Health & Medical Neurological Conditions

Suppression of Proinflammatory Cytokine Improves Neurologic Outcome

Suppression of Proinflammatory Cytokine Improves Neurologic Outcome
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.

Traumatic brain injury (TBI) is a leading cause of death in Western industrialized nations, with an estimated 50,000 deaths annually in the United States. The causes of TBI vary with age but the medical and financial impact of these injuries is substantial. In the United States alone, an estimated 1.6 million cases of TBI occur annually, with approximately 300,000 cases of sufficient severity to require hospitalization. The mortality with severe TBI can reach 40% and neurologic morbidity among survivors is high. The neurologic sequelae in survivors of TBI include cognitive impairment, dementia, epilepsy, depression and neurodegenerative disease. Current standards of care for TBI focus largely on supportive measures. There is a major unmet need for TBI therapies that attenuate long-term, functional neurologic deficits.

Insults to the central nervous system (CNS) induce a neuroinflammatory response characterized by activation of microglia and astrocytes, damage to the blood-brain-barrier (BBB), and acute up-regulation of proinflammatory cytokines such as interleukin (IL)-1β, tumor necrosis factor (TNF)α, and IL-6. In the case of TBI, this complex neuroinflammatory cascade can lead to opposing effects: beneficial outcomes through production of reparative and protective factors, or detrimental outcomes when the production of proinflammatory mediators is prolonged, excessive, or temporally inappropriate [for review, see ]. There is increasing recognition that suppression of the CNS proinflammatory cytokine cascade should be explored as a therapeutic approach to TBI because of its contribution to secondary injury that includes cerebral edema, neuronal damage and cytotoxicity.

A variety of studies using pharmacological or genetic methods have demonstrated beneficial effects of suppressing the CNS proinflammatory cytokine cascade induced by TBI. For example, treatment of rats with IL-1 receptor antagonist (IL-1ra), a protein that antagonizes IL-1 activity, administered either by intracerebroventricular administration, or by implantation of IL-1ra-expressing fibroblasts into the wound cavity reduced the extent of neurologic injury after experimental head injury. Similar protection was found in transgenic mice with CNS-selective over-expression of IL1ra. Other studies showed that suppression of TNFα production or activity by administration of small molecules (HU-211, pentoxifylline) or a TNFα binding protein reduced neurologic injury.

Taken together, preclinical data indicate that targeting glia proinflammatory cytokine overproduction may represent an effective new therapeutic intervention for TBI. However, many current cytokine-modulating drugs are macromolecules, and using macromolecules as a therapeutic approach has a number of disadvantages, such as instability, high cost and potential for immune responses to the therapy. There is an unmet clinical need for a small molecule therapeutic that attenuates the acute cytokine and chemokine surge with resultant improvement in longer term neurologic outcomes when the drug is administered in a clinically relevant time window following the injury.

In the present studies, we tested the hypothesis that suppression of the acute increase in proinflammatory cytokines following TBI would attenuate neurologic injury and neurobehavioral impairment. As a step toward addressing the need for novel therapeutics, we explored the potential utility of Minozac (Mzc) administered hours post-injury in a murine closed-skull, cortical impact model of TBI. Mzc is a bioavailable, brain-penetrant, small molecule experimental therapeutic that improves synaptic dysfunction and neurobehavioral impairment when administered after the initiation of the injury stimulus in animal models of epilepsy and Alzheimer's disease. The mechanism of Mzc action is selective reduction of excessive proinflammatory cytokine production by activated glia back towards basal levels. We report here that administration of Mzc at 3 h and 9 h following TBI attenuates the acute increase in proinflammatory cytokine and chemokine levels and reduces the longer term astrocyte activation, neurologic injury and neurobehavioral deficits observed 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 clinical TBI. These data lend support both to the potential of glial activation as a therapeutic target in acute brain injury and the utility of Mzc for the treatment of TBI.

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