title: Nitric oxide facilitates delivery and mediates improved outcome of autologous bone marrow mononuclear cells in a rodent stroke model.
abstract: BACKGROUND
  Bone marrow mononuclear cells (MNC) represent an investigational treatment for stroke. The objective of this study was to determine the relevance of vasoactive mediators, generated in response to MNC injection, as factors regulating cerebral perfusion (CP), the biodistribution of MNC, and outcome in stroke.
  
  
  METHODS
  Long Evans rats underwent transient middle cerebral artery occlusion. MNC were extracted from the bone marrow at 22 hrs and injected via the internal carotid artery or the femoral vein 2 hours later. CP was measured with MRI or continuous laser Doppler flowmetry. Serum samples were collected to measure vasoactive mediators. Animals were treated with the Nitric Oxide (NO) inhibitor, L-NAME, to establish the relevance of NO-signaling to the effect of MNC. Lesion size, MNC biodistribution, and neurological deficits were assessed.
  
  
  RESULTS
  CP transiently increased in the peri-infarct region within 30 min after injecting MNC compared to saline or fibroblast control. This CP increase corresponded temporarily to serum NO elevation and was abolished by L-NAME. Pre-treatment with L-NAME reduced brain penetration of MNC and prevented MNC from reducing infarct lesion size and neurological deficits.
  
  
  CONCLUSIONS
  NO generation in response to MNC may represent a mechanism underlying how MNC enter the brain, reduce lesion size, and improve outcome in ischemic stroke.
authors.affiliation: Department of Neurology, Stroke Team, The University of Texas-Houston Medical School, Houston, Texas, United States of America.
authors.forename: Mallikarjunarao
authors.initials: M
authors.lastname: Kasam
authors.forename: Bing
authors.initials: B
authors.lastname: Yang
authors.forename: Roger
authors.initials: R
authors.lastname: Strong
authors.forename: Krystal
authors.initials: K
authors.lastname: Schaar
authors.forename: Vivek
authors.initials: V
authors.lastname: Misra
authors.forename: Xiaopei
authors.initials: X
authors.lastname: Xi
authors.forename: James C
authors.initials: JC
authors.lastname: Grotta
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Aronowski
authors.forename: Sean I
authors.initials: SI
authors.lastname: Savitz
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010477:Perfusion; D051381:Rats; D020521:Stroke / Q000401:mortality / Q000628:therapy*; D013997:Time Factors; D014182:Transplantation, Autologous; D016896:Treatment Outcome
chemical_list: D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester