Neuroprotective effects of a dihydropyridine derivative, 1,4-dihydro- 2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 6-(5- phenyl-3-pyrazolyloxy)hexyl ester (CV-159), on rat ischemic brain injury

Hiroyuki Miyazaki, Shinji Tanaka, Yukiko Fujii, Kazuko Shimizu, Kazuo Nagashima, Masato Kamibayashi, Takashi Uehara, Yasunobu Okuma, Yasuyuki Nomura

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

CV-159, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5- pyridinedicarboxylic acid methyl 6-(5-phenyl-3-pyrazolyloxy)hexyl ester, is a dihydropyridine derivative that blocks the L-type Ca2+ channel and inhibits the calmodulin (CaM)-dependent pathway. In this study, we examined the effects of CV-159 on rat ischemic brain injury. CV-159 (5 and 10 mg/kg, p.o.) gave significant protection against delayed neuronal death in the hippocampal CA1 region after 15-min transient forebrain ischemia. In contrast, the Ca2+ antagonists nicardipine (1 and 10 mg/kg, p.o.) and nifedipine (1 mg/kg, i.p.) and the CaM antagonist N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W- 7, 500 ng, i.c.v.) had no effect on this hippocampal neuronal death. CV-159 also diminished the size of the brain infarct after permanent middle cerebral artery (MCA) occlusion, although physiological variables, including regional cerebral blood flow, were not affected. The increase in the water content of the infarcted cortex induced by MCA occlusion was significantly reduced by CV-159. On the other hand, neither nicardipine nor nifedipine affected the brain infarct size, volume or increased water content induced by MCA occlusion, as previously reported (A. Sauter and M. Rudin, Am. J. Hypertens. 4 121S-127S, 1991). These findings indicate that Ca2+ antagonists, such as nicardipine and nifedipine, and W-7 have no effect on rat ischemic brain injury. The results suggest that CV-159 protects against ischemic brain injury. This might be mediated by both blocking the L-type Ca2+ channel and inhibiting CaM-dependent function via Ca2+/CaM binding at a different binding site from that of W-7 to CaM (H. Umekawa, K. Yamakawa, K. Nunoki, N. Taira, T. Tanaka, and H. Hidaka, Biochem. Pharmacol. 37 3377-3381, 1988).

Original languageEnglish
Pages (from-to)869-878
Number of pages10
JournalLife Sciences
Volume64
Issue number10
DOIs
Publication statusPublished - Jan 29 1999
Externally publishedYes

Fingerprint

Neuroprotective Agents
Brain Injuries
Calmodulin
Rats
Brain
Derivatives
Nicardipine
Middle Cerebral Artery Infarction
Nifedipine
Cerebrovascular Circulation
Water content
Hippocampal CA1 Region
Water
Regional Blood Flow
Prosencephalon
1,4-dihydropyridine
CV 159
Esters
Ischemia
Binding Sites

Keywords

  • Ca/calmodulin
  • Cerebral ischemia
  • Delayed neuronal death
  • Neuroprotection

ASJC Scopus subject areas

  • Pharmacology

Cite this

Neuroprotective effects of a dihydropyridine derivative, 1,4-dihydro- 2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 6-(5- phenyl-3-pyrazolyloxy)hexyl ester (CV-159), on rat ischemic brain injury. / Miyazaki, Hiroyuki; Tanaka, Shinji; Fujii, Yukiko; Shimizu, Kazuko; Nagashima, Kazuo; Kamibayashi, Masato; Uehara, Takashi; Okuma, Yasunobu; Nomura, Yasuyuki.

In: Life Sciences, Vol. 64, No. 10, 29.01.1999, p. 869-878.

Research output: Contribution to journalArticle

Miyazaki, Hiroyuki ; Tanaka, Shinji ; Fujii, Yukiko ; Shimizu, Kazuko ; Nagashima, Kazuo ; Kamibayashi, Masato ; Uehara, Takashi ; Okuma, Yasunobu ; Nomura, Yasuyuki. / Neuroprotective effects of a dihydropyridine derivative, 1,4-dihydro- 2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 6-(5- phenyl-3-pyrazolyloxy)hexyl ester (CV-159), on rat ischemic brain injury. In: Life Sciences. 1999 ; Vol. 64, No. 10. pp. 869-878.
@article{6fda623c51e94630912c56874d7ee495,
title = "Neuroprotective effects of a dihydropyridine derivative, 1,4-dihydro- 2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 6-(5- phenyl-3-pyrazolyloxy)hexyl ester (CV-159), on rat ischemic brain injury",
abstract = "CV-159, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5- pyridinedicarboxylic acid methyl 6-(5-phenyl-3-pyrazolyloxy)hexyl ester, is a dihydropyridine derivative that blocks the L-type Ca2+ channel and inhibits the calmodulin (CaM)-dependent pathway. In this study, we examined the effects of CV-159 on rat ischemic brain injury. CV-159 (5 and 10 mg/kg, p.o.) gave significant protection against delayed neuronal death in the hippocampal CA1 region after 15-min transient forebrain ischemia. In contrast, the Ca2+ antagonists nicardipine (1 and 10 mg/kg, p.o.) and nifedipine (1 mg/kg, i.p.) and the CaM antagonist N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W- 7, 500 ng, i.c.v.) had no effect on this hippocampal neuronal death. CV-159 also diminished the size of the brain infarct after permanent middle cerebral artery (MCA) occlusion, although physiological variables, including regional cerebral blood flow, were not affected. The increase in the water content of the infarcted cortex induced by MCA occlusion was significantly reduced by CV-159. On the other hand, neither nicardipine nor nifedipine affected the brain infarct size, volume or increased water content induced by MCA occlusion, as previously reported (A. Sauter and M. Rudin, Am. J. Hypertens. 4 121S-127S, 1991). These findings indicate that Ca2+ antagonists, such as nicardipine and nifedipine, and W-7 have no effect on rat ischemic brain injury. The results suggest that CV-159 protects against ischemic brain injury. This might be mediated by both blocking the L-type Ca2+ channel and inhibiting CaM-dependent function via Ca2+/CaM binding at a different binding site from that of W-7 to CaM (H. Umekawa, K. Yamakawa, K. Nunoki, N. Taira, T. Tanaka, and H. Hidaka, Biochem. Pharmacol. 37 3377-3381, 1988).",
keywords = "Ca/calmodulin, Cerebral ischemia, Delayed neuronal death, Neuroprotection",
author = "Hiroyuki Miyazaki and Shinji Tanaka and Yukiko Fujii and Kazuko Shimizu and Kazuo Nagashima and Masato Kamibayashi and Takashi Uehara and Yasunobu Okuma and Yasuyuki Nomura",
year = "1999",
month = "1",
day = "29",
doi = "10.1016/S0024-3205(99)00011-9",
language = "English",
volume = "64",
pages = "869--878",
journal = "Life Sciences",
issn = "0024-3205",
publisher = "Elsevier Inc.",
number = "10",

}

TY - JOUR

T1 - Neuroprotective effects of a dihydropyridine derivative, 1,4-dihydro- 2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 6-(5- phenyl-3-pyrazolyloxy)hexyl ester (CV-159), on rat ischemic brain injury

AU - Miyazaki, Hiroyuki

AU - Tanaka, Shinji

AU - Fujii, Yukiko

AU - Shimizu, Kazuko

AU - Nagashima, Kazuo

AU - Kamibayashi, Masato

AU - Uehara, Takashi

AU - Okuma, Yasunobu

AU - Nomura, Yasuyuki

PY - 1999/1/29

Y1 - 1999/1/29

N2 - CV-159, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5- pyridinedicarboxylic acid methyl 6-(5-phenyl-3-pyrazolyloxy)hexyl ester, is a dihydropyridine derivative that blocks the L-type Ca2+ channel and inhibits the calmodulin (CaM)-dependent pathway. In this study, we examined the effects of CV-159 on rat ischemic brain injury. CV-159 (5 and 10 mg/kg, p.o.) gave significant protection against delayed neuronal death in the hippocampal CA1 region after 15-min transient forebrain ischemia. In contrast, the Ca2+ antagonists nicardipine (1 and 10 mg/kg, p.o.) and nifedipine (1 mg/kg, i.p.) and the CaM antagonist N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W- 7, 500 ng, i.c.v.) had no effect on this hippocampal neuronal death. CV-159 also diminished the size of the brain infarct after permanent middle cerebral artery (MCA) occlusion, although physiological variables, including regional cerebral blood flow, were not affected. The increase in the water content of the infarcted cortex induced by MCA occlusion was significantly reduced by CV-159. On the other hand, neither nicardipine nor nifedipine affected the brain infarct size, volume or increased water content induced by MCA occlusion, as previously reported (A. Sauter and M. Rudin, Am. J. Hypertens. 4 121S-127S, 1991). These findings indicate that Ca2+ antagonists, such as nicardipine and nifedipine, and W-7 have no effect on rat ischemic brain injury. The results suggest that CV-159 protects against ischemic brain injury. This might be mediated by both blocking the L-type Ca2+ channel and inhibiting CaM-dependent function via Ca2+/CaM binding at a different binding site from that of W-7 to CaM (H. Umekawa, K. Yamakawa, K. Nunoki, N. Taira, T. Tanaka, and H. Hidaka, Biochem. Pharmacol. 37 3377-3381, 1988).

AB - CV-159, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5- pyridinedicarboxylic acid methyl 6-(5-phenyl-3-pyrazolyloxy)hexyl ester, is a dihydropyridine derivative that blocks the L-type Ca2+ channel and inhibits the calmodulin (CaM)-dependent pathway. In this study, we examined the effects of CV-159 on rat ischemic brain injury. CV-159 (5 and 10 mg/kg, p.o.) gave significant protection against delayed neuronal death in the hippocampal CA1 region after 15-min transient forebrain ischemia. In contrast, the Ca2+ antagonists nicardipine (1 and 10 mg/kg, p.o.) and nifedipine (1 mg/kg, i.p.) and the CaM antagonist N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W- 7, 500 ng, i.c.v.) had no effect on this hippocampal neuronal death. CV-159 also diminished the size of the brain infarct after permanent middle cerebral artery (MCA) occlusion, although physiological variables, including regional cerebral blood flow, were not affected. The increase in the water content of the infarcted cortex induced by MCA occlusion was significantly reduced by CV-159. On the other hand, neither nicardipine nor nifedipine affected the brain infarct size, volume or increased water content induced by MCA occlusion, as previously reported (A. Sauter and M. Rudin, Am. J. Hypertens. 4 121S-127S, 1991). These findings indicate that Ca2+ antagonists, such as nicardipine and nifedipine, and W-7 have no effect on rat ischemic brain injury. The results suggest that CV-159 protects against ischemic brain injury. This might be mediated by both blocking the L-type Ca2+ channel and inhibiting CaM-dependent function via Ca2+/CaM binding at a different binding site from that of W-7 to CaM (H. Umekawa, K. Yamakawa, K. Nunoki, N. Taira, T. Tanaka, and H. Hidaka, Biochem. Pharmacol. 37 3377-3381, 1988).

KW - Ca/calmodulin

KW - Cerebral ischemia

KW - Delayed neuronal death

KW - Neuroprotection

UR - http://www.scopus.com/inward/record.url?scp=0033613884&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033613884&partnerID=8YFLogxK

U2 - 10.1016/S0024-3205(99)00011-9

DO - 10.1016/S0024-3205(99)00011-9

M3 - Article

C2 - 10096437

AN - SCOPUS:0033613884

VL - 64

SP - 869

EP - 878

JO - Life Sciences

JF - Life Sciences

SN - 0024-3205

IS - 10

ER -