Neuronal Damage following Intraspinal Injection of a Nitric Oxide Synthase Inhibitor in the Rat

Yezierski, Robert P.; Liu, Shanliang; Ruenes, Gladys; Busto, Raul; Dietrich, W. Dalton

doi:10.1097/00004647-199609000-00025

Cited by 36 publications

(22 citation statements)

References 39 publications

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“…age and the loss of sensory, motor, and/or autonomie Included in this cascade is the release of injurious medi-'The Miami Project to Cure Paralysis and Departments of 2Neurological Surgery, 3Anatomy and Cell Biology, and ''Neurology, University of Miami, Miami, Florida. ators, including excitatory amino acids (EAAs), oxidative metabolites, and inflammatory cytokines (Anderson and Hall, 1994;Hsu et al, 1994;Ishikawa and Marsala, 1996). In recent years, putative mediators of this secondary injury cascade have been investigated using the technique of intraspinal microinjection (Liu et al, 1997;Yezierski et al, , 1996. The results of these studies have provided important new data related to the pathophysiological consequences of manipulating EAA and nitric oxide (NO) levels in the spinal cord.…”

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confidence: 99%

“…One of the putative mediators of central nervous system (CNS) injury is NO (Beal, 1997;Lipton and Stamler, 1997;Yezierski et al, 1996). In recent years, neuroprotective as well as neurotoxic effects following traumatic and/or ischémie brain injury have been described following administration of drugs that increase or decrease NO availability (Moneada et al, 1992;Kuluz et al, 1993;Dawson, 1994).…”

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confidence: 99%

“…In recent years, neuroprotective as well as neurotoxic effects following traumatic and/or ischémie brain injury have been described following administration of drugs that increase or decrease NO availability (Moneada et al, 1992;Kuluz et al, 1993;Dawson, 1994). In a recent study, Yezierski et al (1996) showed that intraspinal injection of /V-nitro-Larginine methyl ester (l-NAME), a nonspecific NO synthase inhibitor, produced a dose-dependent neuronal loss that was reversed by L-arginine and inversely related to tissue levels of the constitutive form of NO synthase. Similar to what has been proposed in the brain (Iadecola et al, 1993), reducing spinal levels of NO was believed to cause vasoconstriction and reduced blood flow leading to focal ischemia and the initiation of an excitotoxic cascade.…”

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Intraspinal Injection of Adenosine Agonists Protect Againstl-NAME Induced Neuronal Loss in the Rat

Dora¹,

Koch²,

Sánchez³

et al. 1998

Journal of Neurotrauma

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Intraspinal injection of the nonspecific inhibitor of nitric oxide synthase N-nitro-L-arginine methyl ester (L-NAME) results in a dose-dependent loss of neurons in the rat spinal cord. This effect is thought to result from a reduction in basal levels of nitric oxide (NO), thereby producing an ischemic reaction secondary to vasoconstriction and reduced spinal cord blood flow (SCBF). An important component of this ischemic reaction is the release of excitatory amino acids and the initiation of an excitotoxic cascade. In the present study, microinjections of adenosine A1 and A2 receptor agonists were made in the spinal cord to evaluate the neuroprotective effects of these drugs against neuronal loss produced by L-NAME. Animals were divided into six groups based on the composition of injected solutions: (a) L-NAME; (b) L-NAME + N6-cyclopentyladenosine (CPA, A1 agonist); (c) L-NAME + 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA, A2 agonist); (d) L-NAME + CPA + CPCA; (e) N-methyl D-aspartate (NMDA); and (f) NMDA + CPA. Injections of L-NAME or NMDA produced a unilateral loss of spinal neurons, a local inflammatory response, and darkly stained pyknotic nuclei surrounding the area of neuronal loss. CPA and CPCA significantly reduced the area of L-NAME-induced neuronal loss, and a synergistic effect was observed when ineffective doses of these agonists were co-injected with L-NAME. The excitotoxic effects of NMDA were not affected by CPA. The results have shown that A1 and A2 receptor agonists provide significant neuroprotection against L-NAME induced neuronal loss, presumably by inhibiting ischemia induced release of excitatory amino acids (A1 agonist), or by restoring SCBF secondary to vasodilation (A2 agonist). It is suggested by these results that the intraspinal injection of L-NAME is an effective model to study the pathological consequences of vasoconstriction, reduced SCBF, and ischemia secondary to decreased NO production in the rat spinal cord. Finally, the results provide support for the continued investigation of specific adenosine agonists as therapeutic agents directed against the ischemic and excitotoxic components of spinal injury.

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Intraspinal Injection of Adenosine Agonists Protect Againstl-NAME Induced Neuronal Loss in the Rat

Dora¹,

Koch²,

Sánchez³

et al. 1998

Journal of Neurotrauma

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“…There is also evidence indicating that inhibitors of NOS reduce nerve-induced vasodilation, increase the basal tone of the vasculature, and abolish nerve-evoked protein output (Dama 1992;Edwards and Garrett 1993;Buckle et al 1995;Anderson and Garrett 1998). Hypoxic-ischemic reaction in spinal tissues secondary to decreased blood flow by L-NAME has been also reported (Yezierski et al 1996). The possibility that the salivary gland functions may be disturbed by the existing low blood flow under the experimental treatment by L-NAME is proposed.…”

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confidence: 86%

Prevention by L-Arginine/Nitric Oxide of Chlordiazepoxide-Induced Toxic Reactions in the Rat Salivary Gland

Ahmed

Sharifzadeh

Nikfar

et al. 2006

Toxicology Mechanisms and Methods

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The effects of chlordiazepoxide, L-Arginine (nitric oxide precursor), L-NAME (nitric oxide synthesis inhibitor), and concurrent treatment of these drugs on concentration of salivary total protein, calcium, sodium, potassium concentrations, amylase activity, and flow rate in rats were studied. Total saliva was collected 2 hours postintraperitoneal administration of chlordiazepoxide (5 mg/kg), L-Arginine (250 mg/kg), and L-NAME (10 mg/kg) intraorally by polyethylene cannula from anaesthetized rats for 30 min using pilocarpine (6 mg/kg) as secretagogue. Chlordiazepoxide reduced flow rate to 43%, total protein concentration to 30%, calcium concentration to 33%, and amylase activity to 33% of control. Potassium and sodium levels were not affected by chlordiazepoxide. L-Arginine increased flow rate to 10%, total protein to 65%, and calcium to 17%, while L-NAME decreased flow rate to 9%, total protein to 55%, and calcium to 25%. Concurrent treatment of rats by chlordiazepoxide plus L-Arginine or L-NAME influenced chlordiazepoxide-induced alterations in saliva composition. The inhibitory effects of chlordiazepoxide on salivary flow rate, amylase activity, and concentrations of total protein and calcium were blocked by L-Arginine while potentiated by L-NAME coadministrations. It is concluded that benzodiazepines induce toxicity in salivary gland function by disturbing the homeostasis of inositol triphosphate and Ca homeostasis in the cells. Administration of L-Arginine prevents benzodiazepine-induced toxicity most probably through its vasoregulatory action and balancing intracellular Ca homeostasis.

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“…However, other authors claim that intra-spinal microinjection of L-NAME increases neuronal damage in a dose-dependent manner (41), pointing out the complexity of the actions of NO in SCI. Functional outcomes of rats subjected to SCI and treated with CsA are different depending on the time when treatment is started (7).…”

Section: Discussionmentioning

confidence: 99%

Cyclosporin-A Inhibits Constitutive Nitric Oxide Synthase Activity and Neuronal and Endothelial Nitric Oxide Synthase Expressions after Spinal Cord Injury in Rats

et al. 2005

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Nitric oxide (NO) plays a role in the pathophysiology of spinal cord injury (SCI). NO is produced by three types of nitric oxide synthase (NOS) enzymes: The constitutive Ca2+/calmodulin-dependent neuronal NOS (nNOS) and endothelial NOS (eNOS) isoforms, and the inducible calcium-independent isoform (iNOS). During the early stages of SCI, nNOS and eNOS produce significant amounts of NO, therefore, the regulation of their activity and expression may participate in the damage after SCI. In the present study, we used Cyclosporin-A (CsA) to further substantiate the role of Ca-dependent NOS in neural responses associated to SCI. Female Wistar rats were subjected to SCI by contusion, and killed 4 h after lesion. Results showed an increase in the activity of constitutive NOS (cNOS) after lesion, inhibited by CsA (2.5 mg/kg i.p.). Western blot assays showed an increased expression of both nNOS and eNOS after trauma, also antagonized by CsA administration.

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Neuronal Damage following Intraspinal Injection of a Nitric Oxide Synthase Inhibitor in the Rat

Cited by 36 publications

References 39 publications

Intraspinal Injection of Adenosine Agonists Protect Againstl-NAME Induced Neuronal Loss in the Rat

Intraspinal Injection of Adenosine Agonists Protect Againstl-NAME Induced Neuronal Loss in the Rat

Prevention by L-Arginine/Nitric Oxide of Chlordiazepoxide-Induced Toxic Reactions in the Rat Salivary Gland

Cyclosporin-A Inhibits Constitutive Nitric Oxide Synthase Activity and Neuronal and Endothelial Nitric Oxide Synthase Expressions after Spinal Cord Injury in Rats

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