title: Therapeutic benefit of treatment of stroke with simvastatin and human umbilical cord blood cells: neurogenesis, synaptic plasticity, and axon growth.
abstract: The therapeutic efficacy of cell-based therapy after stroke can be enhanced by making the host brain tissue more receptive to the administered cells, which thereby facilitates brain plasticity. We hypothesized that simvastatin increases human umbilical cord blood cell (HUCBC) migration  into the ischemic brain and promotes brain plasticity and neurological functional outcome after stroke. Rats were subjected to 2-h middle cerebral artery occlusion (MCAo) and administered subtherapeutic doses of simvastatin (0.5 mg/kg, gavaged daily for 7 days), HUCBCs (1 × 10(6),  one time injection via tail vein), or combination simvastatin with HUCBCs starting at 24 h after stroke. Combination treatment of stroke showed an interactive effect in improvement of neurological outcome compared with simvastatin or HUCBC monotherapy groups. In addition, combination treatment  significantly increased brain-derived neurotrophic factor/TrkB expression and the number of engrafted HUCBCs in the ischemic brain compared with HUCBC monotherapy. The number of engrafted HUCBCs was significantly correlated with functional outcome (modified neurological severity score). Combination  treatment significantly increased neurogenesis and synaptic plasticity in the ischemic brain, and promoted neuroblast migration in cultured subventricular zone explants. Using primary cultured neurons (PCNs), we found that combination treatment enhanced neurite outgrowth compared with nontreatment  control, simvastatin or HUCBC supernatant monotherapy. Inhibition of TrkB significantly attenuated combination treatment-induced neurite outgrowth. Our data indicate that combination simvastatin and HUCBC treatment of stroke increases BDNF/TrkB expression, enhances HUCBC migration into the  ischemic brain, amplifies endogenous neurogenesis, synaptic plasticity and axonal growth, and thereby improves functional outcome after stroke.
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Cui
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
authors.forename: Amjad
authors.initials: A
authors.lastname: Shehadah
authors.forename: Alex
authors.initials: A
authors.lastname: Zacharek
authors.forename: Nicole
authors.initials: N
authors.lastname: Kuzmin-Nichols
authors.forename: Cyndy Davis
authors.initials: CD
authors.lastname: Sanberg
authors.forename: Junhao
authors.initials: J
authors.lastname: Dai
authors.forename: Chunling
authors.initials: C
authors.lastname: Zhang
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ueno
authors.forename: Cynthia
authors.initials: C
authors.lastname: Roberts
authors.forename: Jieli
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001369:Axons / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000637:transplantation*; D006801:Humans; D008297:Male; D016501:Neurites / Q000378:metabolism / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020813:Receptor, trkB / Q000378:metabolism; D019821:Simvastatin / Q000627:therapeutic use*; D020521:Stroke / Q000378:metabolism / Q000628:therapy*
chemical_list: D000924:Anticholesteremic Agents; D019208:Brain-Derived Neurotrophic Factor; D019821:Simvastatin; D020813:Receptor, trkB