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Thrombin Inhibition Reduces the Expression of Brain Inflammation Markers upon
Systemic LPS Treatment
#MMPMID30018633
Shavit Stein E
; Ben Shimon M
; Artan Furman A
; Golderman V
; Chapman J
; Maggio N
Neural Plast
2018[]; 2018
(?): 7692182
PMID30018633
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Systemic inflammation and brain pathologies are known to be linked. In the
periphery, the inflammation and coagulation systems are simultaneously activated
upon diseases and infections. Whether this well-established interrelation also
counts for neuroinflammation and coagulation factor expression in the brain is
still an open question. Our aim was to study whether the interrelationship
between coagulation and inflammation factors may occur in the brain in the
setting of systemic inflammation. The results indicate that systemic injections
of lipopolysaccharide (LPS) upregulate the expression of both inflammatory and
coagulation factors in the brain. The activity of the central coagulation factor
thrombin was tested by a fluorescent method and found to be significantly
elevated in the hippocampus following systemic LPS injection (0.5?±?0.15?mU/mg
versus 0.2?±?0.03?mU/mg in the control). A panel of coagulation factors and
effectors (such as thrombin, FX, PAR1, EPCR, and PC) was tested in the
hippocampus, isolated microglia, and N9 microglia cell by Western blot and
real-time PCR and found to be modulated by LPS. One central finding is a
significant increase in FX expression level following LPS induction both in vivo
in the hippocampus and in vitro in N9 microglia cell line (5.5?±?0.6- and
2.3?±?0.1-fold of increase, resp.). Surprisingly, inhibition of thrombin activity
(by a specific inhibitor NAPAP) immediately after LPS injection results in a
reduction of both the inflammatory (TNF?, CXL9, and CCL1; p < 0.006) and
coagulation responses (FX and PAR1; p < 0.004) in the brain. We believe that
these results may have a profound clinical impact as they might indicate that
reducing coagulation activity in the setting of neurological diseases involving
neuroinflammation may improve disease outcome and survival.
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