Novel Therapies for Traumatic Brain Injury: Targeting the Acute Cytokine Surge

This project will test the hypothesis that novel, selective suppressors of the acute proinflammatory cytokine surge by activated glia will attenuate the neurodegenerative sequelae in a mouse model of diffuse traumatic brain injury (TBI). Data from animal models and human head injury patients suggest that excessive glial activation is a major factor contributing to undesirable outcomes following TBI, and that selective targeting of glia proinflammatory cytokine up-regulation may be beneficial when administered in the acute post-traumatic time window consistent with clinical presentation and the period of increasing cytokine production. We have developed the Minozac family (3-amino-6-phenylpyridazines) of CNS-penetrant, small molecule drugs that act by reducing the injury-induced up-regulation of glial cell inflammatory mediators. Minozac compounds are efficacious in a variety of animal models of diseases where proinflammatory cytokine overproduction is a component of disease progression, including TBI. In this project, we propose to test two Minozac compounds, termed MW-151 and MW-189, in a midline, closed head injury (CHI) model of diffuse traumatic injury. This model exhibits a well-defined injury-induced cytokine surge linked to downstream neurologic and behavioral impairments. Studies of therapeutic window (dose and timing) will be done, and mechanism of action, neurologic and functional recovery outcomes measured. Because both compounds have undergone extensive preclinical and safety studies, and MW-189 has successfully completed a phase I human trial, our results could have immediate translational implications and be attractive to future partners who may have an interest in developing one or both of the drugs for TBI indications. Our specific aims are: Aim 1. Test dose dependence and therapeutic efficacy window of MW-151 and MW-189. Our feasibility results have demonstrated the temporal profile of the cytokine surge after the injury, and have shown that low doses of the parental Minozac compound, MW-151, administered post-injury suppress the acute cytokine up-regulation. This aim will extend these findings by testing dose dependence and the optimal therapeutic window for MW-151 and MW-189 effectiveness, as well as demonstrating that the drugs engage their mechanism of action: i.e., suppression of glial and cytokine endpoints. Aim 2. Test the efficacy of MW-151 and MW-189 on neurologic and functional recovery after CHI. This aim will test whether suppression of the acute cytokine surge by intervention with drugs will lead to amelioration of longer-term neurologic injury after CHI. We predict that drug treatment will provide protection against neuron death, axonal and synaptic injury impairments, as well as improved behavioral outcomes as measured by tests of vestibulomotor and cognitive function. Demonstration of efficacy of our drugs will provide support for our hypothesis, as well as strong impetus for further therapeutic development of the Minozac compounds for TBI.