-treated 1 hr before or post-treated 2 hr after KA i.c.v. injection, significantly attenuated KA-induced death of pyramidal neurons in CA3 region. Celecoxib obviously suppressed KA-induced microglial activation and subsequent iNOS expression. KAinduced phosphorylation of c-Jun N-terminal kinases (JNK) was attenuated with celecoxib treatments. The results of the present study demonstrate that suppression of JNK phosphorylation by celecoxib contributes to its neuroprotective action against KA-induced excitotoxicity suggesting that celecoxib may be a potentially valuable in the treatment of acute brain pathologies associated with excitotoxic neuronal damage such as epilepsy, stroke, and traumatic brain injury.

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“…In fact, we have demonstrated that mice that express TLR4 normally (C3H/HeN) and received a treatment with 1400W, a specific iNOS inhibitor, after the ischemic insult show a partial protective effect, as indicated by a recovery in the neurological deficit and a reduction in the infarct volume, which is quantitatively similar to previously reported data. 16,27 Similar to iNOS, TLR4 is also able to trigger the expression of COX-2 via nuclear factor -B translocation. 8,28,29 This enzyme also participates in the ischemic inflammatory cascade and in the subsequent ischemic brain damage.…”

Section: Discussionmentioning

confidence: 99%

“…15 Two groups of C3H/HeN mice were treated with 20 and 40 mg/kg N-(3-(aminomethyl)benzyl) acetamidine (1400W, a specific iNOS inhibitor, donated by GlaxoSmithKline, Stevenage, Herts, UK) at 8-hour intervals by an intraperitoneal injection volume of 0.25 mL/100 g body weight during 1 day after MCAO (nϭ6), according to previous data. 16 A group of C3H/HeN mice was also treated with 10 mg/kg NS398 (a COX-2 inhibitor). NS398 was administered intraperitoneally 3 times; 1 hour before, 1 hour after, and 6 hours after MCAO (nϭ6), as previously described.…”

Section: Induction Of Focal Cerebral Ischemiamentioning

confidence: 99%

Toll-Like Receptor 4 Is Involved in Brain Damage and Inflammation After Experimental Stroke

et al. 2007

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Background-Stroke is the second to third leading cause of death. Toll-like receptor 4 (TLR4) is a signaling receptor in innate immunity that is a specific immunologic response to systemic bacterial infection and cerebral injury. The role of TLR4 in brain ischemia has not been examined yet. We have therefore investigated whether cerebral ischemia and inflammation produced by permanent occlusion of the middle cerebral artery differ in mice that lack a functional TLR4 signaling pathway. Methods and Results-Permanent occlusion of the middle cerebral artery was performed on 2 strains of TLR4-deficient mice (C3H/HeJ and C57BL/10ScNJ) and respective controls (C3H/HeN and C57BL/10ScSn). Stroke outcome was evaluated by determination of infarct volume and assessment of neurological scores. Brains were collected 24 hours and 7 days after stroke. When compared with control mice, TLR4-deficient mice had lower infarct volumes and better outcomes in neurological and behavioral tests. Mice that lacked TLR4 had minor expression of stroke-induced interferon regulatory factor-1, inducible nitric oxide synthase, and cyclooxygenase-2, mediators implicated in brain damage. The levels of interferon-␤ and of the lipid peroxidation marker malondialdehyde were also lower in brains from TLR4-deficient mice than in those from control mice. In addition, the expression of matrix metalloproteinase-9, which is induced and mediates brain damage, was also reduced in TLR4-deficient mice after experimental stroke. Conclusions-TLR4-deficient mice have minor infarctions and less inflammatory response after an ischemic insult. These data demonstrate that TLR4 signaling and innate immunity are involved in brain damage and in inflammation triggered by ischemic injury.

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Inhibition of iNOS activity by 1400W decreases glutamate release and ameliorates stroke outcome after experimental ischemia

Cited by 91 publications

References 57 publications

Kainic Acid-induced Neuronal Death is Attenuated by Aminoguanidine but Aggravated by L-NAME in Mouse Hippocampus

Kainic Acid-induced Neuronal Death is Attenuated by Aminoguanidine but Aggravated by L-NAME in Mouse Hippocampus

Celecoxib Attenuates Kainic Acid-induced Neuronal Cell Death Through Suppression of Microglial c-Jun N-terminal Kinase Phosphorylation

Toll-Like Receptor 4 Is Involved in Brain Damage and Inflammation After Experimental Stroke

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