Dual Orexin Antagonist Treatment to Prevent the Neurobehavioral Sequelae of TBI
Abstract
Traumatic brain injury (TBI) is a common problem in civilians and military personnel alike, with over 1.5 million new cases each year and over 5 million people living in the U.S. currently with TBI-related disability. Consequences of TBI can not only lead to disability but also cause a societal and economic toll. TBI leads to neurological consequences including sleep disturbances, posttraumatic epilepsy (PTE), cognitive impairment as well as mood and anxiety disorders (depression and posttraumatic stress disorder - PTSD), which we collectively termed neurobehavioral sequelae. All the sequelae are much more common in military personnel compared to civilians. Moreover, all the sequelae are interrelated, as sleep and epilepsy as well as sleep and mood disorders have a bidirectional relationship where they exacerbate each other. Similarly, cognitive disturbances are common after TBI but also common due to epilepsy as well as mood and anxiety disorders. A major gap in clinical care and research is lack of a complete understanding into mechanisms and molecular targets for treatment of sequelae of TBI. The long-term vision of this application to foster preventive therapies for the sequelae of TBI. In the prior study, we hypothesized that treatment with sleep aids immediately after TBI will restore sleep disturbances and prevent posttraumatic epilepsy. We recorded EEG (electroencephalogram) for sleep-wake patterns and seizures periodically for 3 months during and after a month-long treatment with two sleep aids. The first acts on GABAA receptors in the brain (THIP) and a second acts as a blocker of the receptors of a brain hormone orexin, which is responsible for maintaining wakefulness and vigilance during the day (dual orexin receptor antagonist or DORA). We found that TBI resulted in sleep disturbances and PTE. Contrary to our hypothesis, treatment with DORA but not THIP, restored the sleep homeostatic process but also suppressed PTE. In a mechanistic study in brain slices, we found that TBI impaired GABAergic inhibition (a balance of excitation and inhibition is required normally) in a brain region important for seizures (dentate gyrus) and DORA treatment restored it. We also found phenotypes of depression and PTSD in mice that were subjected to TBI compared to sham injury. The experimental design for the current proposal was generated from this prior work in a Peer Reviewed Medical Research Program (PRMRP) Idea Development Award (PR161864). Based on the above data, in this PRMRP Expansion Award application, we will perform a confirmatory preclinical study where, following TBI, we will determine if chronic treatment with a sleep aid DORA will mitigate the development of some or all the neurobehavioral sequelae. We will test the hypothesis in a mouse model, where following TBI or sham injury, mice will be treated daily with DORA for 2 months while we perform EEG recordings for sleep-wake pattern and seizure analysis. Towards the end of the treatment, the same animals will undergo behavioral studies for depression, PTSD, and learning/memory. At the end of 2-month-long treatment, animals will be sacrificed for recordings in brain slices from regions that are relevant for sleep disturbances, epilepsy, and mood/anxiety disorders to understand the mechanisms. To further establish the hypothesis, we will also perform comparative study where we will examine sleep parameters, seizures, and behavioral tests after treatment with a drug that activates orexin receptors in the brain (Orexin agonist). The work in this PRMRP Expansion Award is novel, using comprehensive methodology that can foster a clinical trial in humans with TBI to repurpose currently U.S. Food and Drug Administration (FDA)-approved sleep aids (orexin receptor 1 and 2 or dual orexin antagonists) as a novel therapy. The data from this preclinical study can support clinical studies in military personnel, Veterans, as well as civilians. Preventing the neurobehavioral
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310200
Entities
People
- Rama Maganti
Organizations
- United States Army
- University of Wisconsin–Madison