Attenuation of traumatic brain injury-induced cognitive impairment in mice by targeting increased cytokine levels with a small molecule experimental therapeutic

Journal of Neuroinflammation

Linda J Van Eldik³  D Martin Watterson²  Jonathan E Morton¹  Danielle S Goulding¹  Scott J Webster¹  Adam D Bachstetter¹ 

[1]Sanders-Brown Center on Aging, University of Kentucky, 800 S Limestone Street, Lexington, KY, USA

[2]Department of Pharmacology, Northwestern University, 303 E Chicago Avenue, Chicago, IL, USA

[3]Department of Anatomy and Neurobiology, University of Kentucky, 800 Rose Street, Lexington, KY, USA

关键词: Cognitive dysfunction;    Closed head injury;    Traumatic brain injury;    Astrocytes;    Microglia;    Drug discovery;    Neuroinflammation;    Interleukin;    Glia;    Cytokines;   

Others  :  1227097
DOI  :  10.1186/s12974-015-0289-5

 received in 2015-01-28, accepted in 2015-03-24,  发布年份 2015

【 摘 要 】

Background

Evidence from clinical studies and preclinical animal models suggests that proinflammatory cytokine overproduction is a potential driving force for pathology progression in traumatic brain injury (TBI). This raises the possibility that selective targeting of the overactive cytokine response, a component of the neuroinflammation that contributes to neuronal dysfunction, may be a useful therapeutic approach. MW151 is a CNS-penetrant, small molecule experimental therapeutic that selectively restores injury- or disease-induced overproduction of proinflammatory cytokines towards homeostasis. We previously reported that MW151 administered post-injury (p.i.) is efficacious in a closed head injury (CHI) model of diffuse TBI in mice. Here we test dose dependence of MW151 to suppress the target mechanism (proinflammatory cytokine up-regulation), and explore the therapeutic window for MW151 efficacy.

Methods

We examined suppression of the acute cytokine surge when MW151 was administered at different times post-injury and the dose-dependence of cytokine suppression. We also tested a more prolonged treatment with MW151 over the first 7 days post-injury and measured the effects on cognitive impairment and glial activation.

Results

MW151 administered up to 6 h post-injury suppressed the acute cytokine surge, in a dose-dependent manner. Administration of MW151 over the first 7 days post-injury rescues the CHI-induced cognitive impairment and reduces glial activation in the focus area of the CHI.

Conclusions

Our results identify a clinically relevant time window post-CHI during which MW151 effectively restores cytokine production back towards normal, with a resultant attenuation of downstream cognitive impairment.

【 授权许可】

   
2015 Bachstetter et al.; licensee BioMed Central.

【 图 表 】

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