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Titolo:
Death of dopaminergic neurons in vitro and in nigral grafts: Reevaluating the role of caspase activation
Autore:
Hurelbrink, CB; Armstrong, RJE; Luheshi, LM; Dunnett, SB; Rosser, AE; Barker, RA;
Indirizzi:
Cambridge Ctr Brain Repair, Cambridge CB2 2PY, England Cambridge Ctr BrainRepair Cambridge England CB2 2PY ge CB2 2PY, England Univ Wales Coll Cardiff, Sch Biosci, Cardiff CF10 3US, S Glam, Wales Univ Wales Coll Cardiff Cardiff S Glam Wales CF10 3US 3US, S Glam, Wales
Titolo Testata:
EXPERIMENTAL NEUROLOGY
fascicolo: 1, volume: 171, anno: 2001,
pagine: 46 - 58
SICI:
0014-4886(200109)171:1<46:DODNIV>2.0.ZU;2-O
Fonte:
ISI
Lingua:
ENG
Soggetto:
INTERLEUKIN-1-BETA CONVERTING-ENZYME; DOMINANT-NEGATIVE MUTANT; PROGRAMMED CELL-DEATH; PARKINSONS-DISEASE; BRAIN INJURY; TIME-COURSE; IL-1-BETA-CONVERTING ENZYME; NEURAL TRANSPLANTATION; MEDIATED APOPTOSIS; CEREBRAL-ISCHEMIA;
Keywords:
Parkinson's disease; Ac-YVAD-cmk; AcDEVD-cmk; apoptosis; cleaved caspase-3; neural transplantation; rat;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
56
Recensione:
Indirizzi per estratti:
Indirizzo: Hurelbrink, CB Cambridge Ctr Brain Repair, Forvie Site,Robinson Way, Cambridge CB2 2PY, England Cambridge Ctr Brain Repair Forvie Site,Robinson Way Cambridge England CB2 2PY
Citazione:
C.B. Hurelbrink et al., "Death of dopaminergic neurons in vitro and in nigral grafts: Reevaluating the role of caspase activation", EXP NEUROL, 171(1), 2001, pp. 46-58

Abstract

Caspases are cysteine proteases involved in apoptotic cell death, and pharmacological caspase inhibition has been demonstrated to prevent neuronal cell death in certain experimental paradigms. In this study, the role of caspase-1 and -3 in the death of dopaminergic neurons derived from the E14 rat ventral mesencephalon (VM) has been examined in two model systems using peptide caspase inhibitors. First, cell death was induced in vitro by withdrawing serum after 2 days. Different doses of caspase-1 (IL-1 beta converting enzyme) and caspase-3 inhibitors (Ac-DEVD-cmk) were added to the medium at the time of serum withdrawal, and the ability of the inhibitors to promote dopaminergic neuronal survival and prevent activation of caspase-3 was assessed at 7 days. Immunostaining using tyrosine hydroxylase (TH) and cleaved caspase-3 antibodies demonstrated that caspase-1 and -3 inhibitors reduce caspase-3 activation as well as overall cell death. This did not, however, improve the survival of TH-positive neurons, although it did appear to promote their maturation. The second paradigm investigated the effects of these inhibitors in the 6-hydroxydopamine rat model of PD, and similarly, addition of caspase-1 or -3 inhibitor during tissue preparation or immediately prior to grafting of VM tissue did not promote dopaminergic neuronal survival. These results demonstrate that the reduction of apoptotic cell death by pharmacological inhibition of caspase-1 and -3 does not increase dopaminergicneuronal survival in these paradigms and suggest either that caspase-3 activation is not the major determinant of dopaminergic neuronal death in vitro and in grafts or that the ability of caspase inhibitors to rescue cells depends upon the degree of apoptotic stress. This implies that strategies toimprove dopaminergic cell survival in clinical programmes of transplantation for PD will need to target other pathways of cell death. (C) 2001 Academic Press.

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Documento generato il 02/07/20 alle ore 22:36:17