Reduction of myocardial infarction by calpain inhibitors A-705239 and A-705253 in isolated perfused rabbit hearts

Neuhof, Christiane; Fabiunke, Verena; Deibele, Karin; Speth, Maria; Möller, Achim; Lubisch, W.; Fritz, Hans; Tillmanns, Harald; Neuhof, H.

doi:10.1515/bc.2004.139

Cited by 23 publications

(16 citation statements)

References 31 publications

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“…This finding is important in light of the fact that the proteasome complex contributes to a variety of neurodegenerative disorders (Rubinsztein, 2006;Pan et al, 2008). A-705253 has previously been shown to rapidly and effectively penetrate myocardial tissues, and it exerts its effects on cellular targets within minutes after perfusion (Neuhof et al, 2003(Neuhof et al, , 2004, making it an ideal compound for studying calpain in vivo.…”

Section: Calpain Inhibition Prevents Excitotoxicity In Vivo 349mentioning

confidence: 98%

Inhibition of Calpain Prevents N-Methyl-d-aspartate-Induced Degeneration of the Nucleus Basalis and Associated Behavioral Dysfunction

Nimmrich¹,

Szabo²,

Nyakas³

et al. 2008

J Pharmacol Exp Ther

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N-Methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity is thought to underlie a variety of neurological disorders, and inhibition of either the NMDA receptor itself, or molecules of the intracellular cascade, may attenuate neurodegeneration in these diseases. Calpain, a calcium-dependent cysteine protease, has been identified as part of such an NMDA receptorinduced excitotoxic signaling pathway. The present study addressed the question of whether inhibition of calpain can prevent neuronal cell death and associated behavioral deficits in a disease-relevant animal model, which is based on excitotoxic lesions of the cholinergic nucleus basalis magnocellularis of Meynert. Excitotoxic lesions of the nucleus basalis with NMDA induced a markedly impaired performance in the novel object recognition test. Treatment with the calpain inhibitor,, dose-dependently prevented the behavioral deficit. Subsequent analysis of choline acetyltransferase in the cortical mantle of the lesioned animals revealed that application of A-705253 dose-dependently and significantly attenuated cholinergic neurodegeneration. Calpain inhibition also significantly diminished the accompanying gliosis, as determined by immunohistochemical analysis of microglia activation. Finally, inhibition of calpain by A-705253 and the peptidic calpain inhibitor N-acetyl-Leu-LeuNle-CHO did not impair long-term potentiation in hippocampal slices, indicating that calpain inhibition interrupts NMDA excitotoxicity pathways without interfering with NMDA receptormediated signaling involved in cognition. We conclude that inhibition of calpains may represent a valuable strategy for the prevention of excitotoxicity-induced neuronal decline without interfering with the physiological neuronal functions associated with learning and memory processes. Thus, calpain inhibition may be a promising and novel approach for the treatment of various neurodegenerative disorders.Calpains in the central nervous system are Ca 2ϩ -dependent cysteine proteases, which can modulate the conformation, localization, and activity of various proteins. Calpaininduced modifications have a profound affect on biological processes as different as cell cycle progression and vesicular trafficking. They are an integrative part of several signaling cascades, but they can also contribute to apoptotic and necrotic cell death in pathological conditions. For this reason, calpains have been discussed extensively as target for therapeutic interventions in a number of neurodegenerative disease that are associated with neuronal loss (for review, see Huang and Wang, 2001;Goll et al., 2003;Zatz and Starling, 2005).In that respect, it has recently been shown that inhibition of calpains prevents excitotoxic neuronal cell death in vitro (Caba et al., 2002;Ray et al., 2006) and in vivo (Chiu et al., 2005;Takano et al., 2005). Excitotoxicity is caused by an overstimulation of N-methyl-D-aspartate (NMDA) receptors, and there is now growing evidence that calpain cleaves sevArticle, publication date, and cita...

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Section: Calpain Inhibition Prevents Excitotoxicity In Vivo 349mentioning

confidence: 98%

Inhibition of Calpain Prevents N-Methyl-d-aspartate-Induced Degeneration of the Nucleus Basalis and Associated Behavioral Dysfunction

Nimmrich¹,

Szabo²,

Nyakas³

et al. 2008

J Pharmacol Exp Ther

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“…Furthermore, calpains have been implicated in the execution of myocardial cell death during ischemia-reperfusion. Calpain activation mediates Ca 2ϩ overload-induced proteolysis in these processes, as is evident from observations that pharmacological inhibition of calpains has significantly attenuated myocardial stunning and reduced infarct size after ischemia-reperfusion (5)(6)(7)(8)(9)(11)(12)(13)(14).…”

mentioning

confidence: 98%

Calpain-dependent Cleavage of N-cadherin Is Involved in the Progression of Post-myocardial Infarction Remodeling

Kudo-Sakamoto

Akazawa

Ito

et al. 2014

Journal of Biological Chemistry

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Background:The consequences of calpain activation after myocardial infarction (MI) are not fully elucidated. Results: Post-MI remodeling was exacerbated in calpastatin-deficient hearts, and calpain activation disrupted N-cadherinbased cell adhesions. Conclusion: Unregulated activation of calpains contributes to progression of post-MI remodeling. Significance: Pharmacological intervention of the calpain-calpastatin system will be a promising strategy in the treatment of post-MI remodeling.

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“…To evaluate therapeutic procedures and drugs aimed at modulating infarct size, it is important not only to measure the size of an infarct but also to know how much myocardium was at risk. 4,5 Thus, the percentage of infarcted myocardium within the area at risk provides an index that controls for factors that modulate infarct size other than the intervention or treatment. 6 -8 Measuring the area at risk is difficult in patients with acute myocardial infarction (MI).…”

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confidence: 99%

Retrospective Determination of the Area at Risk for Reperfused Acute Myocardial Infarction With T2-Weighted Cardiac Magnetic Resonance Imaging

et al. 2006

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Background-The aim of this study was to determine whether edema imaging by T2-weighted cardiac magnetic resonance (CMR) imaging could retrospectively delineate the area at risk in reperfused myocardial infarction. We hypothesized that the size of the area at risk during a transient occlusion would be similar to the T2-weighted hyperintense region observed 2 days later, that the T2-weighted hyperintense myocardium would show partial functional recovery after 2 months, and that the T2 abnormality would resolve over 2 months. Methods and Results-Seventeen dogs underwent a 90-minute coronary artery occlusion, followed by reperfusion. The area at risk, as measured with microspheres (9 animals), was comparable to the size of the hyperintense zone on T2-weighted images 2 days later (43.4Ϯ3.3% versus 43.0Ϯ3.4% of the left ventricle; PϭNS), and the 2 measures correlated (Rϭ0.84). The infarcted zone was significantly smaller (23.1Ϯ3.7; both PϽ0.001). To test whether the hyperintense myocardium would exhibit partial functional recovery over time, 8 animals were imaged on day 2 and 2 months later. Systolic strain was mapped with displacement encoding with stimulated echoes. Edema, as detected by a hyperintense zone on T2-weighted images, resolved, and regional radial systolic strain partially improved from 4.9Ϯ0.7 to 13.1Ϯ1.5 (Pϭ0.001) over 2 months. Conclusions-These findings are consistent with the premise that the T2 abnormality depicts the area at risk, a zone of reversibly and irreversibly injured myocardium associated with reperfused subendocardial infarctions. The persistence of postischemic edema allows T2-weighted CMR to delineate the area at risk 2 days after reperfused myocardial infarction.

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Reduction of myocardial infarction by calpain inhibitors A-705239 and A-705253 in isolated perfused rabbit hearts

Cited by 23 publications

References 31 publications

Inhibition of Calpain Prevents N-Methyl-d-aspartate-Induced Degeneration of the Nucleus Basalis and Associated Behavioral Dysfunction

Inhibition of Calpain Prevents N-Methyl-d-aspartate-Induced Degeneration of the Nucleus Basalis and Associated Behavioral Dysfunction

Calpain-dependent Cleavage of N-cadherin Is Involved in the Progression of Post-myocardial Infarction Remodeling

Retrospective Determination of the Area at Risk for Reperfused Acute Myocardial Infarction With T2-Weighted Cardiac Magnetic Resonance Imaging

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