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(Stroke. 2001;32:1028.)
© 2001 American Heart Association, Inc.

Original Contributions

Calbindin D28K Overexpression Protects Striatal Neurons From Transient Focal Cerebral Ischemia

Midori A. Yenari, MD; Masabumi Minami, PhD; Guo Hua Sun, MD, PhD; Timothy J. Meier, PhD; David M. Kunis, BA; John R. McLaughlin, BA; Dora Y. Ho, PhD; Robert M. Sapolsky, PhD Gary K. Steinberg, MD, PhD

From the Departments of Neurosurgery (M.A.Y., M.M., G.H.S., D.M.K., G.K.S.), Neurology (M.A.Y., R.M.S.), and Biological Sciences (T.J.M., J.R.M., D.Y.H., R.M.S.) and Stanford Stroke Center (M.A.Y., M.M., G.H.S., T.J.M., D.M.K., J.R.M., D.Y.H., R.M.S., G.K.S.), Stanford University (Calif).

Correspondence to Midori A. Yenari, MD, Departments of Neurosurgery, Neurology, and Neurological Sciences, Stanford University School of Medicine, 1201 Welch Rd, MSLS Bldg B P304, Stanford, CA 94305-5487. E-mail yenari{at}stanford.edu

Background and Purpose—Increased intracellular calcium accumulation is known to potentiate ischemic injury. Whether endogenous calcium-binding proteins can attenuate this injury has not been clearly established, and existing data are conflicting. Calbindin D28K (CaBP) is one such intracellular calcium buffer. We investigated whether CaBP overexpression is neuroprotective against transient focal cerebral ischemia.

Methods—Bipromoter, replication-incompetent herpes simplex virus vectors that encoded the genes for cabp and, as a reporter gene, lacZ were used. Sprague-Dawley rats received bilateral striatal injections of viral vector 12 to 15 hours before ischemia onset. With the use of an intraluminal occluding suture, animals were subjected to 1 hour of middle cerebral artery occlusion followed by 47 hours of reperfusion. Brains were harvested and stained with X-gal (to visualize ß-galactosidase, the gene product of lacZ). The number of remaining virally transfected, X-gal–stained neurons in both the ischemic and contralateral striata were counted and expressed as the percentage of surviving neurons in the ischemic striatum relative to the contralateral nonischemic striatum.

Results—Striatal neuron survivorship among cabp-injected animals was 53.5±4.1% (n=10) versus 26.8±5.4% among those receiving lacZ (n=9) (mean±SEM; P<0.001).

Conclusions—We conclude that viral vector–mediated overexpression of CaBP leads to neuroprotection in this model of central nervous system injury. This is the first demonstration that CaBP overexpression protects neurons in a focal stroke model.

Key Words: calcium • calcium-binding protein • cerebral ischemia, focal • cerebral ischemia, transient • gene therapy

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