Nilvadipine suppresses inflammation via inhibition of P-SYK and restores spatial memory deficits in a mouse model of rep
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RESEARCH
Nilvadipine suppresses inflammation via inhibition of P‑SYK and restores spatial memory deficits in a mouse model of repetitive mild TBI Alexander Morin1,2,3* , Benoit Mouzon1,2,3, Scott Ferguson1,2,3, Daniel Paris1,2,3, Mackenzie Browning1, William Stewart4, Mike Mullan1,2 and Fiona Crawford1,2,3
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.
Introduction Globally, 61 million individuals are estimated to sustain Traumatic brain injury (TBI) each year [5]. In the United States alone, TBI affects over 2.5 million people annually, with mTBI representing 80% of all TBI cases, and to date accounts for more than 13 million cases of long-term *Correspondence: [email protected] 1 The Roskamp Institute, Sarasota, FL, USA Full list of author information is available at the end of the article
disability [32]. Repeated exposure to mTBI (r-mTBI) has been to linked to higher risks of chronic neurodegenerative disorders including Alzheimers disease (AD) and Chronic Traumatic Encephalopathy (CTE) [4, 6, 12, 13, 31]. In fact, the pathologies of late r-mTBI share similar features with AD and CTE and include a marked neuroinflammatory response, the presence of neurofibrillary tangles (NFTs), and to a lesser extent, the presence of amyloid-β (Aβ ) pathology [9, 14, 30, 31]. Among them, neuroinflammation is a key element of both acute and ch
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