Neuroprotective effects of M826, a reversible caspase‐3 inhibitor, in the rat malonate model of Huntington's disease

Toulmond, Sylvie; Tang, Kenneth; Bureau, Y; Ashdown, Helen; Degen, Sarah; O’Donnell, Ruth; Tam, John; Han, Yongxin; Colucci, John; Giroux, André; Zhu, Yanqiu; Boucher, Mathieu; Pikounis, Bill; Xanthoudakis, Steven; Roy, Sophie; Rigby, Michael; Zamboni, Robert; Robertson, George S.; Ng, Gordon; Nicholson, Donald W.; Flückiger, Jean-Pierre

doi:10.1038/sj.bjp.0705662

Cited by 54 publications

(45 citation statements)

References 41 publications

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“…M-826, a small reversible caspase-3 inhibitor, blocked brain tissue damage in an animal model of hypoxia-ischemia when injected intracerebroventricularly 2 h after ligation (Han et al, 2002). In a mouse model of Huntington's disease, M-826 also prevented cell death of striatal neurons (Toulmond et al, 2004). The broad spectrum caspase inhibitor M-920 as well as the caspase 3-specific inhibitor M-791 decreased lymphocyte apoptosis in thymus and spleen of mice subjected to polymicrobial sepsis induced by cecal ligation-puncture and rescued 80 to 90% of animals from lethal septic shock (Hotchkiss et al, 2000).…”

Section: Fischer and Schulze-osthoffmentioning

confidence: 99%

New Approaches and Therapeutics Targeting Apoptosis in Disease

2005

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Section: Fischer and Schulze-osthoffmentioning

confidence: 99%

New Approaches and Therapeutics Targeting Apoptosis in Disease

2005

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“…This is the model of striatal injury generated by unilateral injections of malonate, another complex II inhibitor that, in contrast with 3-nitropropionic acid, produces cell death through the activation of apoptotic pathways [it activates NMDA receptors and caspase-3 (66)]. Using this model, we found neuroprotection when rats were administered with a selective CB 2 receptor agonist, but not with a selective CB 1 receptor agonist or with an antioxidant cannabinoid with no affinity for both receptor types as CBD (15).…”

Section: Cannabinoids and Neuroprotection In Huntington's Diseasementioning

confidence: 99%

Cannabinoids and Neuroprotection in Basal Ganglia Disorders

et al. 2007

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Cannabinoids have been proposed as clinically promising neuroprotective molecules, as they are capable to reduce excitotoxicity, calcium influx, and oxidative injury. They are also able to decrease inflammation by acting on glial processes that regulate neuronal survival and to restore blood supply to injured area by reducing the vasoconstriction produced by several endothelium-derived factors. Through one or more of these processes, cannabinoids may provide neuroprotection in different neurodegenerative disorders including Parkinson's disease and Huntington's chorea, two chronic diseases that are originated as a consequence of the degeneration of specific nuclei of basal ganglia, resulting in a deterioration of the control of movement. Both diseases have been still scarcely explored at the clinical level for a possible application of cannabinoids to delay the progressive degeneration of the basal ganglia. However, the preclinical evidence seems to be solid and promising. There are two key mechanisms involved in the neuroprotection by cannabinoids in experimental models of these two disorders: first, a cannabinoid receptor-independent mechanism aimed at producing a decrease in the oxidative injury and second, an induction/upregulation of cannabinoid CB2 receptors, mainly in reactive microglia, that is capable to regulate the influence of these glial cells on neuronal homeostasis. Considering the relevance of these preclinical data and the lack of efficient neuroprotective strategies in both disorders, we urge the development of further studies that allow that the promising expectatives generated for these molecules progress from the present preclinical evidence till a real clinical application.

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“…Recently, Toulmond et al 75 showed that an inhibition of caspase-3 activity by the reversible caspase-3 inhibitor (M-826) results in a significant reduction in neuronal death after striatal lesions in adult rats.…”

Section: Caspase-3 In Neurological Diseasementioning

confidence: 99%

Neuronal caspase-3 signaling: not only cell death

2009

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Caspases are a family of cysteinyl aspartate-specific proteases that are highly conserved in multicellular organisms and function as central regulators of apoptosis. A member of this family, caspase-3, has been identified as a key mediator of apoptosis in neuronal cells. Recent studies in snail, fly and rat suggest that caspase-3 also functions as a regulatory molecule in neurogenesis and synaptic activity. In this study, in addition to providing an overview of the mechanism of caspase-3 activation, we review genetic and pharmacological studies of apoptotic and nonapoptotic functions of caspase-3 and discuss the regulatory mechanism of caspase-3 for executing nonapoptotic functions in the central nervous system. Knowledge of biochemical pathway(s) for nonapoptotic activation and modulation of caspase-3 has potential implications for the understanding of synaptic failure in the pathophysiology of neurological disorders. Fine-tuning of caspase-3 lays down a new challenge in identifying pharmacological avenues for treatment of many neurological disorders.

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Neuroprotective effects of M826, a reversible caspase‐3 inhibitor, in the rat malonate model of Huntington's disease

Cited by 54 publications

References 41 publications

New Approaches and Therapeutics Targeting Apoptosis in Disease

New Approaches and Therapeutics Targeting Apoptosis in Disease

Cannabinoids and Neuroprotection in Basal Ganglia Disorders

Neuronal caspase-3 signaling: not only cell death

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