Treatment With Nilvadipine Mitigates Inflammatory Pathology and Improves Spatial Memory in Aged hTau Mice After Repetitive Mild TBI

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Abstract

Mild traumatic brain injury (mTBI) is the most common form of brain trauma worldwide. The effects of mTBI are not well-studied within the elderly population, yet older adults constitute a significant portion of all mTBI patients. Few preclinical studies have focused on the effects of mTBI, or mTBI treatments, in the aged brain, and none have explored repetitive mTBI (r-mTBI). In this study, we have administered our well-characterized 5-injury model (5 r-mTBI) to hTau mice aged 24 months to explore the neurobehavioral and neuropathological outcomes, and the effects of treatment with the dihydropyridine, Nilvadipine. Our previous studies have shown that Nilvadipine inhibits spleen tyrosine kinase (Syk), is effective at reducing inflammation, tau hyperphosphorylation, and amyloid production, and it has recently been investigated in a European Phase III clinical trial for Alzheimer’s disease (AD). In our 24-month-old r-mTBI mice, we observed increased neuroinflammation and a trend toward impaired cognitive performance compared to sham controls. Treatment with Nilvadipine mitigated the TBI-induced inflammatory response in aged r-mTBI animals and significantly improved spatial memory. To our knowledge, this is the only preclinical study focusing on the treatment of r-mTBI in aged, and these results suggest a therapeutic potential of Nilvadipine for consequences of mTBI.

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Most cited references 57

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Current and future estimates of Alzheimer disease (AD) are essential for public health planning. To provide prevalence estimates of AD for the US population from 2000 through 2050. Alzheimer disease incidence estimates from a population-based, biracial, urban study, using a stratified random sampling design, were converted to prevalence estimates and applied to US Census Bureau estimates of US population growth. A geographically defined community of 3 adjacent neighborhoods in Chicago, Ill, applied to the US population. Alzheimer disease incidence was measured in 3838 persons free of AD at baseline; 835 persons were evaluated for disease incidence. Main Outcome Measure Current and future estimates of prevalence of clinically diagnosed AD in the US population. In 2000, there were 4.5 million persons with AD in the US population. By 2050, this number will increase by almost 3-fold, to 13.2 million. Owing to the rapid growth of the oldest age groups of the US population, the number who are 85 years and older will more than quadruple to 8.0 million. The number who are 75 to 84 years old will double to 4.8 million, while the number who are 65 to 74 years old will remain fairly constant at 0.3 to 0.5 million. The number of persons with AD in the US population will continue to increase unless new discoveries facilitate prevention of the disease.

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Raquel Gardner, Kristine Yaffe (2015)

Every year an estimated 42 million people worldwide suffer a mild traumatic brain injury (MTBI) or concussion. More severe traumatic brain injury (TBI) is a well-established risk factor for a variety of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Recently, large epidemiological studies have additionally identified MTBI as a risk factor for dementia. The role of MTBI in risk of PD or ALS is less well established. Repetitive MTBI and repetitive sub-concussive head trauma have been linked to increased risk for a variety of neurodegenerative diseases including chronic traumatic encephalopathy (CTE). CTE is a unique neurodegenerative tauopathy first described in boxers but more recently described in a variety of contact sport athletes, military veterans, and civilians exposed to repetitive MTBI. Studies of repetitive MTBI and CTE have been limited by referral bias, lack of consensus clinical criteria for CTE, challenges of quantifying MTBI exposure, and potential for confounding. The prevalence of CTE is unknown and the amount of MTBI or sub-concussive trauma exposure necessary to produce CTE is unclear. This review will summarize the current literature regarding the epidemiology of MTBI, post-TBI dementia and Parkinson's disease, and CTE while highlighting methodological challenges and critical future directions of research in this field. This article is part of a Special Issue entitled SI:Traumatic Brain Injury.

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Author and article information

Contributors

Alexander Morin: URI : https://loop.frontiersin.org/people/469527/overview

Benoit Mouzon: URI : https://loop.frontiersin.org/people/137133/overview

Scott Ferguson: URI : https://loop.frontiersin.org/people/472475/overview

Nicole Saltiel: URI : https://loop.frontiersin.org/people/586032/overview

Carlyn Lungmus: URI : https://loop.frontiersin.org/people/477113/overview

Fiona Crawford: URI : https://loop.frontiersin.org/people/550328/overview

Journal

Journal ID (nlm-ta): Front Aging Neurosci

Journal ID (iso-abbrev): Front Aging Neurosci

Journal ID (publisher-id): Front. Aging Neurosci.

Title: Frontiers in Aging Neuroscience

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1663-4365

Publication date (Electronic): 11 October 2018

Publication date Collection: 2018

Volume: 10

Electronic Location Identifier: 292

Affiliations

[1] ¹The Roskamp Institute , Sarasota, FL, United States

[2] ²The Open University , Milton-Keynes, United Kingdom

[3] ³James A Haley Veterans Administration , Tampa, FL, United States

Author notes

Edited by: Merce Pallas, University of Barcelona, Spain

Reviewed by: Adel Helmy, University of Cambridge, United Kingdom; Ayodeji A. Asuni, New York University, United States

*Correspondence: Alexander Morin amorin@ 123456roskampinstitute.net

Article

DOI: 10.3389/fnagi.2018.00292

PMC ID: 6193195

PubMed ID: 30364309

SO-VID: b6cb81c0-e4ac-4fdf-827b-c96add66baa5

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 01 June 2018

Date accepted : 04 September 2018

Page count

Figures: 8, Tables: 0, Equations: 0, References: 73, Pages: 13, Words: 9253

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