Cerebrolysin enhances neurogenesis in the ischemic brain and improves functional outcome after stroke.
Cerebrolysin is a peptide preparation mimicking the action of neurotrophic factors and has beneficial effects on neurodegenerative diseases and stroke. The present study investigated the effect of Cerebrolysin on neurogenesis in a rat model of embolic middle cerebral artery occlusion (MCAo). Treatment with Cerebrolysin at doses of 2.5 and 5 ml/kg significantly increased the number of bromodeoxyuridine-positive (BrdU(+)) subventricular zone (SVZ) neural progenitor cells and doublecortin (DCX) immunoreactivity (migrating neuroblasts) in the ipsilateral SVZ and striatal ischemic boundary 28 days after stroke when the treatment was initiated 24 hr after stroke. The treatment also reduced TUNEL(+) cells by ∼50% in the ischemic boundary. However, treatment with Cerebrolysin at a dose of 2.5 ml/kg initiated at 24 and 48 hr did not significantly reduce infarct volume but substantially improved neurological outcomes measured by an array of behavioral tests 21 and 28 days after stroke. Incubation of SVZ neural progenitor cells from ischemic rats with Cerebrolysin dose dependently augmented BrdU(+) cells and increased the number of Tuj1(+) cells (a marker of immature neurons). Blockage of the PI3K/Akt pathway abolished Cerebrolysin-increased BrdU(+) cells. Moreover, Cerebrolysin treatment promoted neural progenitor cell migration. Collectively, these data indicate that Cerebrolysin treatment when initiated 24 and 48 hr after stroke enhances neurogenesis in the ischemic brain and improves functional outcome and that Cerebrolysin-augmented proliferation, differentiation, and migration of adult SVZ neural progenitor cells contribute to Cerebrolysin-induced neurogenesis, which may be related to improvement of neurological outcome. The PI3K/Akt pathway mediates Cerebrolysin-induced progenitor cell proliferation.
Zhang
Chunling
C
Department of Neurology, Henry Ford Hospital, Detroit, Michigan 48202, USA.
Chopp
Michael
M
Cui
Yisheng
Y
Wang
Lei
L
Zhang
Ruilan
R
Zhang
Li
L
Lu
Mei
M
Szalad
Alexandra
A
Doppler
Edith
E
Hitzl
Monika
M
Zhang
Zheng Gang
ZG
D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D000089662:Doublecortin Protein; D007150:Immunohistochemistry; D008297:Male; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology
D000596:Amino Acids; D000089662:Doublecortin Protein; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C000714848:Dcx protein, rat; C006952:cerebrolysin