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1.
Brain Res ; 1149: 181-90, 2007 May 29.
Article in English | MEDLINE | ID: mdl-17391653

ABSTRACT

The immunosuppressant cyclosporin A (CsA) has been shown to exert potent neuroprotective effects, possibly via the inhibition of calcineurin and mitochondrial permeability transition pore formation. Here, we investigated the neuroprotective profile of a novel derivative of CsA, FR901459, by evaluating its effects against in vitro mitochondrial damage and in vivo brain damage in transient global or focal cerebral ischemia models, in comparison with those of CsA. Efficacy of calcineurin inhibition was estimated from its immunosuppressive effect on the mixed lymphocyte reaction. Results showed that the immunosuppressive effect of FR901459 was approximately 7-fold less potent than that of CsA. In contrast, FR901459 suppressed Ca(2+)-induced mitochondrial swelling measured in isolated liver mitochondria with greater potency than CsA. Further, FR901459 showed approximately 30-fold greater neuroprotective potency than CsA against neuronal cell damage induced by thapsigargin in SH-SY5Y cells. In a transient global cerebral ischemia model in gerbils, FR901459 showed the dose-dependent suppression of neuronal cell death, while FR901459 was less efficacious than CsA. In a rat transient focal ischemia model, FR901459 tended to reduce brain damage on both intravenous injection as well as intracerebroventricular infusion, but with less efficacy than CsA which significantly reduced the damage. These findings suggest that FR901459 exerts a potent neuroprotective effect by inhibiting mitochondrial damage in vitro, but that in in vivo transient cerebral ischemia, its immunosuppressive component which possibly acts via the inhibition of calcineurin may play a more important role in attenuating brain damage than its inhibitory effect against mitochondrial damage.


Subject(s)
Cyclosporine/pharmacology , Hypoxia, Brain/prevention & control , Ischemic Attack, Transient/drug therapy , Mitochondria/drug effects , Neuroprotective Agents/pharmacology , Animals , Cell Line, Tumor , Gerbillinae , Humans , Hypoxia, Brain/etiology , In Vitro Techniques , Ischemic Attack, Transient/complications , Lymphocyte Culture Test, Mixed , Mitochondria/pathology , Rats
2.
Eur J Pharmacol ; 498(1-3): 179-88, 2004 Sep 13.
Article in English | MEDLINE | ID: mdl-15363993

ABSTRACT

We compared the antithrombotic efficacy of FK419 [(S)-2-acetylamino-3-[(R)-[1-[3-(piperidin-4-yl)propionyl]piperidin-3-ylcarbonyl]amino] propionic acid trihydrate], a novel nonpeptide glycoprotein IIb/IIIa antagonist, with recombinant tissue plasminogen activator (rt-PA) and other antithrombotic agents (aspirin, ozagrel, argatroban and heparin). FK419 not only inhibited ADP- and collagen-induced guinea pig platelet aggregation, but also induced disaggregation for ADP-induced aggregated platelets in vitro. In the photochemically induced middle cerebral artery thrombosis model in guinea pigs, FK419 dose-dependently shortened the time to first reperfusion and the total middle cerebral artery occlusion time and reduced ischemic brain damage and ameliorated neurological deficits measured 24 h after middle cerebral artery occlusion. Rt-PA similarly improved the middle cerebral artery patency, brain damage and neurological deficits. Neither aspirin, ozagrel, argatroban nor heparin restored the middle cerebral artery blood flow and improved the brain damage or neurological deficits. These results demonstrated that novel glycoprotein IIb/IIIa antagonist FK419 could disperse thrombus and ameliorated ischemic brain damage, suggesting that FK419 would be an attractive intervention for stroke patients.


Subject(s)
Fibrinolytic Agents/pharmacology , Middle Cerebral Artery/drug effects , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Thrombosis/drug therapy , Animals , Blood Coagulation/drug effects , Blood Flow Velocity/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Fibrinolysis/drug effects , Fibrinolytic Agents/therapeutic use , Guinea Pigs , Male , Middle Cerebral Artery/pathology , Middle Cerebral Artery/physiopathology , Platelet Aggregation/drug effects , Quinolines/pharmacology , Time Factors
3.
J Pharmacol Exp Ther ; 310(2): 425-36, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15075382

ABSTRACT

The activation of poly(ADP-ribose) polymerase-1 (PARP-1) after exposure to nitric oxide or oxygen-free radicals can lead to cell injury via severe, irreversible depletion of NAD. Genetic deletion or pharmacological inhibition of PARP-1 attenuates brain injury after focal ischemia and neurotoxicity in several neurodegenerative models in animals. FR247304 (5-chloro-2-[3-(4-phenyl-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone) is a novel PARP-1 inhibitor that has recently been identified through structure-based drug design. In an enzyme kinetic analysis, FR247304 exhibits potent and competitive inhibition of PARP-1 activity, with a K(i) value of 35 nM. Here, we show that prevention of PARP activation by FR247304 treatment protects against both reactive oxygen species-induced PC12 cell injury in vitro and ischemic brain injury in vivo. In cell death model, treatment with FR247304 (10(-8)-10(-5) M) significantly reduced NAD depletion by PARP-1 inhibition and attenuated cell death after hydrogen peroxide (100 microM) exposure. After 90 min of middle cerebral artery occlusion in rats, poly(ADP-ribosy)lation and NAD depletion were markedly increased in the cortex and striatum from 1 h after reperfusion. The increased poly(ADP-ribose) immunoreactivity and NAD depletion were attenuated by FR247304 (32 mg/kg i.p.) treatment, and FR247304 significantly decreased ischemic brain damage measured at 24 h after reperfusion. Whereas other PARP inhibitors such as 3-aminobenzamide and PJ34 [N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylactamide] showed similar neuroprotective actions, they were less potent in in vitro assays and less efficacious in an in vivo model compared with FR247304. These results indicate that the novel PARP-1 inhibitor FR247304 exerts its neuroprotective efficacy in in vitro and in vivo experimental models of cerebral ischemia via potent PARP-1 inhibition and also suggest that FR247304 or its derivatives could be attractive therapeutic candidates for stroke and neurodegenerative disease.


Subject(s)
Brain Ischemia/enzymology , Enzyme Inhibitors/pharmacology , Neurons/drug effects , Neurons/enzymology , Poly(ADP-ribose) Polymerase Inhibitors , Pyridines/pharmacology , Quinazolines/pharmacology , Animals , Brain/drug effects , Brain/enzymology , Brain Ischemia/prevention & control , Cell Death/drug effects , Cell Death/physiology , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Humans , Hydrogen Peroxide/toxicity , Male , Mice , PC12 Cells , Poly (ADP-Ribose) Polymerase-1 , Poly(ADP-ribose) Polymerases/metabolism , Pyridines/chemistry , Pyridines/therapeutic use , Quinazolines/chemistry , Quinazolines/therapeutic use , Quinazolinones , Rats , Rats, Wistar
4.
J Pharmacol Exp Ther ; 308(3): 1094-101, 2004 Mar.
Article in English | MEDLINE | ID: mdl-14634048

ABSTRACT

Platelet activation and subsequent aggregation play a key role in the pathogenesis of ischemic brain damage. Recent studies revealed that enhanced platelet activation is also observed after ischemia, suggesting that secondary thrombus formation might participate in the development of cerebral infarction. The binding of platelet glycoprotein GPIIb/IIIa (integrin alpha(IIb)beta3) to fibrinogen is the final common pathway in platelet aggregation. Therefore, GPIIb/IIIa antagonists might be useful in acute ischemic stroke as well as in the secondary prevention of ischemic stroke. In the present study, we evaluated the effect of three compounds, FK419 ((S)-2-acetylamino-3-[(R)-[1-[3-(piperidin-4-yl) propionyl] piperidin-3-ylcarbonyl] amino] propionic acid trihydrate), a novel nonpeptide GPIIb/IIIa antagonist, ozagrel, a selective thromboxane A(2) synthase inhibitor, and argatroban, a thrombin inhibitor, on middle cerebral artery (MCA) patency and ischemic brain damage using photochemically induced MCA thrombosis model in guinea pigs. FK419, ozagrel, or argatroban was administered 5 min after the termination of photoirradiation. FK419 dose-dependently improved MCA patency by decreasing the total occlusion time, time to continuous reperfusion, and the number of cyclic flow reductions, at doses that inhibited ADP-induced platelet aggregation ex vivo. In contrast, ozagrel only improved total occlusion time, and argatroban showed no improvement in MCA patency. FK419 also reduced ischemic brain damage in a dose-dependent fashion, whereas ozagrel and argatroban did not. Finally, FK419 ameliorated neurological deficits, whereas ozagrel and argatroban did not. These results indicate that FK419, a GPIIb/IIIa antagonist, ameliorates ischemic brain damage by improving MCA patency after occlusion and that FK419 is a promising candidate for the treatment of acute ischemic stroke.


Subject(s)
Antithrombins/therapeutic use , Infarction, Middle Cerebral Artery/drug therapy , Platelet Aggregation Inhibitors/therapeutic use , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Animals , Arginine/analogs & derivatives , Blood Coagulation/drug effects , Blood Platelets/drug effects , Blood Platelets/physiology , Brain Ischemia/complications , Brain Ischemia/drug therapy , Disease Models, Animal , Guinea Pigs , Male , Methacrylates/therapeutic use , Pipecolic Acids/therapeutic use , Reperfusion Injury/prevention & control , Sulfonamides , Thromboxane B2/metabolism
5.
J Biol Chem ; 277(1): 623-9, 2002 Jan 04.
Article in English | MEDLINE | ID: mdl-11679586

ABSTRACT

Emerging evidence has shown that tumor suppressor p53 expression is enhanced in response to brain ischemia/hypoxia and that p53 plays a critical role in the cell death pathway in such an acute neurological insult. However the mechanism remains unclear. Recently it was reported that Peg3/Pw1, originally identified as a paternally expressed gene, plays a pivotal role in the p53-mediated cell death pathway in mouse fibroblast cell lines. In this study, we found that Peg3/Pw1 expression is enhanced in peri-ischemic neurons in rat stroke model by in situ hybridization analysis, where p53 expression was also induced by immunohistochemical analysis. Moreover, we found that p53 was co-localized with Peg3/Pw1 in brain ischemia/hypoxia by double staining analysis. In human neuroblastoma-derived SK-N-SH cells, Peg3/Pw1 mRNA expression is enhanced remarkably at 24 h post-hypoxia, when p53 protein expression was also enhanced at high levels. Subcellular localization of Peg3/Pw1 was observed in the nucleus. Adenovirus-mediated high dose p53 overexpression induced Peg3/Pw1 mRNA expression. Overexpression of Peg3/Pw1 reduced cell viability under hypoxic conditions, whereas that of the C-terminal-deleted mutant and anti-sense Peg3/Pw1 inhibited hypoxia-induced cell death. These results suggest that Peg3/Pw1 is involved in the p53-mediated cell death pathway as a downstream effector of p53 in brain ischemia/hypoxia.


Subject(s)
Hypoxia-Ischemia, Brain/metabolism , Protein Kinases , Proteins/physiology , Transcription Factors , Tumor Suppressor Protein p53/physiology , Animals , Cell Death , Cell Survival , DNA-Binding Proteins , Gene Expression Regulation , Hypoxia-Ischemia, Brain/pathology , Kruppel-Like Transcription Factors , Proteins/analysis , Proteins/genetics , RNA, Messenger/analysis , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction , Tumor Suppressor Protein p53/analysis
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