Paclitaxel Reduces Brain Injury from Repeated Head Trauma in Mice

Abstract

Repetitive mild traumatic brain injury (rmTBI) is known to disturb axonal integrity and may play an important role in the pathogenic cascades leading to neurodegeneration. One critical approach to reduce the future onset of neurodegeneration is to intervene in this process at an early stage following a brain injury. Previously we showed that direct application of the microtubulestabilizing drug, paclitaxel, on the brain following controlled cortical impact improved motor function and reduced lesion size. Herein, we extended these findings to a model of mild brain injury induced by repeated closed-skull impacts. Paclitaxel was administered intranasally to circumvent its poor transport across the blood-brain barrier. Mice received five mild closed-skull impacts (one per day for five days). Intranasal paclitaxel was administered once only, immediately after the first impact. We found that paclitaxel prevented injury-induced deficits in a spatial memory task in a water tread maze. In vivo magnetic resonance imaging (MRI) and positron emission tomography with 18F-flurodeoxyglucose (FDG-PET) revealed that paclitaxel prevented structural injury and hypometabolism. On MRI, apparent, injury-induced microbleeds were observed in 100% of vehicle-treated rmTBI mice, but not in paclitaxel-treated subjects. FDG-PET revealed a 42% increase in whole brain glucose metabolism in paclitaxel-treated mice as compared to vehicle-treated rmTBI. Immunohistochemistry found reduced evidence of axonal injury and synaptic loss. Our results indicate that intranasal paclitaxel administration imparts neuroprotection

Immediate induction of varicosities by transverse compression but not uniaxial stretch in axon mechanosensation

“…Diffuse axonal injury (DAI) is the most common neuropathology in mTBI, in which uniaxial stretch is believed to play a central role. It has been postulated that uniaxial stretch induces microtubule breakage to disrupt axonal transport of various organelles and other cargos, causing axonal dysfunction and hence classical symptoms of decreased processing speed and memory impairment [ 3 – 7 ]. Whereas DAI has been extensively described using animal models and postmortem human tissues, mechanistic insights into axonal injury by uniaxial stretch have been provided by elegantly designed in vitro assays using primary neuron cultures combined with compartment chamber, stretchable membrane and/or magnetic tweezers [ 3 , 8 – 11 ].…”

Rapid and Reversible Development of Axonal Varicosities: A New Form of Neural Plasticity

“…Microtubule-stabilizing agents are being developed as potential therapeutics for cancer and neurodegenerative disorders (Magen and Gozes, 2013 ; Brunden et al, 2014 ; Lou et al, 2014 ). Microtubule breakage was implicated in DAI in mTBI or concussion (Tang-Schomer et al, 2012 ; Johnson et al, 2013 ; del Mar et al, 2015 ; Chuckowree et al, 2018 ; Cross et al, 2019 ). Microtubule-associated protein tau forms pathological aggregates in mTBI-induced chronic traumatic encephalopathy, while microtubule disruption is believed to underlie tauopathies (Terrell et al, 2008 ; Abrahams et al, 2019 ; Derry et al, 2019 ; Katsumoto et al, 2019 ).…”

Hippocampal-Dependent Cognitive Dysfunction following Repeated Diffuse Rotational Brain Injury in Male and Female Mice

“…[12][13][14][15][16] Behavioral dysfunction, including hippocampal-dependent learning and memory deficits, are also reliably observed following TBI in rodents 17,18 and several drugs have been identified in translational studies that prevent or reverse both axonal damage and cognitive deficits. 15,[19][20][21] However, despite the numerous promising pharmacological agents recognized in pre-clinical trials, all phase III clinical trials have failed and at present there is no U.S. Food and Drug Administration-approved therapy for TBI. 22,23 Nevertheless, translational models of clinical relevance remain critical in furthering the understanding of the pathophysiological cascades following injury, functional consequences of TBI, and subsequent testing of potential therapeutic agents.…”