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.
|Journal||Journal of Neuroinflammation|
|State||Published - Apr 10 2015|
Bibliographical noteFunding Information:
We thank Edgardo Dimayuga for his assistance with various aspects of this work. This research was supported in part by NIH/NIA (K99AG044445 to ADB), NIH/NINDS (F32 NS084605 to SJW), and the Kentucky Spinal Cord and Head Injury Research Trust (12-20A to LVE).
© Bachstetter et al.
- Closed head injury
- Cognitive dysfunction
- Drug discovery
- Traumatic brain injury
ASJC Scopus subject areas
- Neuroscience (all)
- Cellular and Molecular Neuroscience