Abstract
BackgroundTraumatic brain injury (TBI) is a global health concern that typically causes emotional disturbances and cognitive dysfunction. Secondary pathologies following TBI may be associated with chronic neurodegenerative disorders and an enhanced likelihood of developing dementia-like disease in later life. There are currently no approved drugs for mitigating the acute or chronic effects of TBI.MethodsThe effects of the drug pomalidomide (Pom), an FDA-approved immunomodulatory agent, were evaluated in a rat model of moderate to severe TBI induced by controlled cortical impact. Post-TBI intravenous administration of Pom (0.5 mg/kg at 5 or 7 h and 0.1 mg/kg at 5 h) was evaluated on functional and histological measures that included motor function, fine more coordination, somatosensory function, lesion volume, cortical neurodegeneration, neuronal apoptosis, and the induction of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6).ResultsPom 0.5 mg/kg administration at 5 h, but not at 7 h post-TBI, significantly mitigated the TBI-induced injury volume and functional impairments, neurodegeneration, neuronal apoptosis, and cytokine mRNA and protein induction. To evaluate underlying mechanisms, the actions of Pom on neuronal survival, microglial activation, and the induction of TNF-α were assessed in mixed cortical cultures following a glutamate challenge. Pom dose-dependently ameliorated glutamate-mediated cytotoxic effects on cell viability and reduced microglial cell activation, significantly attenuating the induction of TNF-α.ConclusionsPost-injury treatment with a single Pom dose within 5 h significantly reduced functional impairments in a well-characterized animal model of TBI. Pom decreased the injury lesion volume, augmented neuronal survival, and provided anti-inflammatory properties. These findings strongly support the further evaluation and optimization of Pom for potential use in clinical TBI.
Highlights
Traumatic brain injury (TBI) is a global health concern that typically causes emotional disturbances and cognitive dysfunction
In the light of our recent studies demonstrating that the novel and more potent TNF-α synthesis inhibitor 3,6′-dithiothalidomide could effectively mitigate the neuronal apoptosis, gliosis, and behavioral impairments instigated by weight drop-induced mild TBI in mice [20] and other neurodegenerative conditions [21, 22], in the present study, we evaluated a clinically available, more potent amino thalidomide analog, pomalidomide (Pom), in a moderate to severe TBI model
To further assess for potential changes in body temperature induced by Pom and anesthesia, a series of sham and TBI animals were administered with both doses of drug and their body temperature was likewise monitored over a 3-h interval
Summary
Traumatic brain injury (TBI) is a global health concern that typically causes emotional disturbances and cognitive dysfunction. Secondary pathologies following TBI may be associated with chronic neurodegenerative disorders and an enhanced likelihood of developing dementia-like disease in later life. Traumatic brain injury (TBI) is the leading cause of death and long-term disability in the developed world. With increases in survival following initial injury, TBI can result in substantial and lifelong cognitive, physical, and behavioral impairments that require long-term access to health care and disability services [6, 7]. In light of the lack of any available therapeutic [10], it is important to understand the mechanisms underpinning TBI in order to develop effective strategies that can attenuate the neuronal dysfunction and loss that ensues from head injury
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