Inhibition of calpain-mediated cell death by a novel peptide inhibitor

McCollum, Adrian T.; Jafarifar, Faegheh; Lynn, Bert C.; Agu, Remigius U.; Stinchcomb, Audra L.; Chen, Qinghua; Guttmann, Rodney P.

doi:10.1016/j.expneurol.2006.07.016

Cited by 11 publications

(10 citation statements)

References 37 publications

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“…This subcellular localization could restrict the access of the inhibitor to calpain located in the proximity of dynamin 1. Regardless of this apparent difference between the lower doses of A-705253 needed to significantly block the cleavage of tau and dynamin 1, our results showed that this inhibitor is effective in nanomolar concentrations instead of the micromolar concentrations needed for other calpain inhibitors (Battaglia et al, 2003;Park and Ferreira, 2005;Kelly and Ferreira, 2006;McCollum et al, 2006). These differences in efficiency could be due to the improved pharmacokinetics of A-705253.…”

Section: Discussionmentioning

confidence: 67%

The novel calpain inhibitor A-705253 potently inhibits oligomeric beta-amyloid-induced dynamin 1 and tau cleavage in hippocampal neurons

Sinjoanu

Kleinschmidt

Bitner

et al. 2008

Neurochemistry International

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We have previously shown that beta-amyloid (Aβ) oligomers induced dynamin 1 and tau cleavage in cultured hippocampal neurons. As a result of this cleavage, dynamin 1 levels decreased and a toxic tau fragment was generated. Aβ-induced cleavage of these proteins was calpain-mediated and impacted both synaptic vesicle recycling and the integrity of neuronal processes (Kelly et al., 2005;Park and Ferreira, 2005;Ferreira, 2006, Kelly andFerreira ,2007). Building on previous reports, these results identified calpain as a potential target for therapeutic intervention in Alzheimer's disease. In the present study, we tested the ability of A-705253, a novel water-soluble calpain inhibitor with oral availability and enhanced metabolic stability, to prevent Aβ-induced dynamin 1 and tau cleavage in cultured hippocampal neurons. Quantitative Western blot analysis indicated that the incubation of these cells with A-705253 prior to the addition of oligomeric Aβ reduced both dynamin 1 and tau cleavage in a dose-dependent manner. In addition, our results showed that this calpain inhibitor significantly ameliorated the cleavage of these proteins when added simultaneously with oligomeric Aβ. Furthermore, our data indicated that the use of this calpain inhibitor could have some beneficial effects even when added after the cleavage of these proteins have been triggered by Aβ. Collectively, these results suggest that, indeed, specific calpain inhibitors could play an important role in the treatment of Alzheimer's disease. KeywordsAlzheimer's disease; proteolysis; tau; dynamin 1; calpain inhibitors Two types of pathological structures, senile plaques and dystrophic neurites containing neurofibrillary tangles, are easily detectable in brain areas associated with learning and memory *Correspondence should be addressed to: Adriana Ferreira, M.D., Ph.D., Department of Cell and Molecular Biology, Ward Building Room 8-140, 303 East Chicago Avenue, Chicago, IL 60611, Phone (312) 503 0597, Fax (312) 503 7345, E-mail: aferreira@northwestern.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Glenner and Wong, 1984;Kosik et al., 1986;Wood et al., 1986;Kondo et al., 1988;Yankner and Mesulam, 1991;Selkoe, 1994;Parihar and Hemnani, 2004;Stern et al., 2004). The coexistence of senile plaques and neurofibrillary tangles in the same brain areas prompted the search for a potential mechanistic link between them. Most of those studies, carried out using cultured neurons as model systems, supported the hypothesis that aggregated Aβ triggered tau phosphorylation followed by the formation of dystrophic neu...

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Section: Discussionmentioning

confidence: 67%

The novel calpain inhibitor A-705253 potently inhibits oligomeric beta-amyloid-induced dynamin 1 and tau cleavage in hippocampal neurons

Sinjoanu

Kleinschmidt

Bitner

et al. 2008

Neurochemistry International

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“…This pentapeptide does not target the active site of calpain [302], but instead binds to the isolated domain IV of calpain 1 [303]. The Leu-Ser-Glu-AlaLeu sequence has high homology to conserved regions of calpastatin's subdomains A and C [302].…”

Section: Inhibitors Lacking a Warheadmentioning

confidence: 99%

Calpains: Attractive Targets for the Development of Synthetic Inhibitors

Pietsch

Chua²,

Abell

2010

CTMC

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The physiological roles of calpains are discussed, as are the associated pathological disorders that result from their over-activation. We also present practical information for establishing functional inhibition assays and an overview of X-ray crystal structures of calpain-inhibitor complexes to aid inhibitor design. These structures reveal the expected extended beta-strand conformation for the inhibitor backbone, a geometry that has been engineered into inhibitors with the introduction of either an N-terminal heterocycle or a macrocycle that links the P(1) and P(3) residues. The structure and function of all the main classes of inhibitors are reviewed, with most examples being classified according to the nature of the C-terminal reactive warhead group that reacts with the active site cysteine of calpains. These inhibitor classes include epoxysuccinate derivatives, aldehydes, aldehyde prodrugs (hemiacetals) and alpha-keto carbonyl compounds. Inhibitors derived from the endogenous inhibitor calpastatin and examples lacking a warhead, are now known and these are also discussed.

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“…Calpains are highly expressed in the spinal cord [8], and it is known that prolonged calpain activation may lead to the degradation of several proteins, including receptors, transporters and cytoskeletal proteins, which results in neuronal damage and an increased susceptibility to toxic stimulation [9][10][11][12]. Accordingly, cell permeable calpain inhibitors, such as leupeptin, provide significant neuroprotection in several in vitro and in vivo models of neurotoxicity, including hypoxia, ischemia, nerve and spinal cord injury, and excitotoxicity [12,[13][14][15][16][17][18][19][20][21][22]. Thus, the second aim of the present work was to know whether the inhibition of calpain by leupeptin could protect rats from the excitotoxic effects of the microdialysis perfusion of AMPA, along the temporal course of its effects.…”

Section: Introductionmentioning

confidence: 99%

Calpain Inhibition Protects Spinal Motoneurons from the Excitotoxic Effects of AMPA In vivo

Corona

Tapia

2008

Neurochem Res

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Microdialysis perfusion of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) in rat lumbar spinal cord produces severe motoneuron damage and consequently hindlimb paralysis. Here we studied the time course of the AMPA-induced neurodegenerative changes and motor alterations, and the protective effect of leupeptin, an inhibitor of calpain, a Ca(2+)-activated protease. Paralysis occurs at 4-6 h after AMPA perfusion, but cresyl violet staining showed that motoneuron damage starts at about 3 h and progresses until reaching 50% neuronal loss at 6 h and 90% loss at 12 h. In contrast, choline acetyltransferase (ChAT) immunohistochemistry revealed that the enzyme is already decreased at 30 min after AMPA perfusion and practically disappears at 3 h. Microdialysis coperfusion of leupeptin with AMPA prevented the motor alterations and paralysis and remarkably reduced both the decrement in ChAT immunoreactivity and the loss of motoneurons. We conclude that an increased Ca(2+) influx through Ca(2+)-permeable AMPA receptors activates calpain, and as a consequence ChAT content decreases earlier than other Ca(2+)-dependent processes, including the proteolytic activity of calpain, cause the death of motoneurons.

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Inhibition of calpain-mediated cell death by a novel peptide inhibitor

Cited by 11 publications

References 37 publications

The novel calpain inhibitor A-705253 potently inhibits oligomeric beta-amyloid-induced dynamin 1 and tau cleavage in hippocampal neurons

The novel calpain inhibitor A-705253 potently inhibits oligomeric beta-amyloid-induced dynamin 1 and tau cleavage in hippocampal neurons

Calpains: Attractive Targets for the Development of Synthetic Inhibitors

Calpain Inhibition Protects Spinal Motoneurons from the Excitotoxic Effects of AMPA In vivo

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