Donna J. Cross
University of Utah, USA
Title: Preclinical neuroimaging of microtubule-stabilizing therapeutics for brain injury and Alzheimer’s disease
Biography
Biography: Donna J. Cross
Abstract
Approximately 1.7 million traumatic brain injuries (TBIs) occur per year in the United States. In addition, TBI is a significant environmental risk factor for the development of neurodegenerative diseases such as chronic traumatic encephalopathy (CTE) and Alzheimer’s disease (AD). In TBI, shear forces generated by impact cause cytoskeleton misalignment and disruption of axonal transport followed by a cascade of metabolic and neuroinflammatory events. We hypothesize that cytoskeletal injuries may synergistically increase the initiation and progression of the neurodegenerative process. However, there is no effective pharmacological intervention to improve outcome in TBI or slow the neurodegenerative progress of Alzheimer’s disease. We propose that microtubule-stabilizing drugs under use as chemotherapeutics, may be administered in low doses to stabilize the cytoskeleton and to maintain axonal transport known to be disrupted in TBI and AD. Although, taxanes such as paclitaxel do not significantly penetrate across blood brain barrier, this limitation may be overcome by intranasal delivery. This research used preclinical neuroimaging (FDG-PET and MRI) combined with neurocognitive testing in mouse models of TBI and AD to show the therapeutic efficacy of intranasal paclitaxel. In addition, immunohistochemistry for AD pathology supported in vivo findings and the ability of the drug to restore axonal transport was shown using in vitro kinetic analysis of axonal dynamics. This study provides evidence of the efficacy for intranasally administered paclitaxel to improve outcome following TBI and to slow cognitive decline and development of pathology in AD. The use of in vivo neuroimaging for therapeutic development aids clinical translation.