Delayed minocycline treatment reduces long-term functional deficits and histological injury in a rodent model of focal ischemia.
The absence of effective treatments for stroke presents a critical need for novel strategies that can reduce ischemic injury. Neuroinflammation following focal ischemia induces secondary injury in the region surrounding the insult, thus anti-inflammatory agents are potential neuroprotectants. Minocycline is one such agent possessing neuroprotective properties, however many studies examining minocycline after ischemia have used minimal delays between ischemia and treatment, short survival periods, and lack measures of functional outcome. Such studies do not distinguish whether minocycline provides sustained protection or merely delays cell death. This study was designed to address some of these concerns. Male Sprague-Dawley rats were treated with multiple doses of minocycline (45 mg/kg i.p.) or vehicle beginning 2.5 h after endothelin-1-induced focal ischemia. Measures of forelimb asymmetry and skilled reaching (staircase test) were used to determine functional outcome 7, 15 and 28 days after ischemia. Long-term functional assessment indicates that minocycline provides limited benefit in the staircase test, but confers long-term benefit in the forelimb asymmetry test. Subcortical and whole hemisphere infarct volumes were reduced by 41 and 39% respectively in minocycline-treated animals. Further analysis revealed that minocycline attenuated long-term white matter damage adjacent to the striatal injury core, which correlated with sustained functional benefits. This study indicates that delayed minocycline treatment improves long-term functional outcome which is linked to protection of both white and gray matter.
Hewlett
K A
KA
Basic Medical Sciences, Faculty of Medicine, Memorial University, St. John's, NL, Canada.
Corbett
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D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D020520:Brain Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D002545:Brain Ischemia / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D019332:Endothelin-1 / Q000633:toxicity; D007839:Functional Laterality / Q000502:physiology; D008297:Male; D008911:Minocycline / Q000008:administration & dosage*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects*; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome
D019332:Endothelin-1; D018696:Neuroprotective Agents; D008911:Minocycline