The role of autotaxin (ATX)-lysophosphatidic acid (LPA)
is yet
to be explored in the context of liver cirrhosis and associated encephalopathy.
Our objective of this study was to evaluate the role of an ATX inhibitor
in biliary cirrhosis and associated hepatic encephalopathy in rats.
The preliminary investigation revealed significant impairment in liver
function, which eventually led to the development of hepatic encephalopathy.
Interestingly, LPA levels were significantly increased in the plasma,
liver, and brain of rats following bile duct ligation. Subsequently,
we tested the efficacy of an ATX inhibitor, CBT-295, in bile duct-induced
biliary cirrhosis and neuropsychiatric symptoms associated with hepatic
encephalopathy. CBT-295 showed good oral bioavailability and favorable
pharmacokinetic properties. CBT-295 exhibited a significant reduction
in inflammatory cytokines like TGF-β, TNF-α, and IL-6
levels, also reduced bile duct proliferation marker CK-19, and lowered
liver fibrosis, as evident from reduced collagen deposition. The reversal
of liver fibrosis with CBT-295 led to a reduction in blood and brain
ammonia levels. Furthermore, CBT-295 also reduced neuroinflammation
induced by ammonia, which is characterized by a significant reduction
in brain cytokine levels. It improved neuropsychiatric symptoms such
as locomotor activities, cognitive impairment, and clinical grading
scores associated with hepatic encephalopathy. The improvement in
hepatic encephalopathy observed with the ATX inhibitor could be the
result of its hepatoprotective action and its ability to attenuate
neuroinflammation. Therefore, inhibition of ATX-LPA signaling can
be a multifactorial approach for the treatment of chronic liver diseases.