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(Stroke. 2007;38:1597.)
© 2007 American Heart Association, Inc.

Original Contributions

The Phosphodiesterase Inhibitor Rolipram Promotes Survival of Newborn Hippocampal Neurons After Ischemia

Tsutomu Sasaki, MD, PhD; Kazuo Kitagawa, MD, PhD; Emi Omura-Matsuoka, MD; Kenichi Todo, MD; Yasukazu Terasaki, MD; Shiro Sugiura, MD, PhD; Jun Hatazawa, MD, PhD; Yoshiki Yagita, MD, PhD Masatsugu Hori, MD, PhD

From the Department of Cardiovascular Medicine, Division of Stroke Research (T.S., K.K., E.O.-M., K.T., Y.T., S.S., Y.Y., M.H.), and the Department of Nuclear Medicine and Tracer Kinetics (T.S., J.H.), Osaka University Graduate School of Medicine, Osaka, Japan.

Correspondence to Tsutomu Sasaki, Division of Stroke Research, Department of Cardiovascular Medicine (A8), Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka 565-0871, Japan. E-mail sasaki{at}medone.med.osaka-u.ac.jp

Background and Purpose— Brain ischemia stimulates neurogenesis. However, newborn neurons show a progressive decrease in number over time. Under normal conditions, the cAMP–cAMP responsive element binding protein (CREB) pathway regulates the survival of newborn neurons. Constitutive activation of CREB after brain ischemia also stimulates hippocampal neurogenesis. Thus, activation of cAMP-CREB signaling may provide a promising strategy for enhancing the survival of newborn neurons. We examined whether treatment of mice with the phosphodiesterase-4 inhibitor rolipram enhances hippocampal neurogenesis after ischemia.

Methods— Both common carotid arteries in mice were occluded for 12 minutes. Bromodeoxyuridine (BrdU) was used to label proliferating cells. Mice were perfused transcardially with 4% paraformaldehyde, and immunohistochemistry was performed. To evaluate the role of CREB in the survival of newborn neurons after ischemia, intrahippocampal injection of a CRE-decoy oligonucleotide was delivered for 1 week. We examined whether the activation of cAMP-CREB signaling by rolipram enhanced the proliferation and survival of newborn neurons.

Results— Phospho-CREB immunostaining was markedly upregulated in immature neurons, decreasing to low levels in mature neurons. The number of BrdU-positive cells 30 days after ischemia was significantly less in the CRE-decoy treatment group than in the vehicle group. Rolipram enhanced the proliferation of newborn cells under physiologic conditions but not under ischemic conditions. Rolipram significantly increased the survival of nascent BrdU-positive neurons, accompanied by an enhancement of phospho-CREB staining and decreased newborn cell death after ischemia.

Conclusions— CREB phosphorylation regulates the survival of newborn neurons after ischemia. Chronic pharmacological activation of cAMP-CREB signaling may be therapeutically useful for the enhancement of neurogenesis after ischemia.

Key Words: CREB • hippocampus • neurogenesis • ischemia