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

Abstract

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...

The Calpain Inhibitor A-705253 Attenuates Alcohol-Seeking and Relapse with Low Side-Effect Profile

“…Not unexpectedly, very similar to NDMAR antagonists (Nyakas et al, 2011), calpain inhibitors exert neuroprotective effects in an animal model (Nimmrich et al, 2008). The present study suggests that calpain inhibitors may share other therapeutically interesting effects described previously for NMDAR antagonists.…”

“…One possible path forward to solve this problem is identification of processes downstream to NMDARs that would be able to retain therapeutic efficacy and not the side effects. Adding to the previously published evidence on neuroprotective effects of calpain inhibition (Nimmrich et al, 2008), the present study further points at calpain inhibition as the strategy to selectively retain therapeutic benefits of NMDAR antagonists.…”

“…A-705253 has a Ki for calpain inhibition of 53 nM, and has been previously used in in vivo studies (Nimmrich et al, 2008), with a sufficiently long half-life (2.3-5 h) and, at C max , brain levels reach 90 ng/g (186 nM) after subcutaneous administration of 10 mg/kg in the rat (AbbVie, unpublished data; Lubisch et al, 2003) .…”

Calpains: Attractive Targets for the Development of Synthetic Inhibitors

“…Compound (19f) has also been shown to significantly reduce beta-amyloid-induced calpain-mediated cleavage of dynamin 1 and tau in an in vitro model of Alzheimer's disease [285]. Moreover, (19f) prevents N-methyl-D-aspartate-induced neurodegeneration of nuclear basalis magnocellularis and associated decrease of cortical cholinergic innervation in rat, and attenuates cognitive deficits that occur as a result of such neurodegeneration [286].…”

Calpain 2 Activated through N-Methyl-d-Aspartic Acid Receptor Signaling Cleaves CPEB3 and Abrogates CPEB3-Repressed Translation in Neurons

“…ischemia (7,19,31). In several neurodegenerative mouse models, the inhibition of calpain activity ameliorates neuronal death and improves behaviors (15,25,39). This study shows that a short pulse of NMDA, a paradigm used to induce c-LTD, and sustained NMDA incubation accompanied with excitotoxicity, all induce calpain activity to proteolyze CPEB3.…”