NEUROPROTECTIVE EFFICACY OF CASPASE-9 INHIBITORS AGAINST DEPOLARIZATION INJURY TO CA1 PYRAMIDAL NEURONS IN RAT HIPPOCAMPAL SLICES
Abstract number :
1.081
Submission category :
Year :
2002
Submission ID :
348
Source :
www.aesnet.org
Presentation date :
12/7/2002 12:00:00 AM
Published date :
Dec 1, 2002, 06:00 AM
Authors :
Roi Ann Wallis, Kimberly L. Panizzon. Neurology, Sepulveda VA GLAHS, North Hills, CA; Neurology, UCLA, Los Angeles, CA
RATIONALE: Seizure-induced neuronal damage appears to involve apoptosis. Caspase-9 is a key enzyme involved in apoptosis. Therefore, we assessed the neuroprotective effects of Caspase-9 inhibitors against depolarization-induced CA1 neuronal injury in the hippocampal slice. Upon the conclusion of this presentation, participants should have an understanding of the neuroprotective effects of Caspase-9 inhibitors against CA1 neuronal injury induced by depolarization.
METHODS: Using in vitro rat hippocampal slices, we monitored the CA1 orthodromic and antidromic population spike (PS) amplitude during hypoxia with and without caspase-9 inhibitor treatment.
RESULTS: Caspase-9 inhibitor II, a cell permeable, reversible inhibitor, provided robust neuroprotection of CA1 PS amplitude in stimulated hippocampal slices subjected to depolarization-induced injury. At a Caspase-9 inhibitor II concentration of 5 uM CA1 orthodromic and antidromic PS amplitude recovered to 92.0% [plusminus] 1.6 and 92.2% [plusminus] 1.7, compared to unmedicated slices which recovered to 13.4% [plusminus] 1.7, and 13.5 % [plusminus] 3.6, respectively. A potent, cell permeable, irreversible inhibitor of caspase-9, caspase-9 inhibitor I also provided significant protection of CA1 PS amplitude in stimulated hippocampal slices subjected to depolarization-induced injury. At a Caspase-9 inhibitor I concentration of 5 uM CA1 orthodromic and antidromic PS amplitude recovered to 89.5%[plusminus] 2.9 and 89.6% [plusminus] 3.2, compared to unmedicated slices which recovered to 14.0% [plusminus] 0.7, and 14.6% [plusminus] 1.7, respectively. Similarly, Caspase-9 inhibitor III provided excellent neuroprotection of CA1 PS amplitude in stimulated hippocampal slices subjected to depolarization-induced injury. At a Caspase-9 inhibitor III concentration of 5 uM CA1 orthodromic and antidromic PS amplitude recovered to 92.7% [plusminus] 3.6 and 92.8% [plusminus] 2.1, compared to unmedicated slices which recovered to 13.6% [plusminus] 1.6, and 14.3 % [plusminus] 2.4, respectively.
CONCLUSIONS: These studies demonstrate that inhibitors of Caspase-9 provide neuroprotection in an in vitro model of depolarization injury. In addition, these data suggest that the use of Caspase-9 inhibitors may be a useful strategy in the prevention of brain injury during status epilepticus.
[Supported by: VA Research Service and UCLA Brain Injury Research Center.]