HX600, a synthetic agonist for RXR-Nurr1 heterodimer complex, prevents ischemia-induced neuronal damage

Abstract

Ischemic stroke is amongst the leading causes of death and disabilities. The available treatments are suitable for only a fraction of patients and thus novel therapies are urgently needed. Blockage of one of the cerebral arteries leads to massive and persisting inflammatory reaction contributing to the nearby neuronal damage. Targeting the detrimental pathways of neuroinflammation has been suggested to be beneficial in conditions of ischemic stroke. Nuclear receptor 4A-family (NR4A) member Nurr1 has been shown to be a potent modulator of harmful inflammatory reactions, yet the role of Nurr1 in cerebral stroke remains unknown. Here we show for the first time that an agonist for the dimeric transcription factor Nurr1/retinoid X receptor (RXR), HX600, reduces microglia expressed proinflammatory mediators and prevents inflammation induced neuronal death in in vitro co-culture model of neurons and microglia. Importantly, HX600 was protective in a mouse model of permanent middle cerebral artery occlusion and alleviated the stroke induced motor deficits. Along with the anti-inflammatory capacity of HX600 in vitro, treatment of ischemic mice with HX600 reduced ischemia induced Iba-1, p38 and TREM2 immunoreactivities, protected endogenous microglia from ischemia induced death and prevented leukocyte infiltration. These anti-inflammatory functions were associated with reduced levels of brain lysophosphatidylcholines (lysoPCs) and acylcarnitines, metabolites related to proinflammatory events. These data demonstrate that HX600 driven Nurr1 activation is beneficial in ischemic stroke and propose that targeting Nurr1 is a novel candidate for conditions involving neuroinflammatory component.

FGF21 alleviates neuroinflammation following ischemic stroke by modulating the temporal and spatial dynamics of microglia/macrophages

“…Inflammation-associated conditions regulated by pro-inflammatory and anti-inflammatory cytokines are associated with impaired neurogenesis and neuronal survival [39]. Our findings are in agreement with a previous report [40], which showed upregulation of almost all inflammatory cytokines immediately following stroke, with levels peaking at or 48 h after stroke.…”

Metabolome Changes in Cerebral Ischemia

“…From the perspective of therapeutic considerations, preclinical studies addressing the neuroprotective potential of manipulating certain metabolites associated with various pathways of cerebral ischemia include excitotoxic metabolites using a peptide inhibitor of c-Jun [33], anaerobic glycolysis-induced lactic acidosis using dichloroacetate [34] or induction of normoglycemia [35], and proinflammatory pathway mediators (lysophosphatidylcholines (lysoPCs) and acylcarnitines) using a synthetic agonist for RXR-Nurr1 heterodimer complex [36]. The approach to treat cerebral ischemia from the metabolism perspective is an important methodological consideration that differs from the current treatment methods that are based on mitigating the etiology of stroke by preventing or opening up the vascular occlusion.…”

Kellerin alleviates cognitive impairment in mice after ischemic stroke by multiple mechanisms

“…Increasing evidence has shown that microglia‐mediated inflammation can result in neuronal damage and death, which are crucial contributors to the pathogenesis of ischemic stroke (Loppi et al, ; Won, Lee, & Stein, ). Targeting microglia is considered as an important strategy in treating ischemic stroke (Ma et al, ).…”