Title |
Attenuation of traumatic brain injury-induced cognitive impairment in mice by targeting increased cytokine levels with a small molecule experimental therapeutic
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Published in |
Journal of Neuroinflammation, April 2015
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DOI | 10.1186/s12974-015-0289-5 |
Pubmed ID | |
Authors |
Adam D Bachstetter, Scott J Webster, Danielle S Goulding, Jonathan E Morton, D Martin Watterson, Linda J Van Eldik |
Abstract |
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. 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. 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. 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. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 31 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Other | 6 | 19% |
Student > Ph. D. Student | 5 | 16% |
Student > Bachelor | 4 | 13% |
Student > Doctoral Student | 3 | 10% |
Student > Master | 2 | 6% |
Other | 6 | 19% |
Unknown | 5 | 16% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 7 | 23% |
Neuroscience | 5 | 16% |
Psychology | 4 | 13% |
Agricultural and Biological Sciences | 3 | 10% |
Biochemistry, Genetics and Molecular Biology | 3 | 10% |
Other | 3 | 10% |
Unknown | 6 | 19% |