Limits...
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 LJ, Watterson DM, Wainwright MS - J Neuroinflammation (2008)

Bottom Line: Traumatic brain injury (TBI) with its associated morbidity is a major area of unmet medical need that lacks effective therapies.Mzc-treated animals also have no significant increase in brain water content (edema), a major cause of the neurologic morbidity associated with 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Critical Care, Department of Pediatrics, Children's Memorial Hospital, 2300 Children's Plaza, Chicago, IL 60614, USA. Eal1@neoucom.edu

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.

Show MeSH

Related in: MedlinePlus

Time course of acute changes in proinflammatory cytokines following TBI. Levels of the cytokines IL-1β (A), IL6 (B), TNFα (C) and the chemokine CCL2 (D) in pooled hippocampus and cortex extracts following sham procedure (open bars) or closed head TBI (filled bars) were measured by ELISA. Animals were sacrificed at 0-, 1-, 4-, and 12-hr recovery. Data are expressed as mean ± S.E.M of n = 6–8 animals per group. Significantly different from sham: *P < 0.05 vs Sham control; **P < 0.01 vs Sham; #P < 0.001 vs Sham by ANOVA.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2483713&req=5

Figure 1: Time course of acute changes in proinflammatory cytokines following TBI. Levels of the cytokines IL-1β (A), IL6 (B), TNFα (C) and the chemokine CCL2 (D) in pooled hippocampus and cortex extracts following sham procedure (open bars) or closed head TBI (filled bars) were measured by ELISA. Animals were sacrificed at 0-, 1-, 4-, and 12-hr recovery. Data are expressed as mean ± S.E.M of n = 6–8 animals per group. Significantly different from sham: *P < 0.05 vs Sham control; **P < 0.01 vs Sham; #P < 0.001 vs Sham by ANOVA.

Mentions: Mice were subjected to a closed-skull cortical impact (TBI) or sham procedure, and the time course (Fig. 1) of the acute increase in levels of proinflammatory cytokines (IL-1β, IL6 and TNF-α) and the chemokine CCL2 was determined. Levels of the cytokines/chemokine in pooled hippocampus and cortex extracts were measured at 0-, 1-, 4-, and 12-hr after TBI or sham procedure (n = 4 per group). There was a trend toward an increase at 4-hr post injury but this did not reach significance. By 12 hours after injury, levels of IL-1β, IL6, TNF-α, and CCL2 were significantly increased compared to sham controls. To confirm that the cytokine and chemokine response to injury was transient, we measured cytokine levels at 7 and 14 days after TBI or sham procedure (Fig. 2). There were no differences between Sham and TBI groups at either of these later timepoints for any of the cytokines examined.


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 LJ, Watterson DM, Wainwright MS - J Neuroinflammation (2008)

Time course of acute changes in proinflammatory cytokines following TBI. Levels of the cytokines IL-1β (A), IL6 (B), TNFα (C) and the chemokine CCL2 (D) in pooled hippocampus and cortex extracts following sham procedure (open bars) or closed head TBI (filled bars) were measured by ELISA. Animals were sacrificed at 0-, 1-, 4-, and 12-hr recovery. Data are expressed as mean ± S.E.M of n = 6–8 animals per group. Significantly different from sham: *P < 0.05 vs Sham control; **P < 0.01 vs Sham; #P < 0.001 vs Sham by ANOVA.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2483713&req=5

Figure 1: Time course of acute changes in proinflammatory cytokines following TBI. Levels of the cytokines IL-1β (A), IL6 (B), TNFα (C) and the chemokine CCL2 (D) in pooled hippocampus and cortex extracts following sham procedure (open bars) or closed head TBI (filled bars) were measured by ELISA. Animals were sacrificed at 0-, 1-, 4-, and 12-hr recovery. Data are expressed as mean ± S.E.M of n = 6–8 animals per group. Significantly different from sham: *P < 0.05 vs Sham control; **P < 0.01 vs Sham; #P < 0.001 vs Sham by ANOVA.
Mentions: Mice were subjected to a closed-skull cortical impact (TBI) or sham procedure, and the time course (Fig. 1) of the acute increase in levels of proinflammatory cytokines (IL-1β, IL6 and TNF-α) and the chemokine CCL2 was determined. Levels of the cytokines/chemokine in pooled hippocampus and cortex extracts were measured at 0-, 1-, 4-, and 12-hr after TBI or sham procedure (n = 4 per group). There was a trend toward an increase at 4-hr post injury but this did not reach significance. By 12 hours after injury, levels of IL-1β, IL6, TNF-α, and CCL2 were significantly increased compared to sham controls. To confirm that the cytokine and chemokine response to injury was transient, we measured cytokine levels at 7 and 14 days after TBI or sham procedure (Fig. 2). There were no differences between Sham and TBI groups at either of these later timepoints for any of the cytokines examined.

Bottom Line: Traumatic brain injury (TBI) with its associated morbidity is a major area of unmet medical need that lacks effective therapies.Mzc-treated animals also have no significant increase in brain water content (edema), a major cause of the neurologic morbidity associated with 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Critical Care, Department of Pediatrics, Children's Memorial Hospital, 2300 Children's Plaza, Chicago, IL 60614, USA. Eal1@neoucom.edu

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.

Show MeSH
Related in: MedlinePlus