From the Department of Neurology (T.H., K.A., Y.I.) and the Department of
Thoracic and Cardiovascular Surgery (M. Sakurai, M. Sadahiro, K.T.), Tohoku
University School of Medicine, Sendai, Japan, and the Department of Neurology
(K.A.), Okayama University School of Medicine, Okayama, Japan.
Correspondence to K. Abe, Department of Neurology, Okayama University School of Medicine, 2-5-1 Shikata-machi, Okayama, 700-0914 Japan. E-mail hayashi{at}neurol.med.tohoku.ac.jp
Background and Purpose—Some neuronal
subpopulations are especially vulnerable to ischemic injury. In
the spinal cord, large motor neurons are vulnerable to ischemia
and are selectively lost after transient ischemia. However, the
mechanisms of the neuronal loss have been uncertain. We hypothesized
that spinal motor neurons might be lost by apoptosis and
investigated a possible mechanism of neuronal death by detection of
double-strand breaks in genomic DNA and immunohistochemical
analysis for caspases, ie, interleukin-1ß converting enzyme
(ICE), Nedd-2, and CPP32.
Methods—We used a rabbit spinal cord ischemia model
created with a balloon catheter. The spinal cord was removed at 8
hours, 1, 2, or 7 days after 15 minutes of transient ischemia,
and histological changes were studied with
hematoxylin-eosin staining. To detect double-strand breaks in DNA, a
staining with terminal deoxynucleotidyl
transferase–mediated dUTP-biotin in situ nick end labeling (TUNEL) was
performed. Furthermore, expression of ICE, Nedd-2, and
CPP32 was investigated by Western blotting and immunohistochemical
analysis.
Results—Motor neurons were selectively lost at 7 days after
transient ischemia. TUNEL study demonstrated that no cells were
positively labeled until 1 day after ischemia, but nuclei of
some motor neurons were positively labeled at 2 days. Western blot
analysis revealed no immunoreactivity for ICE and slight
immunoreactivities for Nedd-2 and CPP32 in the
sham-operated spinal cords. However, immunoreactivity became apparent
at 8 hours after transient ischemia, decreased at 1 day, and
returned to baseline level at 2 days. Immunohistochemical
analysis demonstrated that motor neurons were responsible for
induction of those caspases.
Conclusions—Double-strand breaks in genomic DNA and induction of
three caspases were demonstrated. These results indicate that motor
neuron death in the spinal cord after transient ischemia is
profoundly associated with activation of apoptotic processes.
Departments of Neurosurgery, Neurology & Neurological Sciences,
Stanford University School of Medicine,
Palo Alto, California
© 1998 American Heart Association, Inc.
Original Contributions
Apoptosis of Motor Neurons With Induction of Caspases in the Spinal Cord After Ischemia
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