Nilvadipine suppresses inflammation via inhibition of P-SYK and restores spatial memory deficits in a mouse model of repetitive mild TBI

Morin, A., Mouzon, B., Ferguson, S., Paris, D., Browning, M., Stewart, W. , Mullan, M. and Crawford, F. (2020) Nilvadipine suppresses inflammation via inhibition of P-SYK and restores spatial memory deficits in a mouse model of repetitive mild TBI. Acta Neuropathologica Communications, 8, 166. (doi: 10.1186/s40478-020-01045-x) (PMID:33076989) (PMCID:PMC7574534)

Abstract

Repeated exposure to mild TBI (mTBI) has been linked to an increased risk of Alzheimer’s disease (AD), chronic traumatic encephalopathy (CTE) and other neurodegenerative diseases. Some pathological features typically observed in AD have been found in postmortem brains of TBI and CTE, hence treatments tested for AD have a potential to be effective against r-mTBI outcomes. Neuroinflammation may present a possible answer due to its central role both in acute brain injury and in chronic degenerative-like disorders. Our previous studies have shown that drug nilvadipine, acting as an inhibitor of spleen tyrosine kinase (SYK), is effective at reducing inflammation, tau hyperphosphorylation and amyloid production in AD mouse models. To demonstrate the effect of nilvadipine in the absence of age-related variables, we introduced the same treatment to young r-mTBI mice. We further investigate therapeutic mechanisms of nilvadipine using its racemic properties. Both enantiomers, (+)-nilvadipine and (−)-nilvadipine, can lower SYK activity, whereas (+)-nilvadipine is also a potent L-type calcium channel blocker (CCB) and shown to be anti-hypertensive. All r-mTBI mice exhibited increased neuroinflammation and impaired cognitive performance and motor functions. Treatment with racemic nilvadipine mitigated the TBI-induced inflammatory response and significantly improved spatial memory, whereas (−)-enantiomer decreased microgliosis and improved spatial memory but failed to reduce the astroglial response to as much as the racemate. These results suggest the therapeutic potential of SYK inhibition that is enhanced when combined with the CCB effect, which indicate a therapeutic advantage of multi-action drugs for r-mTBI.

• Item Type: Articles
• Additional Information: This work was supported by the Department of Veterans Affairs VA Merit [I01RX002334 (PI: F. Crawford)] and by the Roskamp Institute.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Stewart, Dr William
• Authors: Morin, A., Mouzon, B., Ferguson, S., Paris, D., Browning, M., Stewart, W., Mullan, M., and Crawford, F.
• College/School: College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Journal Name: Acta Neuropathologica Communications
• Publisher: BioMed Central
• ISSN: 2051-5960
• ISSN (Online): 2051-5960
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Acta Neuropathologica Communications 8: 166
• Publisher Policy: Reproduced under a Creative Commons License