7-Nitroindazole

Selective Nitric Oxide Synthase Inhibitor 7-Nitroindazole Protects against Cocaine-Induced Oxidative Stress in Rat Brain.[Pubmed:26576217]

Oxid Med Cell Longev. 2015;2015:157876.

One of the mechanisms involved in the development of addiction, as well as in brain toxicity, is the oxidative stress. The aim of the current study was to investigate the effects of 7-Nitroindazole (7-NI), a selective inhibitor of neuronal nitric oxide synthase (nNOS), on cocaine withdrawal and neurotoxicity in male Wistar rats. The animals were divided into four groups: control; group treated with cocaine (15 mg/kg(-1), i.p., 7 days); group treated with 7-NI (25 mg/kg(-1), i.p., 7 days); and a combination group (7-NI + cocaine). Cocaine repeated treatment resulted in development of physical dependence, judged by withdrawal symptoms (decreased locomotion, increased salivation and breathing rate), accompanied by an increased nNOS activity and oxidative stress. The latter was discerned by an increased formation of malondialdehyde (MDA), depletion of reduced glutathione (GSH) levels, and impairment of the enzymatic antioxidant defense system measured in whole brain. In synaptosomes, isolated from cocaine-treated rats, mitochondrial activity and GSH levels were also decreased. 7-NI administered along with cocaine not only attenuated the withdrawal, due to its nNOS inhibition, but also reversed both the GSH levels and antioxidant enzyme activities near control levels.

Effects of 7-nitroindazole, a selective neural nitric oxide synthase inhibitor, on context-shock associative learning in a two-process contextual fear conditioning paradigm.[Pubmed:27481222]

Neurobiol Learn Mem. 2016 Oct;134 Pt B:287-93.

Nitric oxide (NO) is an important retrograde neuronal intracellular messenger which plays an important role in synaptic plasticity and is involved in learning and memory. However, evidence that NO is particularly important for the acquisition of contextual fear conditioning is mixed. Also, little is known about at which stages of the contextual fear conditioning does NO make its contribution. In the present study, we used 7-Nitroindazole to temporarily inhibit neural nitric oxide synthase at either the pre-exposure stage or conditioning stage in a two-process paradigm and examined the potential contribution that NO makes to the contextually conditioned fear. Results showed that the expression of contextual fear memory was significantly impaired in rats treated with 7-Nitroindazole (30mg/kg, i.p.) prior to the pairing of context-shock (p=0.034, n=8), but not after the conditioning phase (p=0.846, n=8). In addition, the expression of contextual fear memory and reconsolidation was not significantly impaired by 7-Nitroindazole administered prior to the context pre-exposure stage or prior to another context-shock learning. These findings suggest that NO is specifically involved in the acquisition but not the consolidation, retrieval or reconsolidation of contextual fear memory.

Lipopolysaccharide-induced memory impairment in rats is preventable using 7-nitroindazole.[Pubmed:26352498]

Arq Neuropsiquiatr. 2015 Sep;73(9):784-90.

Inflammation and oxidative stress have important roles in memory impairment. The effect of 7-Nitroindazole (7NI) on lipopolysaccharide (LPS)-induced memory impairment was investigated. Rats were used, divided into four groups that were treated as follows: (1) control (saline); (2) LPS; (3) 7NI-LPS; and (4) 7NI before passive avoidance (PA). In the LPS group, the latency for entering the dark compartment was shorter than in the controls (p < 0.01 and p < 0.001); while in the 7NI-LPS group, it was longer than in the LPS group (p < 0.01 and p < 0.001). Malondialdehyde (MDA) and nitric oxide (NO) metabolite concentrations in the brain tissues of the LPS group were higher than in the controls (p < 0.001 and p < 0.05); while in the 7NI-LPS group, they were lower than in the LPS group (p < 0.001 and p < 0.05, respectively). The thiol content in the brain of the LPS group was lower than in the controls (p < 0.001); while in the 7NI-LPS group, it was higher than in the LPS group (p < 0.001). It is suggested that brain tissue oxidative damage and NO elevation have a role in the deleterious effects of LPS on memory retention that are preventable using 7NI.

Antidyskinetic Effect of 7-Nitroindazole and Sodium Nitroprusside Associated with Amantadine in a Rat Model of Parkinson's Disease.[Pubmed:27053252]

Neurotox Res. 2016 Jul;30(1):88-100.

Amantadine is the noncompetitive antagonist of N-methyl-D-aspartate, receptor activated by the excitatory neurotransmitter glutamate. It is the only effective medication used to alleviate dyskinesia induced by L-3,4-dihydroxyphenylalanine (L-DOPA) in Parkinson's disease patients. Unfortunately, adverse effects as abnormal involuntary movements (AIMs) known as L-DOPA-induced dyskinesia limit its clinical utility. Combined effective symptomatic treatment modalities may lessen the liability to undesirable events. Likewise drugs known to interfere with nitrergic system reduce AIMs in animal models of Parkinson's disease. We aimed to analyze an interaction between amantadine, neuronal nitric oxide synthase inhibitor (7-Nitroindazole, 7NI), and nitric oxide donor (sodium nitroprusside, SNP) in 6-hydroxydopamine-(6-OHDA)-lesioned rats (microinjection in the medial forebrain bundle) presenting L-DOPA-induced dyskinesia (20 mg/kg, gavage, during 21 days). We confirm that 7NI-30 mg/kg, SNP-2/4 mg/kg and amantadine-40 mg/kg, individually reduced AIMs. Our results revealed that co-administration of sub-effective dose of amantadine (10 mg/kg) plus sub-effective dose of 7NI (20 mg/kg) potentiates the effect of reducing AIMs scores when compared to the effect of the drugs individually. No superior benefit on L-DOPA-induced AIMs was observed with the combination of amantadine and SNP. The results revealed that combination of ineffective doses of amantadine and 7NI represents a new strategy to increase antidyskinetic effect in L-DOPA-induced AIMs. It may provide additional therapeutic benefits to Parkinson's disease patients from these disabling complications at lower and thus safer and more tolerable doses than required when either drug is used alone. To close, we discuss the paradox of both nitric oxide synthase inhibitor and/or donor produced AIMs reduction by targeting nitric oxide synthase.

Selective inhibitors of neuronal nitric oxide synthase--is no NOS really good NOS for the nervous system?[Pubmed:9226999]

Trends Pharmacol Sci. 1997 Jun;18(6):204-11.

It is now ten years since NO was shown to account for the biological activity of endothelium-derived relaxing factor (EDRF). It is also the tenth anniversary of the identification of L-NG monomethyl arginine (L-NMMA) as the very first inhibitor of NO biosynthesis. That EDRF and NO were one and the same sparked an explosion of interest in the biochemistry and pharmacology of NO which has yet to subside. In contrast, the first ever nitric oxide synthase (NOS) inhibitor slipped seamlessly into the literature virtually without comment at the time. Over the following decade, L-NMMA (and like NOS inhibitors) have proved invaluable as tools for probing the biological roles of NO in health and disease and, in particular, have increased our understanding of the function of NO in the nervous system. Further advances in this important area now require the development of inhibitors selective for the neuronal isoform of NOS (nNOS). Here, Philip Moore and Rachel Handy provide an up-to-date account of the literature regarding the biochemical and pharmacological characterization of NOS inhibitors with particular reference to compounds with greater selectivity for the nNOS isoform.

Inhibition of rat cerebellar nitric oxide synthase by 7-nitro indazole and related substituted indazoles.[Pubmed:7693279]

Br J Pharmacol. 1993 Sep;110(1):225-8.

1. 7-Nitro indazole (7-NI) produces potent inhibition of rat cerebellar nitric oxide synthase (NOS) with an IC50 of 0.9 +/- 0.1 microM (n = 6). NOS activity is dependent on the presence of both exogenous CaCl2 and NADPH. The inhibitory potency of 7-NI remained unaltered in the presence of different concentrations of either CaCl2 (0.75-7.5 mM) or NADPH (0.05-5.0 mM). 2. Kinetic (Lineweaver-Burke) analysis of the effect of 7-NI on rat cerebellar NOS revealed that inhibition was of a competitive nature with a Ki value of 5.6 microM. The Km of of cerebellar NOS with respect to L-arginine was 2.5 microM. 3. The following indazole derivatives (IC50 values shown in parentheses, all n = 6) caused concentration-related inhibition of rat cerebellar NOS in vitro: 6-nitro indazole (31.6 +/- 3.4 microM), 5-nitro indazole (47.3 +/- 2.3 microM), 3-chloro indazole (100.0 +/- 5.5 microM), 3-chloro 5-nitro indazole (158.4 +/- 2.1 microM) and indazole (177.8 +/- 2.1 microM). The IC50 values for 5-amino indazole, 6-amino indazole and 6-sulphanilimido indazole were in excess of 1 mM; 3-indazolinone was inactive. 4. 7-NI (10 mg kg-1) administered i.p. to rats produced 60 min thereafter a significant inhibition of NOS activity in cerebellum (31.1 +/- 3.2%, n = 6), cerebral cortex (38.2 +/- 5.6%, n = 6), hippocampus (37.0 +/- 2.8%, n = 6) and adrenal gland (23.7 +/- 3.0%, n = 6). NOS activity in olfactory bulb and stomach fundus were unchanged. 5. These results indicate that 7-NI is a potent and competitive inhibitor of rat brain NOS in vitro and also inhibits NOS in different brain regions and in the adrenal gland in vivo. Inhibition of NOS is a characteristic property of the indazole nucleus. Nitration of the indazole ring at positions 5, 6 and 7 results in a graded increase in inhibitory potency. Indazole-based inhibitors of NOS may prove useful tools with which to evaluate the biological roles of nitric oxide in the central nervous system.

7-Nitro indazole, an inhibitor of nitric oxide synthase, exhibits anti-nociceptive activity in the mouse without increasing blood pressure.[Pubmed:7680591]

Br J Pharmacol. 1993 Feb;108(2):296-7.

7-Nitro indazole (7-NI) inhibits mouse cerebellar nitric oxide synthase (NOS) in vitro with an IC50 of 0.47 microM. Following i.p. administration in mice, 7-NI (10-50 mg kg-1) produces dose-related anti-nociception as evidenced by an inhibition of late phase (15-30 min) but not early phase (0-5 min) hindpaw licking time following subplantar injection of formalin (10 microliters, 5% v/v). The ED50 for this effect was 26 mg kg-1 (equivalent to 159.5 mumol kg-1). Similar i.p. administration of 7-NI (20 and 80 mg kg-1) in urethane-anaesthetized mice failed to increase MAP. Thus, 7-NI is a novel inhibitor of NOS which exhibits selectivity for the brain enzyme. Accordingly, 7-NI may be a useful starting point for the development of selective, centrally acting NOS inhibitors devoid of cardiovascular side effects and as a tool to study the central pharmacological effects of nitric oxide (NO).

Characterization of the novel nitric oxide synthase inhibitor 7-nitro indazole and related indazoles: antinociceptive and cardiovascular effects.[Pubmed:7693278]

Br J Pharmacol. 1993 Sep;110(1):219-24.

1. 7-Nitro indazole (7-NI, 10-50 mg kg-1), 6-nitro indazole and indazole (25-100 mg kg-1) administered i.p. in the mouse produce dose-related antinociception in the late phase of the formalin-induced hindpaw licking and acetic acid-induced abdominal constriction assays. The ED50 values (mg kg-1) were as follows: 7-NI (27.5 and 22.5), 6-nitro indazole (62.5 and 44.0) and indazole (41.0 and 48.5) in the two assays respectively. 3-Indazolinone, 6 amino indazole and 6-sulphanilimido indazole (all 50 mg kg-1) were without effect. With the exception of 5-nitro indazole (50 mg kg-1) which produced sedation, none of the other indazole derivates examined caused overt behavioural changes. 2. The antinociceptive effect of 7-NI (25 mg kg-1, i.p.) in the late phase of the formalin-induced hindpaw licking assay was partially (46.7 +/- 16.2%, n = 18) reversed by pretreatment with L- but not D-arginine (both 50 mg kg-1, i.p.). 3. The time course of 7-NI induced antinociception in the mouse was correlated with inhibition of brain (cerebellum) nitric oxide synthase (NOS) activity. Maximum antinociceptive activity and NOS inhibition was detected 18-30 min following i.p. administration. In contrast, no antinociceptive effect or inhibition of cerebellar NOS was detected 75 min post-injection. 4. 7-NI, 6-nitro indazole, indazole, 3-indazolinone and 6-amino indazole (all 50 mg kg-1) failed to influence mean arterial pressure (MAP) over the 45 min after i.p. administration in the anaesthetized mouse. Similarly, 7-NI (25 mg kg-1) administered i.v. in the anaesthetized rat did not increase MAP or influence the vasodepressor effect of i.v. injected acetylcholine (ACh) over the same period.5. 7-NI (100 microM) did not influence the vasorelaxant effect of ACh (IC50, 0.2 +/- 0.04 microM, cf. 0.16+/-0.06 microM, n = 6) in phenylephrine-precontracted rabbit aortic rings.6. These data provide further evidence that antinociception following administration of 7-NI in the mouse results from inhibition of central NOS activity and is not associated with inhibition of in vivo vascular endothelial cells NOS. Accordingly, 7-NI (or a derivative thereof) may provide an alternative approach to the development of novel antinociceptive drugs.