Nitric oxide synthase inhibition prevents acute quinolinate-induced striatal neurotoxicity
Abstract
Quinolinic acid (QUIN) is an endogenous excitotoxin acting on N-methyl-D-aspartate (NMDA) receptors, that leads to neurotoxic damage resembling the alterations observed in Huntington's disease. Two major end-points of QUIN induced neurotoxicity are both circling behavior (CB) and lipid peroxidation (LP). Recently, nitric oxide (NO) has been implicated as a mediator of cell injury in some neurological disorders, thus, NO as a free radical might be involved in QUIN-induced neurotoxicity and oxidative stress. In the present study we evaluated the possible role of NO on QUIN-induced neurotoxicity, by measuring nitric oxide synthase activity (NOS), before and after QUIN-induced damage and by evaluating the effect of NOS inhibition on acute QUIN-induced CB and LP. Rats were striatally microinjected with QUIN (240 nmol/microl). QUIN administration increased NOS activity by 327% as compared to control values and this enhancement was inhibited by i.v. pretreatment with a NOS inhibitor the N(G)-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg). QUIN-induced CB was also attenuated by pretreatment of rats with 1, 5, 10 and 15 mg/kg of L-NAME by -37, -55, -62 and -74% vs QUIN respectively. Similarly, L-NAME also reduced by 32% the QUIN-induced LP. These findings suggest that enhanced NOS activity may participate in QUIN-induced neurotoxicity and oxidative stress.
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Neurotoxicity in neurons is triggered by overstimulation of NMDA receptors, leading to disruptions in intracellular Ca2+ homeostasis and free radical formation.
“Neurotoxicity in neurons is triggered by the overstimulation of NMDA receptors, leading to disruptions in intracellular Ca2+ homeostasis and free radical formation [53,54].”
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“transcriptionally (and robustly: by 327%) induce NOS activity in in vivo and in vitro experiments (Melillo et al. 1994; Perez-Severiano et al. 1998).”
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“…1983; Foster and Schwarcz, 1989; Winn et al., 1991; Behan et al., 1999; Rios and Santamaria, 1991; Santamaria and Rios, 1993; Stipek et al., 1997; Perez-Severiano et al., 1998, 2004; Stone et al., 2000; Rodriguez-Martinez et al., 2000; Cabrera et al., 2000; Santamaria et al., 2001, 2003;…”
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“NOS inhibitors were proposed as the candidates for the treatment of neurodegenerative disease (20).”
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- Authors
- Pérez-Severiano, F., Escalante, B., & Ríos, C.
- Affiliations
- Instituto Politécnico Nacional (MX)
- Venue
- Neurochemical Research
- Published
- 1998-10
- Volume
- 23
- Issue
- 10
- Pages
- 1297-1302
- ISSN
- 0364-3190 (ISSN-L)
- 1573-6903
- OpenAlex
- W2113919453
- Cited by
- 68
- References
- 0
- Citations by year
- 2024: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2018: 2 · 2017: 3 · 2016: 2 · 2015: 4 · 2013: 3
- FWCI
- 1.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Neurochemical Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Consejo Nacional de Ciencia y Tecnología
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- quinolinic acid, nitric oxide synthase, striatal neurotoxicity, NMDA receptor excitotoxicity, circling behavior, lipid peroxidation, oxidative stress, L-NAME, Huntington's disease model
- MeSH terms
- Animals, Corpus Striatum, Enzyme Inhibitors, Male, Motor Activity, Rats, Wistar, Quinolinic Acid, Nitric Oxide Synthase, NG-Nitroarginine Methyl Ester, Rats
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