Relationship of endothelin-1 and NLRP3 inflammasome activation in HT22 hippocampal cells in diabetes

Diabetes increases the risk and worsens the progression of cognitive decline. Diabetic rats treated with the dual endothelin receptor antagonist bosentan, have been shown to improve hippocampal-based cognitive deficits. The NLRP3 inflammasome has been implicated in vascular complications of diabetes. We hypothesized that diabetes-mediated increase in endothelin-1 (ET-1) in hippocampal cells causes NLRP3 activation and inflammation. An in vitro model was employed by exposing HT22 hippocampal cells to normal (25 mM), low (5.5 mM) and high (50 mM) glucose conditions with and without palmitate (200 μM) in the presence and absence of 10 μM bosentan for 24 h. NLRP3 activity was measured by western blotting for cryopyrin and caspase-1. ET-1 and IL-1β expression was determined by ELISA. HT22 cells synthesize high levels of ET-1 in normal conditions, which was reduced with palmitate and bosentan as well as low and high glucose conditions. Decreased ET-1 levels were associated with greater activation of NLRP3 and IL-1β in normal glucose. High glucose increased NLRP3 markers and activation compared to normal and low glucose. These data suggest that ET-1 may be protective to neurons. Although endothelin antagonism may be beneficial in improving vascular dysfunction and cognitive impairment, its impact on hippocampal neurons should be further explored.