Biotin-deficiency facilitates kindling hyperexcitability in rats.

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Amyloid β-peptide(1-42) and hydrogen peroxide-induced toxicity are mediated by TRPM2 in rat primary striatal cultures

‘The definitive version is available at www.blackwell-synergy.com '. Copyright by Blackwell Publishing. DOI: 10.1111/j.1471-4159.2005.03396.x [Full text of this article is not available in the UHRA]Amyloid β-peptide (Aβ) is the main component of senile plaques which characterize Alzheimer's disease and may induce neuronal death through mechanisms which include oxidative stress. To date, the signalling pathways linking oxidant stress, a component of several neurodegenerative diseases, to cell death in the CNS are poorly understood. Melastatin-like transient receptor potential 2 (TRPM2) is a Ca2+-permeant non-selective cation channel, which responds to increases in oxidative stress levels in the cell and is activated by oxidants such as hydrogen peroxide. We demonstrate here that Aβ and hydrogen peroxide both induce death in cultured rat striatal cells which express TRPM2 endogenously. Transfection with a splice variant that acts as a dominant negative blocker of TRPM2 function (TRPM2-S) inhibited both hydrogen peroxide- and Aβ-induced increases in intracellular-free Ca2+ and cell death. Functional inhibition of TRPM2 activation by the poly(ADP-ribose)polymerase inhibitor SB-750139, a modulator of intracellular pathways activating TRPM2, attenuated hydrogen peroxide- and Aβ-induced cell death. Furthermore, a small interfering RNA which targets TRPM2, reduced TRPM2 mRNA levels and the toxicity induced by hydrogen peroxide and Aβ. These data demonstrate that activation of TRPM2, functionally expressed in primary cultures of rat striatum, contributes to Aβ- and oxidative stress-induced striatal cell death.Peer reviewe

Poly(ADP-ribose) polymerase (PARP) revisited. A new role for an old enzyme: PARP involvement in neurodegeneration and PARP inhibitors as possible neuroprotective agents

PolyADP-ribosylation can, in turn, modify the activities of various proteins. PAW has been shown to be activated by nicks in the DNA molecule and to be involved in DNA plasticity-related phenomena such as DNA repair, carcinogenesis, cell proliferation and gene expression. PARP inhibitors, such as benzamide, have been shown to differently affect the long-term survival of different cell types subjected to varying insults. For example, benzamide can increase the mortality of glucocorticoid-treated mouse lymphoma cells, while it can also prevent the death of a murine macrophage tumor cell line exposed to hydrogen peroxidation. The first part of the present series of studies was undertaken to investigate the possible involvement of PARP in glutamate-induced neurotoxicity in cerebellar granule cells in vitro, and the effects of PAW inhibitors on the survival of these neurons. In the second part of the study, the in vivo effects of PARP inhibitors on MPTP-induced catecholamine neurotoxicity in C57B1/6N mice were examined. Although these compounds might act at other sites in addition to PAW, the results of our studies indicate that PARP inhibitors possess neuroprotective potential in vivo and suggest a role of PARP in MPTP neurotoxicity