Paclitaxel Reduces Brain Injury from Repeated Head Trauma in Mice
Article type: Research Article
Authors: Cross, Donna J.a; * | Meabon, James S.b; d | Cline, Marcella M.c; e | Richards, Todd L.f | Stump, Amanda J.a | Cross, Chloe G.a | Minoshima, Satoshia | Banks, William A.c; g | Cook, David G.c; h
Affiliations: [a] Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT, USA | [b] The Mental Illness Research Education and Clinical Center (MIRECC), and VA Puget Sound Health Care System, Seattle, WA, USA | [c] Geriatric Research Education and Clinical Center (GRECC) and VA Puget Sound Health Care System, Seattle, WA, USA | [d] Department of Psychiatry, University of Washington, Seattle, WA, USA | [e] Department of Molecular and Cellular Biology, University of Washington, Seattle, WA, USA | [f] Department of Radiology, University of Washington, Seattle, WA, USA | [g] Department of Medicine, University of Washington, Seattle, WA, USA | [h] Department of Pharmacology, University of Washington, Seattle, WA, USA
Correspondence: [*] Correspondence to: Donna J. Cross, PhD, Department of Radiology and Imaging Sciences, University of Utah, 30 N. 1900 E. #1A71, Salt Lake City, UT 84132-2140, USA. Tel.: +1 801 585 1346; E-mail: d.cross@utah.edu.
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 microtubule-stabilizing 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 against brain injury and cognitive impairment in mice. The results from this study support the idea that microtubule-stabilization strategies hold therapeutic promise in mitigating traumatic brain injury.
Keywords: Axonal injury, imaging, microtubule-stabilizing drug, repeat mild traumatic brain injury, synaptic preservation
DOI: 10.3233/JAD-180871
Journal: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 859-874, 2019
