Suppression of acute proinflammatory cytokine and chemokine upregulation by post-injury administration of a novel small molecule improves long-term neurologic outcome in a mouse model of traumatic brain injury
Open Access
- 30 June 2008
- journal article
- Published by Springer Science and Business Media LLC in Journal of Neuroinflammation
- Vol. 5 (1), 28
- https://doi.org/10.1186/1742-2094-5-28
Abstract
Background: Traumatic brain injury (TBI) with its associated morbidity is a major area of unmet medical need that lacks effective therapies. TBI initiates a neuroinflammatory cascade characterized by activation of astrocytes and microglia, and increased production of immune mediators including proinflammatory cytokines and chemokines. This inflammatory response contributes both to the acute pathologic processes following TBI including cerebral edema, in addition to longer-term neuronal damage and cognitive impairment. However, activated glia also play a neuroprotective and reparative role in recovery from injury. Thus, potential therapeutic strategies targeting the neuroinflammatory cascade must use careful dosing considerations, such as amount of drug and timing of administration post injury, in order not to interfere with the reparative contribution of activated glia.Methods: We tested the hypothesis that attenuation of the acute increase in proinflammatory cytokines and chemokines following TBI would decrease neurologic injury and improve functional neurologic outcome. We used the small molecule experimental therapeutic, Minozac (Mzc), to suppress TBI-induced up-regulation of glial activation and proinflammatory cytokines back towards basal levels. Mzc was administered in a clinically relevant time window post-injury in a murine closed-skull, cortical impact model of TBI. Mzc effects on the acute increase in brain cytokine and chemokine levels were measured as well as the effect on neuronal injury and neurobehavioral function.Results: Administration of Mzc (5 mg/kg) at 3 h and 9 h post-TBI attenuates the acute increase in proinflammatory cytokine and chemokine levels, reduces astrocyte activation, and the longer term neurologic injury, and neurobehavioral deficits measured by Y maze performance over a 28-day recovery period. Mzc-treated animals also have no significant increase in brain water content (edema), a major cause of the neurologic morbidity associated with TBI.Conclusion: These results support the hypothesis that proinflammatory cytokines contribute to a glial activation cycle that produces neuronal dysfunction or injury following TBI. The improvement in long-term functional neurologic outcome following suppression of cytokine upregulation in a clinically relevant therapeutic window indicates that selective targeting of neuroinflammation may lead to novel therapies for the major neurologic morbidities resulting from head injury, and indicates the potential of Mzc as a future therapeutic for TBI.Keywords
This publication has 63 references indexed in Scilit:
- A novel p38α MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer's disease mouse modelJournal of Neuroinflammation, 2007
- MLCK210 gene knockout or kinase inhibition preserves lung function following endotoxin-induced lung injury in miceAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2007
- Glial Activation Links Early‐Life Seizures and Long‐Term Neurologic Dysfunction: Evidence Using a Small Molecule Inhibitor of Proinflammatory Cytokine UpregulationEpilepsia, 2007
- Development of a novel therapeutic suppressor of brain proinflammatory cytokine up-regulation that attenuates synaptic dysfunction and behavioral deficitsBioorganic & Medicinal Chemistry Letters, 2007
- Chronic ibuprofen administration worsens cognitive outcome following traumatic brain injury in ratsExperimental Neurology, 2006
- Epilepsy after head injuryCurrent Opinion in Neurology, 2004
- Extracellular Superoxide Dismutase Overexpression Improves Behavioral Outcome from Closed Head Injury in the MouseJournal of Neurotrauma, 2001
- Neuroprotective agents in traumatic brain injuryExpert Opinion on Investigational Drugs, 2001
- Head Injury: Recent Past, Present, and FutureNeurosurgery, 2000
- Temporal profile of release of interleukin-1β in neurotraumaNeuroscience Letters, 2000