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(Stroke. 1998;29:677-682.)
© 1998 American Heart Association, Inc.

Original Contributions

Drug-Induced Neuroprotection From Global Ischemia Is Associated With Prevention of Persistent but Not Transient Activation of Nuclear Factor-B in Rats

James A. Clemens, PhD; Diane T. Stephenson, BS; Tinggui Yin, BS; E. Barry Smalstig, BS; Jill A. Panetta, PhD; Sheila P. Little, PhD

From the Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Ind.

Correspondence to James A. Clemens, PhD, Lilly Research Laboratories (0510), Eli Lilly and Co, Lilly Corporate Center, Indianapolis, IN 46285-0814.

Background and Purpose—Nuclear factor-B (NF-B) is an oxidative stress responsive transcription factor that is transiently activated in most forebrain neurons in response to transient global ischemia. However, in hippocampal CA1 neurons destined to die, NF-B remains persistently activated. The present study was performed to determine whether an antioxidant (LY231617) that afforded neuroprotection in previous studies had any effect on NF-B activation in hippocampal CA1 neurons after global ischemia.

Methods—Rats were subjected to 30 minutes of forebrain ischemia by 4-vessel occlusion (4-VO) and killed at 24 and 72 hours after ischemia. LY231617 was administered orally at a dose of 50 mg/kg 30 minutes before 4-VO and again 4 hours after 4-VO. Neuronal damage was evaluated in sections stained with cresyl violet. Other sections were immunostained with antibodies to NF-B p50 to assess nuclear localization. An electrophoretic mobility shift assay was performed on nuclear extracts from sham- and LY231617-treated rats at 24 and 72 hours after ischemia.

Results—The administration of LY231617 had a significant protective effect on hippocampal CA1 neurons at 72 hours after ischemia (control group, 16±7 neurons/mm; treated group, 294±35 neurons/mm, P<.02) and prevented nuclear translocation of activated NF-B as normally seen at 72 hours after ischemia in untreated controls. In contrast, the untreated controls showed activated NF-B at 72 hours after ischemia. At 24 hours after ischemia, both the control group and the LY231617 group showed intense nuclear localization of NF-B.

Conclusions—Activation of NF-B in vitro has been reported to promote proapoptotic as well as antiapoptotic mechanisms, depending on the cell type being investigated. In the present in vivo study, the role of the transient activation of NF-B observed at 24 hours may be responsible for the induction of protective factors in neurons that survive the ischemic insult, whereas the persistent activation of NF-B in hippocampal neurons could be responsible for the induction of proteins that result in CA1 neuronal death.

Editorial Comment

W. Dalton Dietrich, PhD; John Bethea, PhD

Guest Editors, Department of Neurological Surgery, University of Miami School of Medicine, Miami, Florida

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