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Titolo:
The novel calpain inhibitor SJA6017 improves functional outcome after delayed administration in a mouse model of diffuse brain injury
Autore:
Kupina, NC; Nath, R; Bernath, EE; Inoue, J; Mitsuyoshi, A; Yuen, PW; Wang, KKW; Hall, ED;
Indirizzi:
Pfizer Global Res & Dev, Ann Arbor Labs, Neurosci Therapeut, Ann Arbor, MI48015 USA Pfizer Global Res & Dev Ann Arbor MI USA 48015 ut, Ann Arbor, MI48015 USA Senju Pharmaceut Co Ltd, Kobe Creat Ctr, Kobe, Hyogo, Japan Senju Pharmaceut Co Ltd Kobe Hyogo Japan e Creat Ctr, Kobe, Hyogo, Japan Pfizer Global Res & Dev, Ann Arbor Labs, Neurosci Chem, Ann Arbor, MI 48015 USA Pfizer Global Res & Dev Ann Arbor MI USA 48015 m, Ann Arbor, MI 48015 USA
Titolo Testata:
JOURNAL OF NEUROTRAUMA
fascicolo: 11, volume: 18, anno: 2001,
pagine: 1229 - 1240
SICI:
0897-7151(200111)18:11<1229:TNCISI>2.0.ZU;2-E
Fonte:
ISI
Lingua:
ENG
Soggetto:
AMYLOID PRECURSOR PROTEIN; FOCAL CEREBRAL-ISCHEMIA; SPINAL-CORD INJURY; CLOSED-HEAD INJURY; AXONAL INJURY; SPECTRIN PROTEOLYSIS; RAT; NEURONS; CALCIUM; DEGRADATION;
Keywords:
calpain activation; calpain-mediated spectrin proteolysis; neuroprotection; traumatic brain injury;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
61
Recensione:
Indirizzi per estratti:
Indirizzo: Hall, ED Pfizer Global Res & Dev, Ann Arbor Labs, Neurosci Therapeut, 2800PlymouthRd, Ann Arbor, MI 48015 USA Pfizer Global Res & Dev 2800 Plymouth Rd Ann Arbor MI USA 48015 A
Citazione:
N.C. Kupina et al., "The novel calpain inhibitor SJA6017 improves functional outcome after delayed administration in a mouse model of diffuse brain injury", J NEUROTRAU, 18(11), 2001, pp. 1229-1240

Abstract

A principal mechanism of calcium-mediated neuronal injury is the activation of neutral proteases known as calpains. Proteolytic substrates for calpain include receptor and cytoskeletal proteins, signal transduction enzymes and transcription factors. Recently, calpain inhibitors have been shown to provide benefit in rat models of focal head injury and focal cerebral ischemia. The present study sought to investigate, in experiment 1, the time course of calpain-mediated cytoskeletal injury in a mouse model of diffuse headinjury by measuring the 150- and 145-kDa alpha -spectrin breakdown products (SBDP). Secondly, in experiment 2, we examined the effect of early (20 min postinjury) administration of the novel calpain inhibitor SJA6017 on functional outcome measured 24 h following injury and its effect on posttraumatic ce-spectrin degradation. Lastly, in experiment 3, we examined the effectof delayed (4 or 6 h postinjury) administration of SJA6017 on 24-h postinjury functional outcome. In experiment 1, isoflurane-anesthetized male CF-1 mice (18-22 g) were subjected to a 750 g-cm weight drop-induced injury and were sacrificed for SBDP analysis at postinjury times of 30 min, and 1, 2, 6, 24 and 48 h (plus sham). In experiments 2 and 3, mice were injured as described, and delivered a single tail vein injection of either SJA6017 (0.3,1, or 3 mg/kg) or vehicle (administered immediately, 4 or 6 h postinjury [3 mg/kg]). Functional outcome was evaluated in both studies, and, in experiment 2, 24-h postinjury assessment of SBDPs was determined. Following injury, the level of SBDP 145 was significantly different from sham at 24 and 48h in cortical and at 24 h in the hippocampal tissues and at 48 h in the striatum. Immediate postinjury administration of SJA6017 resulted in a dose-related improvement in 24-h functional outcome (p < 0.05 at 3 mg/kg). Significance was maintained after a 4-h delay of the 3 mg/kg, but was lost after a 6-h delay. Despite improvement in functional outcome at 24 h, SJA6017 didnot reduce spectrin breakdown in cortical or hippocampal tissues. These results support a role for calpain-mediated neuronal injury and the potentialfor a practical therapeutic window for calpain inhibition following traumatic brain injury. However, measurements of regional spectrin degradation may not be the most sensitive marker for determining the effects of calpain inhibition.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 23/01/20 alle ore 12:20:02