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Delayed, Long-Term Administration of the Caspase Inhibitor Q-VD-OPh Reduced Brain Injury Induced by Neonatal Hypoxia-Ischemia.

Artikel i vetenskaplig tidskrift
Författare Wei Han
Yanyan Sun
Xiaoyang Wang
Changlian Zhu
Klas Blomgren
Publicerad i Developmental neuroscience
Volym 36
Nummer/häfte 1
Sidor 64-72
ISSN 1421-9859
Publiceringsår 2014
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för klinisk neurovetenskap och rehabilitering
Institutionen för kliniska vetenskaper, Avdelningen för pediatrik
Sidor 64-72
Språk en
Länkar dx.doi.org/10.1159/000357939
Ämnesord CCL2, MCP-1, CCL3, MIP-1 alpha, IL-4, IL-10, Cylinder Rearing Test, Open Field, Brain tissue loss

Ämneskategorier Neurologi, Pediatrik

Sammanfattning

Apoptosis contributes greatly to the morphological and biochemical features of cell death after neonatal cerebral hypoxia-ischemia (HI), making this mode of cell death a promising therapeutic target. We previously showed that 10 mg/kg of the caspase inhibitor Q-VD-OPh at the onset of and immediately after HI on postnatal day 9 reduced brain infarct volume. In this study, delayed administration of Q-VD-OPh, 12 and 36 h after HI, decreased HI-induced caspase-3 activity (DEVD cleavage) by 23% and diminished the levels of the proinflammatory chemokines CCL2 (MCP-1) and CCL3 (MIP-1α) by 29.3 and 29.1%, respectively, but not the levels of the anti-inflammatory cytokines IL-4 and IL-10. Long-term administration of Q-VD-OPh initiated at 12 h after HI, and continued at 24-hour intervals for 2 weeks, reduced total brain tissue loss by 31.3% from 41.5 ± 3.1 mm(3) in the vehicle group to 28.5 ± 3.0 mm(3) in the Q-VD-OPh group when evaluated 16 weeks after HI (p = 0.004). Q-VD-OPh treatment also ameliorated the loss of sensorimotor function, as evaluated by a cylinder rearing test (Q-VD-OPh: 30.8 ± 4.3% vs. vehicle: 59.7 ± 6.3% in nonimpaired forepaw preference) 3 weeks after HI, and reduced HI-induced hyperactivity, as measured in an open field test (Q-VD-OPh: 4,062 ± 198 cm vs. vehicle: 4,792 ± 205 cm in distance moved) 7 weeks after the insult. However, the functional protection was no longer observed when analyzed again at later time points. The mechanisms underlying the discrepancy between sustained morphological protection and transient functional protection remain to be elucidated. © 2014 S. Karger AG, Basel.

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