title: Systemic administration of guanosine promotes functional and histological improvement following an ischemic stroke in rats.
abstract: Previously we have found that extracellular guanosine (Guo) has neuroprotective properties in in vitro and in vivo. Moreover, extracellular Guo significantly increased in the ipsilateral hemisphere within 2h following focal stroke in rats, and remained elevated for one week. Therefore, we hypothesized that Guo could be a potential candidate for a non-toxic neuroprotective agent. In the present study, we examined the effects of Guo on rats following permanent middle cerebral artery occlusion (MCAO). We also determined whether Guo can precondition neurons by modulating endoplasmic reticulum (ER) stress proteins. As most therapies employ a combination treatment regimen, we optimized the neuroprotection by combining pre- and post-MCAO treatments with Guo, attempting to reduce both ischemic cell death and improve functional recovery. A combination of 4mg/kg Guo given 30min pre-stroke and 8mg/kg Guo given 3, 24 and 48h post-stroke exerted the most significant decrease in infarct volume and sustainable improvement in neurological function. Moreover, these effects are not attributable to Guo metabolites. Measurements taken 6h post-MCAO from animals pre-treated with Guo did not reveal any significant changes in ER stress proteins (GRP 78 and 94) or HSP 70, but did reveal significantly increased levels of m-calpain. Thus, our data indicate that there is a treatment regimen for Guo as a neuroprotectant following ischemic stroke. The mechanism by which Guo confers neuroprotection may involve an increase in m-calpain, possibly resulting from a mild increase in intracellular calcium. M-calpain may be involved in the preconditioning response to ischemia by upregulating endogenous pro-survival mechanisms in neurons.
authors.affiliation: Department of Medicine (Neurology, Neurobiochemistry), Health Sciences Centre, Room 4E15, 1200 Main Street West, Hamilton, ON, Canada L8N 3Z5.
authors.forename: Michel P
authors.initials: MP
authors.lastname: Rathbone
authors.forename: Tarek M
authors.initials: TM
authors.lastname: Saleh
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Connell
authors.forename: Ruby
authors.initials: R
authors.lastname: Chang
authors.forename: Caixin
authors.initials: C
authors.lastname: Su
authors.forename: Brandon
authors.initials: B
authors.lastname: Worley
authors.forename: Minji
authors.initials: M
authors.lastname: Kim
authors.forename: Shucui
authors.initials: S
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D006151:Guanosine / Q000008:administration & dosage / Q000627:therapeutic use*; D006360:Heat-Shock Proteins / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D006151:Guanosine; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C053387:endoplasmin