Midkine gene transfer protects against focal brain ischemia and augments neurogenesis.
OBJECTIVE
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.
Ishikawa
Eiichi
E
Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan.
Ooboshi
Hiroaki
H
Kumai
Yasuhiro
Y
Takada
Junnichi
J
Nakamura
Kuniyuki
K
Ago
Tetsuro
T
Sugimori
Hiroshi
H
Kamouchi
Masahiro
M
Kitazono
Takanari
T
Ibayashi
Setsuro
S
Iida
Mitsuo
M
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000503:physiopathology / Q000628:therapy*; D002560:Cerebrovascular Circulation / Q000502:physiology; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000503:physiopathology / Q000628:therapy*; D017078:Laser-Doppler Flowmetry; D008297:Male; D051379:Mice; D000078792:Midkine; D009416:Nerve Regeneration; D055495:Neurogenesis; D015213:Neuroimmunomodulation; D051381:Rats; D011918:Rats, Inbred SHR; D013997:Time Factors
D016207:Cytokines; C485184:enhanced green fluorescent protein; D000078792:Midkine; D049452:Green Fluorescent Proteins