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

Eric Lloyd¹ , Kathleen Somera-Molina²^,3 , Linda J Van Eldik³ , D Martin Watterson³ and Mark S Wainwright²^,3^,4

¹Division of Critical Care, Department of Pediatrics, Children's Memorial Hospital, 2300 Children's Plaza, Chicago, IL 60614, USA

²Division of Neurology, Department of Pediatrics, Children's Memorial Hospital, 2300 Children's Plaza, Chicago, IL 60614, USA

³Center for Drug Discovery and Chemical Biology, Northwestern University, 303 E. Chicago Ave, Mailcode W896, Chicago, IL 60611, USA

⁴Center for Interdisciplinary Research in Pediatric Critical Illness and Injury, Children's Memorial Research Center, 2430 N. Halstead, Chicago, IL 60614, USA

author email corresponding author email

Journal of Neuroinflammation 2008, 5:28doi:10.1186/1742-2094-5-28


Published:	30 June 2008

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.