Midkine gene transfer protects against focal brain ischemia and augments neurogenesis

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• 作者：Eiichi Ishikawa ; Hiroaki Ooboshi ; Yasuhiro Kumai ; Junnichi Takada ; Kuniyuki Nakamura ; Tetsuro Ago ; Hiroshi Sugimori ; Masahiro Kamouchi ; Takanari Kitazono ; Setsuro Ibayashi ; Mitsuo Iida
• 关键词：Midkine ; Gene transfer ; Brain infarction ; Inflammation ; Angiogenesis ; Neurogenesis ; Migration
• 刊名：Journal of the Neurological Sciences
• 出版年：2009
• 出版时间：15 October 2009
• 年：2009
• 卷：285
• 期：1-2
• 页码：78-84
• 全文大小：970 K

文摘

Background and purpose

Midkine is a heparin-binding growth factor having various biological activities including chemotaxis of inflammatory cells, angiogenesis and migration of neuronal cells. These biological activities are expected to have a great impact on the pathology of brain infarction in subacute phase. Therefore, we investigated the effect of post-ischemic gene transfer of midkine in the phase.

Methods

Brain ischemia was produced by the photothrombotic distal middle cerebral artery occlusion in spontaneously hypertensive rats. We measured cerebral blood flow by laser Doppler flowmetry. At 90 min after induction of brain ischemia, adenovirus vectors encoding mouse midkine (AdMK) or enhanced green fluorescence protein (AdGFP) were injected into the lateral ventricle. At 7 days after brain ischemia, the infarct volume, angiogenesis, inflammation and neuronal regeneration were evaluated.

Results

There were no differences in cerebral blood flow changes between AdMK and AdGFP groups. However, infarct volume of AdMK group was significantly smaller than AdGFP group by 33 % . The vascular density, the numbers of leukocytes in blood vessels, infiltrated macrophages and proliferated neuronal precursor cells were not significantly different between both groups. Contrastingly the numbers of migrating neuronal precursor cells toward the brain infarction were significantly increased in AdMK group than AdGFP group.

Conclusions

Neuroprotective effect of midkine gene transfer persisted until the subacute phase of brain infarction. Midkine may contribute to neuronal regeneration. These results suggest the usefulness of midkine gene transfer for treatment of brain infarction.