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Neuroprotection with caspase‐9 inhbition against in vitro and in vivo trauma
Author(s) -
Wallis R. A.,
Panizzon K. L.,
Shin D.
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.81.s1.46_4.x
Subject(s) - in vivo , neuroprotection , pharmacology , chemistry , hippocampal formation , medicine , biology , microbiology and biotechnology
Objective: To evaluate the neuroprotective efficacy of the cell‐permeable caspase‐9 inhibitor, LEHD‐CHO, against in vitro and in vivo traumatic neuronal injury. Methods: The neuroprotective potential of LEHD‐CHO was assessed in vitro using rat hippocampal slices. CA1 orthodromic and antidromic population spike (PS) amplitude was monitored before and after fluid percussion injury in slices treated with or without LEHD‐CHO. Final recovery of PS amplitude was assessed 95 min after trauma. Studies of in vivo neuroprotection with LEHD‐CHO utilized a model of controlled cortical impact (CCI). Rats were given either LEHD‐CHO (10 nmol icv) or an equal volume of vehicle at 5 min following CCI. Rats were perfused 24 h after CCI and brains were processed for histological examination. Results: LEHD‐CHO provided significant protection against loss of CA1 evoked response after fluid percussion. The EC 50 for LEHD‐CHO protection of CA1 orthodromic and antidromic PS amplitude against trauma was 2.1 μ m and 2.3 μ m . Protection extended to preservation of LTP after trauma. In vivo treatment with LEHD‐CHO significantly decreased the appearance of eosinophilic cells in the CA1 region after CCI from 131 ± 23 cells in vehicle‐treated animals to 24 ± 5 in LEHD‐CHO treated animals. Extensive labelling with TUNEL staining was seen in vehicle‐treated animals, whereas sections from LEHD‐CHO treated animals demonstrated little staining. Conclusions: These findings indicate that the caspase 9 inhibitor LHED‐CHO provides concentration‐dependent protection against in vitro CA1 neuronal injury, which extends to protection against in vivo CA1 injury from CCI. They further suggest that inhibition of caspase 9 may be a useful treatment strategy for traumatic brain injury. Acknowledgement: Supported by VA Research and UCLA BIRC.