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

Alexander Morin,Fiona Crawford,Mackenzie Browning,William Stewart,Scott Ferguson,Mike Mullan,Daniel Paris,Benoit Mouzon

doi:10.1186/s40478-020-01045-x

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.

Highlights

61 million individuals are estimated to sustain Traumatic brain injury (TBI) each year [5]
Treatment with nilvadipine in r-mild TBI (mTBI) mice lead to a 44% decrease in cumulative distance (r-mTBI-nilvadipine vs. Repeated exposure to mTBI (r-mTBI)-vehicle p < 0.01, r-mTBI-nilvadipine vs. sham-vehicle p > 0.05, MANOVA) and a 28.6% decrease in the distance traveled (r-mTBI-nilvadipine vs. r-mTBI-vehicle p < 0.0001, r-mTBI-nilvadipine vs. sham-vehicle p < 0.01, MANOVA)
By day 6, a 35% increase in time to locate the box was recorded for the r-mTBInilvadipine mice compared to sham-vehicle

Summary

Introduction

61 million individuals are estimated to sustain Traumatic brain injury (TBI) each year [5]. In our previous pre-clinical work on AD, we have shown that the drug nilvadipine can reduce inflammation, decrease tau phosphorylation, and enhance A β clearance across the blood brain barrier (BBB), while improving cognitive functions [2, 23, 24]. Nilvadipine is a dihydropyridine (DHP) that blocks L-type calcium channels and exhibits anti-hypertensive properties [3]. (+)-nilvadipine is a L-type calcium channel blocker responsible for the anti-hypertensive properties of nilvadipine while (−)-nilvadipine is deprived of anti-hypertensive effect [23, 24]. We have shown that both enantiomers of nilvadipine are able to reduce neuroinflammation, tau hyperphosphorylation, and A β production via a mechanism which appears to be independent of L-type calcium channel inhibition and mediated by SYK inhibition [23].

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