The Neuronal Nitric Oxide Synthase Inhibitor, 7‐Nitroindazole, Protects Against Methamphetamine‐Induced Neurotoxicity In Vivo

Itzhak, Yossef; Ali, Syed F.

doi:10.1046/j.1471-4159.1996.67041770.x

Cited by 165 publications

(107 citation statements)

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“…The protective effects of 7-NI and other nNOS inhibitors against METH-induced dopaminergic neurotoxicity were independent of METH-induced hyperthermia (Itzhak and Ali 1996;Itzhak et al 2000). Likewise, another selective nNOS inhibitor, AR-R17477AR, attenuated the depletion of DA and the neurofilament protein NF68, but not the hyperthermia, caused by METH (Sanchez et al 2003).…”

Section: Discussionmentioning

confidence: 92%

“…The interval between paired injections was 30 min, and each pair of injections was separated by 4-5 h. The dose of the nNOS inhibitor was based on our previous studies which showed that 25 mg/kg 7-NI inhibited about 80% of mouse brain NOS activity (Itzhak 1996) and attenuated METH-induced dopaminergic neurotoxicity in Swiss Webster mice (Itzhak and Ali 1996). In the second experiment, nNOS(-/-) and wild-type (WT) mice (n ¼ 10-12 per group) received saline or fenfluramine (25 mg/kg), twice a day for 2 days.…”

Section: Methodsmentioning

confidence: 99%

“…Animal care was in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council, National Academy Press, 1996) In the first experiment, Swiss Webster mice (n ¼ 10-12 per group) received one of the following treatments twice a day for two consecutive days: (i) Vehicle/saline, (ii) vehicle/fenfluramine (25 mg/kg), (iii) 7-NI (25 mg/kg)/saline and (iv) 7-NI/fenfluramine. The interval between paired injections was 30 min, and each pair of injections was separated by 4-5 h. The dose of the nNOS inhibitor was based on our previous studies which showed that 25 mg/kg 7-NI inhibited about 80% of mouse brain NOS activity (Itzhak 1996) and attenuated METH-induced dopaminergic neurotoxicity in Swiss Webster mice (Itzhak and Ali 1996). In the second experiment, nNOS(-/-) and wild-type (WT) mice (n ¼ 10-12 per group) received saline or fenfluramine (25 mg/kg), twice a day for 2 days.…”

Section: Methodsmentioning

confidence: 99%

“…The major finding of the present study is that NO is not a mediator of fenfluramine-induced serotonergic neurotoxicity. This conclusion is supported by (i) the lack of protective effect of the nNOS inhibitor 7-NI, and (ii) the vulnerability of the nNOS(-/-) mice to serotonergic neurotoxicity.We previously reported that 25 mg/kg 7-NI administered 30 min before METH prevented the depletion of striatal dopaminergic markers (Itzhak and Ali 1996). The protective effects of 7-NI and other nNOS inhibitors against METH-induced dopaminergic neurotoxicity were independent of METH-induced hyperthermia (Itzhak and Ali 1996;Itzhak et al 2000).…”

mentioning

confidence: 92%

“…Evidence for the role of NO in dopaminergic neurotoxicity stems from several in vivo studies. METH-induced dopaminergic neurotoxicity in mice (i) caused a marked increased striatal 3-nitortyrosine which is a marker of peroxynitrite formation in vivo (Imam et al 2001), (ii) was attenuated by selective neuronal nitric oxide synthase (nNOS) inhibitors such as 7-nitroindazole (7-NI) (Di Monte et al 1996;Itzhak and Ali 1996;Itzhak et al 2000), and (iii) was attenuated in mice deficient in the nNOS gene (nNOS knockout; KO) (Itzhak et al 1998). In addition, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity in mice was blocked by 7-NI (Schulz et al 1995), and attenuated in nNOS KO mice (Przedborski et al 1996).…”

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confidence: 99%

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Fenfluramine‐induced serotonergic neurotoxicity in mice: lack of neuroprotection by inhibition/ablation of nNOS

Itzhak

Ali

Anderson

2003

Journal of Neurochemistry

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Previous studies have implicated a role for nitric oxide (NO) and peroxynitrite in methamphetamine-induced dopaminergic neurotoxicity. The present study was undertaken to investigate whether NO is involved in serotonergic neurotoxicity caused by fenfluramine. In the first experiment, the effect of the neuronal nitric oxide synthase (nNOS) inhibitor 7-nitroindazole (7-NI; 25 mg/ kg · 4) on fenfluramine (25 mg/kg · 4)-induced serotonergic neurotoxicity in Swiss Webster mice was investigated. In the second experiment, the effect of fenfluramine (25 mg/kg · 4) on nNOS (-/-) and wild-type (WT) mice was investigated. Fenfluramine induced hypothermia in all three mouse strains, and 7-NI had no thermoregulatory effect. Selective depletion of 5-HT and 5-HT transporter binding sites in the striatum, frontal cortex and hippocampus in all three mouse strains was observed, with no evidence of dopaminergic neurotoxicity. In the first experiment, 7-NI did not attenuate serotonergic neurotoxicity in Swiss Webster mice. In the second experiment, nNOS(-/-) and WT mice were equally sensitive to serotonergic neurotoxicity. These findings suggest that NO and peroxynitrite do not mediate fenfluramineinduced serotonergic neurotoxicity, and that NO is a selective mediator of amphetamines-induced dopaminergic neurotoxicity. Keywords: 7-nitroindazole, fenfluramine, methamphetamine, nitric oxide, serotonergic and dopaminergic neurotoxicity. Fenfluramine is an amphetamine analog with anorectic properties that inhibits the reuptake and increases the release of 5-hydroxytryptamine (5-HT; serotonin). High doses of fenfluramine cause long-lasting depletion of 5-HT and 5-HT transporter (5-HTT) binding sites (Kleven and Seiden 1989;O'Callaghan and Miller 1994), deficits that could be consistent with neurotoxic insult in rodents and non-human primates (Schuster et al. 1986;Ricaurte et al. 1991;McCann et al. 1994). The mechanism underlying the development of serotonergic neurotoxicity is unclear. Endogenous formation of 5,6-dihydroxytryptamine due to 5-HT excess release following the administration of substituted amphetamines (Commins et al. 1987), and the generation of other products of 5-HT oxidation (Wrona et al. 1995) may be involved in degeneration of 5-HT nerve terminals.Other amphetamine analogs, such as methamphetamine (METH) and 3,4-methylenedioxy-methamphetamine (MDMA) cause varying degrees of dopaminergic and serotonergic neurotoxicity, depending on the species examined. Evidence suggests the involvement of free radicals and, specifically, reactive oxygen species in amphetamines-induced dopaminergic neurotoxicity (Cadet and Brannock 1998;Hanson et al. 1998). Peroxynitrite, formed from the interaction between nitric oxide (NO) and superoxide radicals, is considered a major neurotoxin (Beckman et al. 1990). Inactivation of tyrosine hydroxylase (Kuhn et al. 1999), the dopamine transporter (DAT; Park et al. 2002), and oxidation of dopamine (LaVoie and Hastings 1999) by peroxynitrite are thought to be involved in METH-induced dopamin...

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Section: Discussionmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 92%

mentioning

confidence: 99%

See 3 more Smart Citations

Fenfluramine‐induced serotonergic neurotoxicity in mice: lack of neuroprotection by inhibition/ablation of nNOS

Itzhak

Ali

Anderson

2003

Journal of Neurochemistry

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Inhibitors of NO-synthase and donors of NO modulate kainic acid-induced damage in the rat hippocampus

Gabriel¹,

Friguls

Sureda³

et al. 2000

J. Neurosci. Res.

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The effects of nitric oxide synthase (NOS) inhibitors, N(omega)-nitro-L-arginine and 7-nitroindazole, and the NOS substrate L-arginine on kainic acid (KA)-induced microglial reactivity and stress response were studied in the hippocampus 7 and 1 days after KA, respectively. Density of peripheral-type benzodiazepine receptors was measured as an index of microglial reactivity. Histological damage in hippocampus was evaluated at 7 days by neuronal counting. KA increased the maximal number of binding sites (B(max)) versus controls. Administration of either 7-nitroindazole (25 mg/kg) or N(omega)-nitro-L-arginine (20 and 50 mg/kg) 24 hr before KA, further increased B(max). This later effect was abolished by L-arginine (1 g/kg), which given 24 hr before KA decreased B(max) to control values. Also, KA-induced HSP72 stress response was attenuated by pre-treatment with L-arginine. Histological evaluation showed reduced cell numbers in the pyramidal cell layer of the hippocampus in groups receiving KA, either alone or in combination with 7-nitroindazole. Administration of L-arginine before KA attenuated neuronal loss in CA3 but not CA1. A clear protective effect was observed, however, in CA1 and CA3, in rats receiving both L-arginine plus 7-nitroindazole before KA. The results show that the combination of a NO substrate with a NOS inhibitor reduces the neurotoxic effects of KA in the rat hippocampus. This study suggests that extremely fine regulation of NO levels in the different neural cell types can modulate excitotoxicity.

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Melatonin attenuates methamphetamine-induced toxic effects on dopamine and serotonin terminals in mouse brain

Hirata

Asanuma

Cadet

1998

Synapse

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Methamphetamine (METH) is a drug of abuse that causes deleterious effects to brain monoaminergic systems. These toxic effects are thought to be due to oxidative stress. The pineal hormone, melatonin, has been shown to have neuroprotective effects against toxic quinones and oxidative stress produced by catecholamines. The present study was thus undertaken to assess possible protective effects of melatonin against METH-induced neurotoxic effects on the striatum and the nucleus accumbens by using autoradiographic techniques. Four dosages (5, 20, 40, 80 mg/kg) of melatonin were administered to mice intraperitoneally 30 minutes prior to the injections of METH (4 x 5 mg/kg) given at 2-hour intervals. The lowest doses of melatonin (5 mg/kg) had no significant effects against METH-induced toxicity. However, the higher doses (40 or 80 mg/kg) of melatonin significantly attenuated METH-induced toxic effects on both dopamine and serotonin systems. These data provide further evidence for a possible role of oxidative stress in METH-induced toxicity.

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The Neuronal Nitric Oxide Synthase Inhibitor, 7‐Nitroindazole, Protects Against Methamphetamine‐Induced Neurotoxicity In Vivo

Cited by 165 publications

References 16 publications

Fenfluramine‐induced serotonergic neurotoxicity in mice: lack of neuroprotection by inhibition/ablation of nNOS

Fenfluramine‐induced serotonergic neurotoxicity in mice: lack of neuroprotection by inhibition/ablation of nNOS

Inhibitors of NO-synthase and donors of NO modulate kainic acid-induced damage in the rat hippocampus

Melatonin attenuates methamphetamine-induced toxic effects on dopamine and serotonin terminals in mouse brain

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