Paclitaxel Reduces Brain Injury from Repeated Head Trauma in Mice.

Administration, Intranasal Animals Brain / diagnostic imaging Brain Concussion / diagnostic imaging Craniocerebral Trauma / complications Diffusion Tensor Imaging Male Maze Learning Mice Mice, Inbred C57BL Neuroimaging Paclitaxel / administration & dosage Tubulin Modulators / administration & dosage beta-Lactamases
Axonal injury imaging microtubule-stabilizing drug repeat mild traumatic brain injury synaptic preservation

Journal

Journal of Alzheimer's disease : JAD
ISSN: 1875-8908
Titre abrégé: J Alzheimers Dis
Pays: Netherlands
ID NLM: 9814863

Informations de publication

Date de publication:
2019
Historique:
pubmed: 22 1 2019
medline: 30 5 2020
entrez: 22 1 2019
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.3233/JAD-180871 PMID: 30664506 PMC: PMC7043206
pubmed: 30664506
pii: JAD180871
doi: 10.3233/JAD-180871
pmc: PMC7043206
mid: NIHMS1066782
doi:

Substances chimiques

Tubulin Modulators 0
beta-Lactamases EC 3.5.2.6
beta-lactamase MIR-1, Enterobacter cloacae EC 3.5.2.6
Paclitaxel P88XT4IS4D

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

859-874

Subventions

Organisme : NIA NIH HHS
ID : R01 AG046619
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD083091
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002319
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000423
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK017047
Pays : United States

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Auteurs

Donna J Cross (DJ)

Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT, USA.

James S Meabon (JS)

The Mental Illness Research Education and Clinical Center (MIRECC), and VA Puget Sound Health Care System, Seattle, WA, USA.
Department of Psychiatry, University of Washington, Seattle, WA, USA.

Marcella M Cline (MM)

Geriatric Research Education and Clinical Center (GRECC) and VA Puget Sound Health Care System, Seattle, WA, USA.
Department of Molecular and Cellular Biology, University of Washington, Seattle, WA, USA.

Todd L Richards (TL)

Department of Radiology, University of Washington, Seattle, WA, USA.

Amanda J Stump (AJ)

Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT, USA.

Chloe G Cross (CG)

Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT, USA.

Satoshi Minoshima (S)

Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT, USA.

William A Banks (WA)

Geriatric Research Education and Clinical Center (GRECC) and VA Puget Sound Health Care System, Seattle, WA, USA.
Department of Medicine, University of Washington, Seattle, WA, USA.

David G Cook (DG)

Geriatric Research Education and Clinical Center (GRECC) and VA Puget Sound Health Care System, Seattle, WA, USA.
Department of Pharmacology, University of Washington, Seattle, WA, USA.

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Classifications MeSH

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