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

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

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

In the present studies, we have evaluated the effects of N-[4-(2-{[(3-Chlorophenyl)methyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide dihydrochloride (ARL 17477) on recombinant human neuronal NOS (nNOS) and endothelial NOS (eNOS). We then carried out pharmacokinetic studies and measured cortical nitric oxide synthase (NOS) inhibition to determine that the compound crossed the blood brain barrier. Finally, the compound was evaluated in a model of global ischaemia in the gerbil and two models of transient focal ischaemia in the rat. The IC50 values for ARL 17477 on human recombinant human nNOS and eNOS were 1 and 17 μM, respectively. ARL 17477 (50 mg/kg i.p.) produced a significant reduction in the ischaemia-induced hippocampal damage following global ischaemia when administered immediately post-occlusion, but failed to protect when administration was delayed until 30 min post-occlusion. In the endothelin-1 model of focal ischaemia, ARL 17477 (1 mg/kg i.v.) significantly attenuated the infarct volume when administered at either 0, 1 or 2 h post-endothelin-1 (P<0.05). In the intraluminal suture model, ARL 17477 at both 1 and 3 mg/kg i.v. failed to reduce the infarct volume measured at 1, 3 or 7 days post-occlusion. These results demonstrate that ARL 17477 protects against global ischaemia in gerbils and provides some reduction in infarct volume following transient middle cerebral artery occlusion in rats, indicating that nNOS inhibition may be a useful treatment of ischaemic conditions. Copyright (C) 2000 Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)234-244
Number of pages11
JournalBrain Research
Volume871
Issue number2
DOIs
StatePublished - Jul 21 2000
Externally publishedYes

Fingerprint

Neuroprotective Agents
Brain Ischemia
Nitric Oxide Synthase
Ischemia
Animal Models
Gerbillinae
Endothelin-1
Middle Cerebral Artery Infarction
Blood-Brain Barrier
Sutures
Inhibitory Concentration 50
ARL 17477
Pharmacokinetics

Keywords

  • ARL 17477
  • Cerebral ischemia
  • Mongolian gerbil
  • Neuroprotection
  • Nitric oxide
  • Rat

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Developmental Biology
  • Clinical Neurology

Cite this

O'Neill, M. J., Murray, T. K., McCarty, D. R., Hicks, C. A., Dell, C. P., Patrick, K. E., ... Singh, J. P. (2000). ARL 17477, a selective nitric oxide synthase inhibitor, with neuroprotective effects in animal models of global and focal cerebral ischaemia. Brain Research, 871(2), 234-244. https://doi.org/10.1016/S0006-8993(00)02471-9

ARL 17477, a selective nitric oxide synthase inhibitor, with neuroprotective effects in animal models of global and focal cerebral ischaemia. / O'Neill, Michael J.; Murray, Tracey K.; McCarty, Deborah R.; Hicks, Caroline A.; Dell, Colin P.; Patrick, Kelly E.; Ward, Mark A.; Osborne, David J.; Wiernicki, Todd R.; Roman, Carlos R.; Lodge, David; Fleisch, Jerome H.; Singh, Jai Pal.

In: Brain Research, Vol. 871, No. 2, 21.07.2000, p. 234-244.

Research output: Contribution to journalArticle

O'Neill, MJ, Murray, TK, McCarty, DR, Hicks, CA, Dell, CP, Patrick, KE, Ward, MA, Osborne, DJ, Wiernicki, TR, Roman, CR, Lodge, D, Fleisch, JH & Singh, JP 2000, 'ARL 17477, a selective nitric oxide synthase inhibitor, with neuroprotective effects in animal models of global and focal cerebral ischaemia', Brain Research, vol. 871, no. 2, pp. 234-244. https://doi.org/10.1016/S0006-8993(00)02471-9
O'Neill, Michael J. ; Murray, Tracey K. ; McCarty, Deborah R. ; Hicks, Caroline A. ; Dell, Colin P. ; Patrick, Kelly E. ; Ward, Mark A. ; Osborne, David J. ; Wiernicki, Todd R. ; Roman, Carlos R. ; Lodge, David ; Fleisch, Jerome H. ; Singh, Jai Pal. / ARL 17477, a selective nitric oxide synthase inhibitor, with neuroprotective effects in animal models of global and focal cerebral ischaemia. In: Brain Research. 2000 ; Vol. 871, No. 2. pp. 234-244.
@article{3e3d8846e8624ff1abedd09941433afd,
title = "ARL 17477, a selective nitric oxide synthase inhibitor, with neuroprotective effects in animal models of global and focal cerebral ischaemia",
abstract = "In the present studies, we have evaluated the effects of N-[4-(2-{[(3-Chlorophenyl)methyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide dihydrochloride (ARL 17477) on recombinant human neuronal NOS (nNOS) and endothelial NOS (eNOS). We then carried out pharmacokinetic studies and measured cortical nitric oxide synthase (NOS) inhibition to determine that the compound crossed the blood brain barrier. Finally, the compound was evaluated in a model of global ischaemia in the gerbil and two models of transient focal ischaemia in the rat. The IC50 values for ARL 17477 on human recombinant human nNOS and eNOS were 1 and 17 μM, respectively. ARL 17477 (50 mg/kg i.p.) produced a significant reduction in the ischaemia-induced hippocampal damage following global ischaemia when administered immediately post-occlusion, but failed to protect when administration was delayed until 30 min post-occlusion. In the endothelin-1 model of focal ischaemia, ARL 17477 (1 mg/kg i.v.) significantly attenuated the infarct volume when administered at either 0, 1 or 2 h post-endothelin-1 (P<0.05). In the intraluminal suture model, ARL 17477 at both 1 and 3 mg/kg i.v. failed to reduce the infarct volume measured at 1, 3 or 7 days post-occlusion. These results demonstrate that ARL 17477 protects against global ischaemia in gerbils and provides some reduction in infarct volume following transient middle cerebral artery occlusion in rats, indicating that nNOS inhibition may be a useful treatment of ischaemic conditions. Copyright (C) 2000 Elsevier Science B.V.",
keywords = "ARL 17477, Cerebral ischemia, Mongolian gerbil, Neuroprotection, Nitric oxide, Rat",
author = "O'Neill, {Michael J.} and Murray, {Tracey K.} and McCarty, {Deborah R.} and Hicks, {Caroline A.} and Dell, {Colin P.} and Patrick, {Kelly E.} and Ward, {Mark A.} and Osborne, {David J.} and Wiernicki, {Todd R.} and Roman, {Carlos R.} and David Lodge and Fleisch, {Jerome H.} and Singh, {Jai Pal}",
year = "2000",
month = "7",
day = "21",
doi = "10.1016/S0006-8993(00)02471-9",
language = "English (US)",
volume = "871",
pages = "234--244",
journal = "Brain Research",
issn = "0006-8993",
publisher = "Elsevier",
number = "2",

}

TY - JOUR

T1 - ARL 17477, a selective nitric oxide synthase inhibitor, with neuroprotective effects in animal models of global and focal cerebral ischaemia

AU - O'Neill, Michael J.

AU - Murray, Tracey K.

AU - McCarty, Deborah R.

AU - Hicks, Caroline A.

AU - Dell, Colin P.

AU - Patrick, Kelly E.

AU - Ward, Mark A.

AU - Osborne, David J.

AU - Wiernicki, Todd R.

AU - Roman, Carlos R.

AU - Lodge, David

AU - Fleisch, Jerome H.

AU - Singh, Jai Pal

PY - 2000/7/21

Y1 - 2000/7/21

N2 - In the present studies, we have evaluated the effects of N-[4-(2-{[(3-Chlorophenyl)methyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide dihydrochloride (ARL 17477) on recombinant human neuronal NOS (nNOS) and endothelial NOS (eNOS). We then carried out pharmacokinetic studies and measured cortical nitric oxide synthase (NOS) inhibition to determine that the compound crossed the blood brain barrier. Finally, the compound was evaluated in a model of global ischaemia in the gerbil and two models of transient focal ischaemia in the rat. The IC50 values for ARL 17477 on human recombinant human nNOS and eNOS were 1 and 17 μM, respectively. ARL 17477 (50 mg/kg i.p.) produced a significant reduction in the ischaemia-induced hippocampal damage following global ischaemia when administered immediately post-occlusion, but failed to protect when administration was delayed until 30 min post-occlusion. In the endothelin-1 model of focal ischaemia, ARL 17477 (1 mg/kg i.v.) significantly attenuated the infarct volume when administered at either 0, 1 or 2 h post-endothelin-1 (P<0.05). In the intraluminal suture model, ARL 17477 at both 1 and 3 mg/kg i.v. failed to reduce the infarct volume measured at 1, 3 or 7 days post-occlusion. These results demonstrate that ARL 17477 protects against global ischaemia in gerbils and provides some reduction in infarct volume following transient middle cerebral artery occlusion in rats, indicating that nNOS inhibition may be a useful treatment of ischaemic conditions. Copyright (C) 2000 Elsevier Science B.V.

AB - In the present studies, we have evaluated the effects of N-[4-(2-{[(3-Chlorophenyl)methyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide dihydrochloride (ARL 17477) on recombinant human neuronal NOS (nNOS) and endothelial NOS (eNOS). We then carried out pharmacokinetic studies and measured cortical nitric oxide synthase (NOS) inhibition to determine that the compound crossed the blood brain barrier. Finally, the compound was evaluated in a model of global ischaemia in the gerbil and two models of transient focal ischaemia in the rat. The IC50 values for ARL 17477 on human recombinant human nNOS and eNOS were 1 and 17 μM, respectively. ARL 17477 (50 mg/kg i.p.) produced a significant reduction in the ischaemia-induced hippocampal damage following global ischaemia when administered immediately post-occlusion, but failed to protect when administration was delayed until 30 min post-occlusion. In the endothelin-1 model of focal ischaemia, ARL 17477 (1 mg/kg i.v.) significantly attenuated the infarct volume when administered at either 0, 1 or 2 h post-endothelin-1 (P<0.05). In the intraluminal suture model, ARL 17477 at both 1 and 3 mg/kg i.v. failed to reduce the infarct volume measured at 1, 3 or 7 days post-occlusion. These results demonstrate that ARL 17477 protects against global ischaemia in gerbils and provides some reduction in infarct volume following transient middle cerebral artery occlusion in rats, indicating that nNOS inhibition may be a useful treatment of ischaemic conditions. Copyright (C) 2000 Elsevier Science B.V.

KW - ARL 17477

KW - Cerebral ischemia

KW - Mongolian gerbil

KW - Neuroprotection

KW - Nitric oxide

KW - Rat

UR - http://www.scopus.com/inward/record.url?scp=0034698332&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034698332&partnerID=8YFLogxK

U2 - 10.1016/S0006-8993(00)02471-9

DO - 10.1016/S0006-8993(00)02471-9

M3 - Article

C2 - 10899290

AN - SCOPUS:0034698332

VL - 871

SP - 234

EP - 244

JO - Brain Research

JF - Brain Research

SN - 0006-8993

IS - 2

ER -