ARL 17477, a selective nitric oxide synthase inhibitor, with neuroprotective effects in animal models of global and focal cerebral ischaemia

O’Neill, Michael; Murray, Tracey K.; McCarty, Deborah R.; Hicks, Caroline; Dell, C. P.; Patrick, Kelly E.; Ward, Mark A.; Osborne, David J.; Wiernicki, Todd R.; Roman, Carlos R.; Lodge, David; Fleisch, Jerome H.; Singh, Jyoti

doi:10.1016/s0006-8993(00)02471-9

Cited by 48 publications

(36 citation statements)

References 46 publications

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“…simvistatin) caused increased intra-ischemic blood flow and reduced infarct size (Amin-Hanjani et al, 2001;Endres et al, 1998). Use of selective nNOS antagonists (O'Neill et al, 2000) and nNOS knockout mice (Huang et al, 1994), confirmed that neuronal production of nitric oxide contributes to ischemic cell death. iNOS has been associated with oxidative stress , and modifying its activity may have therapeutic potential (Parmentier et al, 1999).…”

Section: Nitric Oxide Synthase Inhibitionmentioning

confidence: 80%

Oxidants, antioxidants and the ischemic brain

Warner

Sheng

Batinić‐Haberle

2004

Journal of Experimental Biology

539

362

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SUMMARY Despite numerous defenses, the brain is vulnerable to oxidative stress resulting from ischemia/reperfusion. Excitotoxic stimulation of superoxide and nitric oxide production leads to formation of highly reactive products,including peroxynitrite and hydroxyl radical, which are capable of damaging lipids, proteins and DNA. Use of transgenic mutants and selective pharmacological antioxidants has greatly increased understanding of the complex interplay between substrate deprivation and ischemic outcome. Recent evidence that reactive oxygen/nitrogen species play a critical role in initiation of apoptosis, mitochondrial permeability transition and poly(ADP-ribose) polymerase activation provides additional mechanisms for oxidative damage and new targets for post-ischemic therapeutic intervention. Because oxidative stress involves multiple post-ischemic cascades leading to cell death, effective prevention/treatment of ischemic brain injury is likely to require intervention at multiple effect sites.

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Section: Nitric Oxide Synthase Inhibitionmentioning

confidence: 80%

Oxidants, antioxidants and the ischemic brain

Warner

Sheng

Batinić‐Haberle

2004

Journal of Experimental Biology

539

362

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“…33 Treatment with a selective neuronal NOS inhibitor directly on occlusion in a permanent MCAO rat model or directly on reperfusion in a transient MCAO rat model provided neuroprotection, but not after delayed administration. 34,35 O'Neill et al 36 also demonstrated that treatment with a selective neuronal NOS and endothelial NOS inhibitor (ARL-17477) directly on reperfusion provided neuroprotection after shortterm global ischemia in the gerbil but not after delayed administration. This low-dose selective neuronal NOS and endothelial NOS inhibitor was not neuroprotective after 2 hours of transient intraluminal MCAO in the adult rat, 36 while earlier studies reported a neuroprotective effect after 7 days in the same model.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotection by Selective Nitric Oxide Synthase Inhibition at 24 Hours After Perinatal Hypoxia-Ischemia

Peeters-Scholte

Koster

Veldhuis

et al. 2002

Stroke

105

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Background and Purpose-Perinatal hypoxia-ischemia is a major cause of neonatal morbidity and mortality. Until now no established neuroprotective intervention after perinatal hypoxia-ischemia has been available. The delay in cell death after perinatal hypoxia-ischemia creates possibilities for therapeutic intervention after the initial insult. Excessive nitric oxide and reactive oxygen species generated on hypoxia-ischemia and reperfusion play a key role in the neurotoxic cascade. The present study examines the neuroprotective properties of neuronal and inducible but not endothelial nitric oxide synthase inhibition by 2-iminobiotin in a piglet model of perinatal hypoxia-ischemia. Methods-Twenty-three newborn piglets were subjected to 60 minutes of hypoxia-ischemia, followed by 24 hours of reperfusion and reoxygenation. Five additional piglets served as sham-operated controls. On reperfusion, piglets were randomly treated with either vehicle (nϭ12) or 2-iminobiotin (nϭ11). At 24 hours after hypoxia-ischemia, the cerebral energy state, presence of vasogenic edema, amount of apparently normal neuronal cells, caspase-3 activity, amount of terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL)-positive cells, and degree of tyrosine nitration were assessed. Results-A 90% improvement in cerebral energy state, 90% reduction in vasogenic edema, and 60% to 80% reduction in apoptosis-related neuronal cell death were demonstrated in 2-iminobiotin-treated piglets at 24 hours after hypoxiaischemia. A significant reduction in tyrosine nitration in the cerebral cortex was observed in 2-iminobiotin-treated piglets, indicating decreased formation of reactive nitrogen species. Conclusions-Simultaneous and selective inhibition of neuronal and inducible nitric oxide synthase by 2-iminobiotin is a promising strategy for neuroprotection after perinatal hypoxia-ischemia.

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“…AR-R17477 is known to penetrate rapidly the rat brain and to ensure effective and long-lasting inhibition of nNOS in vivo (16). The effect of this compound has also been studied in animal models of global and focal cerebral ischaemia (17,18). The structural and biochemical data presented here suggest a promising source of isoform selectivity provided by the isoform-unique residues in the substrate access channel.…”

mentioning

confidence: 89%

Structures of nitric oxide synthase isoforms complexed with the inhibitor AR-R17477 suggest a rational basis for specificity and inhibitor design

Fedorov

Vasan

Ghosh

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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The high level of amino acid conservation and structural similarity of the substrate-binding sites of the oxygenase domains of the nitric oxide synthase (NOS) isoforms (eNOSoxy, iNOSoxy, nNOSoxy) make the interpretation of the structural basis of inhibitor isoform specificity a challenge, and provide few clues for the design of new selective compounds. Crystal structures of iNOSoxy and nNOSoxy complexed with the neuronal NOS-specific inhibitor AR-R17447 suggest that specificity is provided by the interaction of the chlorophenyl group with an isoform-unique substrate access channel residue (L337 in rat neuronal NOS, N115 in mouse inducible NOS). This is confirmed by biochemical analysis of site-directed mutants. Inhibitors combining guanidinium-like structural motifs with long chains specifically targeting this residue are good candidates for rational isoform-specific drug design. Based on this finding, modifications of AR-R17447 to improve the specificity for the human isoforms are suggested. N itric oxide (NO), a ubiquitous signaling molecule, is currently one of the most intensely studied small molecules in biology because of its involvement in numerous biological events such as vasodilation, neurotransmission, and the immune response. The isozymes of NO synthase (NOS) that produce NO are dimeric multidomain polypeptides consisting of three main components: a heme-containing catalytic oxygenase domain (NOSoxy), a calmodulin binding linker, and a NADPH reductase domain. NOS transforms L-arginine to citrulline and NO in two sequential steps consuming oxygen and electrons (1). The cofactor tetrahydrobiopterin bound at the interface of the two oxygenase domains in the NOS dimer is required for NO synthesis (2, 3). In mammals, three NOS isoforms have been identified sharing 50-60% sequence identity, which differ in cellular distribution, regulation, and activity (1). Endothelial NOS (eNOS) regulates vascular tone and smooth muscle tension (4). Neuronal NOS (nNOS) produced NO functions as a diffusible neurotransmitter (5), whereas NO generated by inducible NOS (iNOS) generates cytotoxins with both protective and pathologic effects (1, 6). In line with NO's central biological role, there are a number of pathological processes associated with its over-or underproduction. For example, nNOS is implicated in stroke and migraine, and iNOS is implicated in septic shock, arthritis, and multiple sclerosis. The possibility of treating these and other conditions by inhibiting NOS has elicited intense efforts to identify or design NOS inhibitors. Because the three isoforms of NOS have unique roles in separate tissues, selective inhibition of one isozyme over the others is essential. In particular, it is important not to inhibit eNOS because of its critical role in maintaining vascular tone. Numerous inhibitors of NOS have been developed (7). The majority of the inhibitors contain amidino or ureido functional groups that mimic the guanidino group of the substrate L-arginine. The high level of amino acid conservation and striking...

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ARL 17477, a selective nitric oxide synthase inhibitor, with neuroprotective effects in animal models of global and focal cerebral ischaemia

Cited by 48 publications

References 46 publications

Oxidants, antioxidants and the ischemic brain

Oxidants, antioxidants and the ischemic brain

Neuroprotection by Selective Nitric Oxide Synthase Inhibition at 24 Hours After Perinatal Hypoxia-Ischemia

Structures of nitric oxide synthase isoforms complexed with the inhibitor AR-R17477 suggest a rational basis for specificity and inhibitor design

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