Traumatic brain injury (TBI) constitutes a major health and socio-economic problem with neurobehavioral sequelae contributing to long term disability. Acute brain injury comprises mild TBI or concussion including its short-term sequelae and catastrophic brain injury that may lead to death or subdural hematoma. Chronic brain injury, call dementia pugilistica or chronic traumatic encephalopathy (CTE), is a neurodegenerative disorder due to repeated head trauma. TBI is a strong epigenetic factor for Alzheimer’s disease (AD) which is a neurogenerative disorder characterized by the presence of extracellular senile plaques and intracellular neurofibrillary tangles (NFT). Senile plaques are formed of aggregates of amyloid beta (A 刍) peptides, whereas NFTs are composed of bundles of pathological fibrils called paired helical filaments (PHFs), which are made up of aberrantly phosphorylated tau microtubule associated proteins. There are many pathological features common to both acute brain injury and AD, including A 刍 deposition, tau hyperphosphorylation (peal level at 7 day after TBI), neurite degeneration, synapse loss and microgliosis. In the acute setting, glial activation results in up-regulation of amyloid precursor protein (Muizelaar et al.) as well as other inflammatory mediators. Neuroinflammatory responses may serve as a common denominator between these two entities. Although TBI is associated with AD, the significant efforts are needed to improve prevention, diagnosis, and treatment of these conditions. We will evaluate the effects of acute and long-term treatment with CHF5074 (as known as a microglia modulator in treatment of AD) and AST (our previous study has been shown function as anti-neuroinflammation via microglia) on preventive, treatment and diagnostic role following TBI-induced AD-like chronic traumatic encephalopathy. We will use a rat model of repetitive TBI to induce AD-like lesion and to ascertain: (1) Whether CHF5074 or AST IV treatment in acute stage (1-7 days) after TBI can attenuate the pathogenic events of AD-like chronic traumatic encephalopathy. (2) Whether post-injury (8-28 days after TBI) administration of CHF5074 or AST is able to improve outcome of AD-like chronic traumatic encephalopathy by enhancing neuroregeneration, synaptic plasticity and/or learning and memory; and (3) to detect the plasma and/or brain levels of several biological markers that occurred during acute or chronic stage of TBI-induced chronic traumatic encephalopathy in injured rats with or without CHF5074 or AST IV therapy. Animals will be divided into four groups: (1) sham group; (2) TBI rats treated with vehicle solution (0.9%NaCl 1ml/kg/day, subcutaneously); (3) TBI rat treated with CHF5074 (30mg/kg/day, subcutaneously); (4) TBI rats treated with vehicle solution (0.9%NaCl 1ml/kg/day, intraperitoneally); (5) TBI rats treated with AST (40mg/kg/day, intraperitoneally). In the 1st year, we plan to evaluate brain neuropathological changes, cerebral contusion, cerebral levels of biological markers, brain-blood-barrier permeability, microglia expression of tumor necrosis factor-alpha, and transforming growth factor beta, cerebral levels of tau proteins, and neurological motor functions in TBI rats treated with CHF5074, AST or vehicle solution. In the 2nd year, we plan to evaluate the effects of long term treatment of AST, CHF5074, or vehicle solution on synaptic plasticity, neuroregeneration, and angiogenesis in injured rats. In the 3rd year, we plan to determine the gene array of cytokines and biological markers in both the plasma and brain in TBI rats treated with drugs or vehicle solution. Our preliminary results have demonstrated that AST IV is beneficial in treating TBI-induced chronic traumatic encephalopathy in injured rats. Additionally, our expected results would provide powerful biological markers for prognosis evaluation of TBI-induced encephalopathy.
|Effective start/end date
|8/1/15 → 7/31/16
- traumatic brain injury
- chronic traumatic encephalopathy
- Alzheimer’s disease
- AST IV
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.