Central administration of a caspase inhibitor impairs shuttle-box performance in rats

Stepanichev, M. Yu.; Kudryashova, I. V.; Yakovlev, A. A.; Онуфриев, М. В.; Хаспеков, Л. Г.; Lyzhin, A. A.; Лазарева, Н. А.; Gulyaeva, N. V.

doi:10.1016/j.neuroscience.2005.08.010

Cited by 43 publications

(31 citation statements)

References 76 publications

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“…Similar unidirectional effects of pancaspase inhibitor z-VAD-fmk and caspase 3 specific inhibitor z-DEVD-fmk observed in experiments indicate the key role of caspase 3 in these processes, which is confirmed by experiments on other models [4,8].…”

Section: Resultssupporting

confidence: 80%

“…Study of the central effects of z-DEVD-fmk on the active avoidance model showed that specific caspase 3 inhibitor significantly reduced the total number of avoidance reactions and disordered the formation of escape reaction, a component of avoidance response related to spatial orientation. In addition, a decrease in the total number of responses to conditioned stimulus (light) and in the level of interstimulus reactions was observed, this indicating the effect of the test inhibitors on the mental status and orientation and exploratory activity of animals [8]. We consider that the disagreement in experimental data is caused by the characteristics of experimental models and differences in the protocols of training and caspase treatment.…”

Section: Resultsmentioning

confidence: 91%

“…However, experimental data on the role of caspases in the mechanisms of learning and memory are scanty and contradictory [2,4,5,8].…”

mentioning

confidence: 99%

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Central injection of caspase inhibitors facilitates the formation of freezing behavior in rats

et al. 2007

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Section: Resultssupporting

confidence: 80%

Section: Resultsmentioning

confidence: 91%

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Central injection of caspase inhibitors facilitates the formation of freezing behavior in rats

et al. 2007

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“…In vitro and in vivo studies show that caspase-3 contributes not only to the regulation of neuronal morphology and cell migration, but its cleavage occurs also in mature neurons during long term potentiation of synaptic activity: caspase-3 inhibitors block long term potentiation, memory and learning (53)(54)(55). Long term potentiation, memory and learning are also strongly impaired in NCAM-deficient mice (56).…”

Section: Discussionmentioning

confidence: 99%

Clustering of the Neural Cell Adhesion Molecule (NCAM) at the Neuronal Cell Surface Induces Caspase-8- and -3-dependent Changes of the Spectrin Meshwork Required for NCAM-mediated Neurite Outgrowth

Westphal

Sytnyk

Schachner

et al. 2010

Journal of Biological Chemistry

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Changes in neuronal morphology underlying neuronal differentiation depend on rapid and sustained cytoskeleton rearrangements in the growing neurites. Whereas cell adhesion molecules are well established as regulators of neuronal differentiation, less is known about the signaling mechanisms by which they influence the cytoskeleton. Here we show that the neural cell adhesion molecule (NCAM) associates with the active form of caspase-8 and that clustering of NCAM at the neuronal cell surface leads to activation of caspase-8 and -3 followed by the cleavage of the sub-membranous brain spectrin meshwork, but not of the actin or tubulin cytoskeleton. Inhibitors of caspase-8 and -3 specifically block the NCAM-dependent spectrin cleavage and abolish NCAM-dependent neurite outgrowth. NCAM-dependent rearrangements of the membrane associated spectrin meshwork via caspase-8 dependent caspase-3 activation are thus indispensable for NCAM-mediated neurite outgrowth.The establishment and maintenance of neuronal morphology are essential for brain development and functioning. The neural cell adhesion molecule (NCAM) 2 plays a prominent role in these processes by being involved in regulation of neuronal migration and differentiation as well as synaptogenesis in the developing nervous system and synaptic plasticity in the adult (1-4). NCAM is a member of the immunoglobulin superfamily of adhesion molecules and contains five immunoglobulin and two fibronectin-like type III domains within its extracellular part. In developing neurons, NCAM is highly expressed in two transmembrane isoforms with molecular weights of 140 kDa (NCAM140) and, to a lower extent, 180 kDa (NCAM180), which are generated via alternative splicing of the ncam1 gene. The extracellular portion of NCAM interacts with multiple binding partners on adjacent cells and in the extracellular matrix, including adhesion molecules, such as prion protein (PrP), L1, and NCAM itself (5, 6), growth factor receptors, such as FGFR and GFR␣ (7,8), and other receptors, such as receptor-type protein phosphatase ␤ or its secreted forms (9).Clustering of NCAM at the cell surface by its ligands promotes neurite outgrowth by inducing intracellular signaling cascades, initiated by the association of the intracellular domain of NCAM with and consequent activation of kinases and phosphatases, including CaMKII␣, PKC, and RPTP␣ (10 -12). Palmitoylation of the intracellular domain of NCAM (13) and association of NCAM with the cellular form of prion protein (PrP) (5) promote redistribution of NCAM and associated signaling molecules to lipid rafts where they activate downstream signal transducing proteins including fyn kinase and GAP43 (10,12,14,15).The cytoskeleton plays an important role in NCAM-dependent signaling, and clustering of NCAM at the cell surface induces formation of the spectrin-based cytoskeleton enriched in microdomains (3). However, little is known on how NCAM signaling is coordinated with the cytoskeleton reorganization including not only its polymerization but also local remode...

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“…Stephanichev et al 40 showed that intracerebroventricular administration of z-DEVD-fmk decreased the number of avoidance reactions in some blocks of behavioral trials in active avoidance learning. Application of caspase-3 inhibitor z-DEVD-CHO to the cerebellar vermis stimulated the extinction of an acoustic startle reaction.…”

Section: Caspase-3 and Neuroplasticitymentioning

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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Central administration of a caspase inhibitor impairs shuttle-box performance in rats

Cited by 43 publications

References 76 publications

Central injection of caspase inhibitors facilitates the formation of freezing behavior in rats

Central injection of caspase inhibitors facilitates the formation of freezing behavior in rats

Clustering of the Neural Cell Adhesion Molecule (NCAM) at the Neuronal Cell Surface Induces Caspase-8- and -3-dependent Changes of the Spectrin Meshwork Required for NCAM-mediated Neurite Outgrowth

Neuronal caspase-3 signaling: not only cell death

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