Document Detail


Minozac treatment prevents increased seizure susceptibility in a mouse "two-hit" model of closed skull traumatic brain injury and electroconvulsive shock-induced seizures.
MedLine Citation:
PMID:  20486807     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The mechanisms linking traumatic brain injury (TBI) to post-traumatic epilepsy (PTE) are not known and no therapy for prevention of PTE is available. We used a mouse closed-skull midline impact model to test the hypotheses that TBI increases susceptibility to seizures in a "two-hit" injury model, and that suppression of cytokine upregulation after the first hit will attenuate the increased susceptibility to the second neurological insult. Adult male CD-1 mice underwent midline closed skull pneumatic impact. At 3 and 6 h after impact or sham procedure, the mice were injected IP with either Minozac (Mzc), a suppressor of proinflammatory cytokine upregulation, or vehicle (saline). On day 7 after sham operation or TBI, seizures were induced using electroconvulsive shock (ECS), and susceptibility to seizures was measured by the current required for seizure induction. Activation of glia, neuronal injury, and metallothionein-immunoreactive cells were quantified in the hippocampus by immunohistochemical methods. Neurobehavioral function over 14-day recovery was quantified using the Barnes maze. Following TBI there was a significant increase in susceptibility to seizures induced by ECS, and this susceptibility was prevented by suppression of cytokine upregulation with Mzc. Astrocyte activation, metallothionein expression, and neurobehavioral impairment were also increased in the two-hit group subjected to combined TBI and ECS. These enhanced responses in the two-hit group were also prevented by suppression of proinflammatory cytokine upregulation with Mzc. These data implicate glial activation in the mechanisms of epileptogenesis after TBI, and identify a potential therapeutic approach to attenuate the delayed neurological sequelae of TBI.
Authors:
MaryAnn Chrzaszcz; Charu Venkatesan; Tina Dragisic; D Martin Watterson; Mark S Wainwright
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of neurotrauma     Volume:  27     ISSN:  1557-9042     ISO Abbreviation:  J. Neurotrauma     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-27     Completed Date:  2011-03-25     Revised Date:  2014-09-20    
Medline Journal Info:
Nlm Unique ID:  8811626     Medline TA:  J Neurotrauma     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1283-95     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Anti-Inflammatory Agents, Non-Steroidal / pharmacology,  therapeutic use
Brain Injuries / complications,  physiopathology*
Cytokines / antagonists & inhibitors,  metabolism
Disease Models, Animal
Electroshock / adverse effects
Epilepsy / drug therapy*,  etiology,  physiopathology*
Head Injuries, Closed / complications,  physiopathology
Hippocampus / drug effects,  metabolism,  pathology
Male
Maze Learning / drug effects,  physiology
Mice
Mice, Inbred Strains
Pyridazines / pharmacology*,  therapeutic use
Pyrimidines / pharmacology*,  therapeutic use
Recovery of Function / drug effects,  physiology
Up-Regulation / drug effects,  physiology
Grant Support
ID/Acronym/Agency:
K12 HD052902/HD/NICHD NIH HHS; KO8 NS044998/NS/NINDS NIH HHS; R01 AG031311/AG/NIA NIH HHS; R01 NS056051/NS/NINDS NIH HHS; R01 NS056051/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Anti-Inflammatory Agents, Non-Steroidal; 0/Cytokines; 0/Pyridazines; 0/Pyrimidines; 0/minozac
Comments/Corrections

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