Format

Send to

Choose Destination
J Neuroinflammation. 2015 Apr 10;12:69. doi: 10.1186/s12974-015-0289-5.

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

Author information

1
Sanders-Brown Center on Aging, University of Kentucky, 800 S Limestone Street, Lexington, KY, USA. adam.bachstetter@uky.edu.
2
Sanders-Brown Center on Aging, University of Kentucky, 800 S Limestone Street, Lexington, KY, USA. scott.webster@uky.edu.
3
Sanders-Brown Center on Aging, University of Kentucky, 800 S Limestone Street, Lexington, KY, USA. dsgoul2@uky.edu.
4
Sanders-Brown Center on Aging, University of Kentucky, 800 S Limestone Street, Lexington, KY, USA. jonathan.morton@uky.edu.
5
Department of Pharmacology, Northwestern University, 303 E Chicago Avenue, Chicago, IL, USA. d.m.watterson@gmail.com.
6
Sanders-Brown Center on Aging, University of Kentucky, 800 S Limestone Street, Lexington, KY, USA. linda.vaneldik@uky.edu.
7
Department of Anatomy and Neurobiology, University of Kentucky, 800 Rose Street, Lexington, KY, USA. linda.vaneldik@uky.edu.

Abstract

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.

PMID:
25886256
PMCID:
PMC4396836
DOI:
10.1186/s12974-015-0289-5
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center