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

Abstract

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 hours. 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.

Acute fasting inhibits central caspase-1 activity reducing anxiety-like behavior and increasing novel object and object location recognition

“…In the hypothalamus, cell type was less discernable. While resident immune cells, such as microglia, are principally thought to produce and elaborate inflammatory cytokines, several studies show that human neurons contain an inflammasome [61, 62]. In cultured primary cortical neurons, ethanol can induce caspase-1 activation and HMGB1 release [63].…”

Endothelin Confers Protection against High Glucose-Induced Neurotoxicity via Alleviation of Oxidative Stress

“…Endothelin (ET), a neuromodulator peptide that exists in three isoforms ET-1, -2, and -3 (Inoue et al, 1989), activates two ET receptor subtypes, ET-A and ET-B, with varying degrees of selectivity (Arai et al, 1990). Although high glucose increases ET level in vivo (Schneider et al, 2002) or decreases its level in in vitro models (Ward and Ergul, 2016), the role of ET in high glucose-evoked neurotoxicity remains elusive due to controversial reports on ET effects on the nervous system. For example, ET activation of the ET-A receptor is implicated in cerebral ischemia/reperfusion injury (Matsuo et al, 2001) and in other reports ET confers neuroprotection through both ET-A and -B receptors (Laziz et al, 2011).…”

Endothelin and Diabetic Complications: a Brain-Centric View

“…For example, some studies showed that ET A or dual ET A /ET B receptor antagonism is neuroprotective and improves outcomes after ischemia reperfusion injury of the brain (Dawson et al 1999, Gupta et al 2005, Matsuo et al 2001, Zhang et al 2008. Moreover, endothelial cell specific overexpression of ET-1 worsened cerebral damage (Leung et al 2009) and ET-1 induced degeneration of cultured motor neurons (Ward et al 2016). On the other hand, some studies suggested that the ET receptor blockade exacerbates brain infarction (Chuquet et al 2002) and ET-1 improves neuronal survival in cell culture models (Leung et al 2009, Ward et al 2016.…”

“…Moreover, endothelial cell specific overexpression of ET-1 worsened cerebral damage (Leung et al 2009) and ET-1 induced degeneration of cultured motor neurons (Ward et al 2016). On the other hand, some studies suggested that the ET receptor blockade exacerbates brain infarction (Chuquet et al 2002) and ET-1 improves neuronal survival in cell culture models (Leung et al 2009, Ward et al 2016.…”

“…While some studies reported that ET A antagonist or dual blockade of ET receptors prevent cognitive decline in different disease models (Freeman et al 2016, Singh et al 2014, Singh et al 2017, other studies showed ET B receptor stimulation may be beneficial in prevention of cognitive impairment (Briyal et al 2015, Briyal et al 2014. In a culture system, ET-1 appears to be protective of hippocampal neurons grown in a diabetes-mimicking environment (Ward et al 2016). Thus, our current understanding of the role of ET-1 in diabetic complications will be reviewed with a focus on the cerebrovascular and cognitive dysfunction.…”