title: Enriched rehabilitation promotes motor recovery in rats exposed to neonatal hypoxia-ischemia.
abstract: Despite continuous improvement in neonatology there is no clinically effective treatment for perinatal hypoxia ischemia (HI). Therefore, development of a new therapeutic intervention to minimize the resulting neurological consequences is urgently needed. The immature brain is highly responsive to environmental stimuli, such as environmental enrichment but a more effective paradigm is enriched rehabilitation (ER), which combines environmental enrichment with daily reach training. Another neurorestorative strategy to promote tissue repair and functional recovery is cyclosporine A (CsA). However, potential benefits of CsA after neonatal HI have yet to be investigated. The aim of this study was to investigate the effects of a combinational therapy of CsA and ER in attempts to promote cognitive and motor recovery in a rat model of perinatal hypoxic-ischemic injury. Seven-day old rats were submitted to the HI procedure and divided into 4 groups: CsA+Rehabilitation; CsA+NoRehabilitation; Vehicle+Rehabilitation; Vehicle+NoRehabilitation. Behavioural parameters were evaluated pre (experiment 1) and post 4 weeks of combinational therapy (experiment 2). Results of experiment 1 demonstrated reduced open field activity of HI animals and increased foot faults relative to shams in the ladder rung walking test. In experiment 2, we showed that ER facilitated acquisition of a staircase skilled-reaching task, increased number of zone crosses in open-field exploration and enhanced coordinated limb use during locomotion on the ladder rung task. There were no evident deficits in novel object recognition testing. Delayed administration of CsA, had no effect on functional recovery after neonatal HI. There was a significant reduction of cortical and hemispherical volume and hippocampal area, ipsilateral to arterial occlusion in HI animals; combinational therapy had no effect on these morphological measurements. In conclusion, the present study demonstrated that ER, but not CsA was the main contributor to enhanced recovery of motor ability after neonatal HI.
authors.affiliation: Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Clarissa Pedrini
authors.initials: CP
authors.lastname: Schuch
authors.affiliation: Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; Canadian Partnership for Stroke Recovery, Ottawa, ON, Canada.
authors.forename: Matthew Strider
authors.initials: MS
authors.lastname: Jeffers
authors.affiliation: Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; Canadian Partnership for Stroke Recovery, Ottawa, ON, Canada.
authors.forename: Sabina
authors.initials: S
authors.lastname: Antonescu
authors.affiliation: Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; Canadian Partnership for Stroke Recovery, Ottawa, ON, Canada.
authors.forename: Carine
authors.initials: C
authors.lastname: Nguemeni
authors.affiliation: Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; Canadian Partnership for Stroke Recovery, Ottawa, ON, Canada.
authors.forename: Mariana
authors.initials: M
authors.lastname: Gomez-Smith
authors.affiliation: Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Lenir Orlandi
authors.initials: LO
authors.lastname: Pereira
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Department of Surgery, University of Toronto, Toronto, ON, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada.
authors.forename: Cindi M
authors.initials: CM
authors.lastname: Morshead
authors.affiliation: Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Faculty of Medicine, Memorial University, St. John's, NL, Canada; Canadian Partnership for Stroke Recovery, Ottawa, ON, Canada. Electronic address: dcorbett@uottawa.ca.
authors.forename: Dale
authors.initials: D
authors.lastname: Corbett
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D020520:Brain Infarction / Q000188:drug therapy / Q000209:etiology / Q000534:rehabilitation; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology / Q000534:rehabilitation; D016572:Cyclosporine / Q000627:therapeutic use; D004777:Environment; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy / Q000503:physiopathology* / Q000534:rehabilitation*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D009043:Motor Activity / Q000502:physiology*; D011247:Pregnancy; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine
keywords: Cyclosporine animal models; Hypoxia-ischemia; Neonates; Perinatal asphyxia; Recovery