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.

Lloyd, E., Somera-Molina, K., Van Eldik, L.J., Watterson, D.M., Wainwright, M.S.
Journal   J Neuroinflammation.
Species  
Analytes Measured   IL-6 , MCP-1
Matrix Tested   Brain extracts from closed head injury model
Year   2008
Volume   30
Page Numbers  
Application   Alzheimers , Cytokines and Chemokines
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 & 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 & 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.

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Multiplex
V-PLEX Plus Neuroinflammation Panel 1 Human Kit
CRP, Eotaxin, Eotaxin-3, FGF (basic), ICAM-1, IFN-γ, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12/IL-23p40, IL-13, IL-15, IL-16, IL-17A, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, PlGF, SAA, TARC, Tie-2, TNF-α, TNF-β, VCAM-1, VEGF-A, VEGF-C, VEGF-D, VEGFR-1/Flt-1 | Human
Multiplex
V-PLEX Chemokine Panel 1 NHP Kit
Eotaxin-3, IL-8, IL-8 (HA), IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, TARC | Non-human primate
Multiplex
V-PLEX NHP Cytokine 24-Plex Kit
Eotaxin-3, GM-CSF, IFN-γ, IL-1β, IL-2, IL-5, IL-6, IL-7, IL-8, IL-8 (HA), IL-10, IL-12/IL-23p40, IL-15, IL-16, IL-17A, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, TARC, TNF-β, VEGF-A | Non-human primate
Multiplex
V-PLEX NHP IL-6 Kit
IL-6 | Non-human primate
Singleplex
V-PLEX NHP MCP-1 Kit
MCP-1 | Non-human primate
Singleplex
V-PLEX Plus Chemokine Panel 1 NHP Kit
Eotaxin-3, IL-8, IL-8 (HA), IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, TARC | Non-human primate
Multiplex
V-PLEX Plus NHP Cytokine 24-Plex Kit
Eotaxin-3, GM-CSF, IFN-γ, IL-1β, IL-2, IL-5, IL-6, IL-7, IL-8, IL-8 (HA), IL-10, IL-12/IL-23p40, IL-15, IL-16, IL-17A, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, TARC, TNF-β, VEGF-A | Non-human primate
Multiplex
V-PLEX Plus NHP IL-6 Kit
IL-6 | Non-human primate
Singleplex
V-PLEX Plus NHP MCP-1 Kit
MCP-1 | Non-human primate
Singleplex
V-PLEX Plus Proinflammatory Panel 1 NHP Kit
IFN-γ, IL-1β, IL-2, IL-6, IL-8, IL-10 | Non-human primate
Multiplex
V-PLEX Proinflammatory Panel 1 NHP Kit
IFN-γ, IL-1β, IL-2, IL-6, IL-8, IL-10 | Non-human primate
Multiplex
Human IL-6 Antibody Bulk Product
IL-6
Human MCP-1 Antibody
MCP-1
Mouse IL-6 Antibody
IL-6
Rat IL-6 Antibody
IL-6
V-PLEX Chemokine Panel 1 Human Kit
Eotaxin, Eotaxin-3, IL-8, IL-8 (HA), IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, TARC | Human
Multiplex
V-PLEX Human Cytokine 30-Plex Kit
Eotaxin, Eotaxin-3, GM-CSF, IFN-γ, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-8 (HA), IL-10, IL-12/IL-23p40, IL-12p70, IL-13, IL-15, IL-16, IL-17A, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, TARC, TNF-α, TNF-β, VEGF-A | Human
Multiplex
V-PLEX Human IL-6 Kit
IL-6 | Human
Singleplex
V-PLEX Human MCP-1 Kit
MCP-1 | Human
Singleplex
V-PLEX Human Proinflammatory Panel I (4-Plex)
IFN-γ, IL-1β, IL-6, TNF-α | Human
Multiplex
V-PLEX Human Proinflammatory Panel II (4-Plex)
IL-1β, IL-6, IL-8, TNF-α | Human
Multiplex
V-PLEX Mouse IL-6 Kit
IL-6 | Mouse
Singleplex
V-PLEX Plus Chemokine Panel 1 Human Kit
Eotaxin, Eotaxin-3, IL-8, IL-8 (HA), IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, TARC | Human
Multiplex
V-PLEX Plus Human Cytokine 30-Plex Kit
Eotaxin, Eotaxin-3, GM-CSF, IFN-γ, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-8 (HA), IL-10, IL-12/IL-23p40, IL-12p70, IL-13, IL-15, IL-16, IL-17A, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, TARC, TNF-α, TNF-β, VEGF-A | Human
Multiplex
V-PLEX Plus Human IL-6 Kit
IL-6 | Human
Singleplex
V-PLEX Plus Human MCP-1 Kit
MCP-1 | Human
Singleplex
V-PLEX Plus Human Proinflam. Panel I (4-Plex)
IFN-γ, IL-1β, IL-6, TNF-α | Human
Multiplex
V-PLEX Plus Human Proinflam. Panel II (4-Plex)
IL-1β, IL-6, IL-8, TNF-α | Human
Multiplex
V-PLEX Plus Mouse IL-6 Kit
IL-6 | Mouse
Singleplex
V-PLEX Plus Proinflammatory Panel 1 Human Kit
IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, TNF-α | Human
Multiplex
V-PLEX Plus Proinflammatory Panel1 Mouse Kit
IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, KC/GRO, TNF-α | Mouse
Multiplex
V-PLEX Plus Rat IL-6 Kit
IL-6 | Rat
Singleplex
V-PLEX Proinflammatory Panel 1 Human Kit
IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, TNF-α | Human
Multiplex
V-PLEX Proinflammatory Panel 1 Mouse Kit
IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, KC/GRO, TNF-α | Mouse
Multiplex
V-PLEX Rat IL-6 Kit
IL-6 | Rat
Singleplex
Chemokine Panel 1 Human Control Pack
Eotaxin, Eotaxin-3, IL-8, IP-10, MCP-1, MCP-4, MDC, TARC | Human
Proinflammatory Panel 1 Human Control Pack
IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, TNF-α | Human
Proinflammatory Panel 1 Mouse Control Pack
IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, KC/GRO, TNF-α | Mouse
Proinflammatory Panel 1 Rat Control Pack
IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, KC/GRO, TNF-α | Rat
Human ProInflammatory-4 II Tissue Culture Kit
IL-1β, IL-6, IL-8, TNF-α | Human
Multiplex
Human IL-6 Tissue Culture Kit
IL-6 | Human
Singleplex
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