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

S. Loppi, N. Kolosowska, O. Kärkkäinen, P. Korhonen, M. Huuskonen, A. Grubman, H. Dhungana, S. Wojciechowski, Y. Pomeshchik, M. Giordano, H. Kagechika, A. White, S. Auriola, J. Koistinaho, G. Landreth, K. Hanhineva, K. Kanninen, T. Malm

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)670-681
Number of pages12
JournalBrain, Behavior, and Immunity
Volume73
DOIs
Publication statusPublished - 1 Oct 2018

Keywords

  • Metabolic profiling
  • Microglia
  • Neuroinflammation
  • Nuclear receptors
  • Stroke

Cite this

Loppi, S. ; Kolosowska, N. ; Kärkkäinen, O. ; Korhonen, P. ; Huuskonen, M. ; Grubman, A. ; Dhungana, H. ; Wojciechowski, S. ; Pomeshchik, Y. ; Giordano, M. ; Kagechika, H. ; White, A. ; Auriola, S. ; Koistinaho, J. ; Landreth, G. ; Hanhineva, K. ; Kanninen, K. ; Malm, T. / HX600, a synthetic agonist for RXR-Nurr1 heterodimer complex, prevents ischemia-induced neuronal damage. In: Brain, Behavior, and Immunity. 2018 ; Vol. 73. pp. 670-681.
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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.",
keywords = "Metabolic profiling, Microglia, Neuroinflammation, Nuclear receptors, Stroke",
author = "S. Loppi and N. Kolosowska and O. K{\"a}rkk{\"a}inen and P. Korhonen and M. Huuskonen and A. Grubman and H. Dhungana and S. Wojciechowski and Y. Pomeshchik and M. Giordano and H. Kagechika and A. White and S. Auriola and J. Koistinaho and G. Landreth and K. Hanhineva and K. Kanninen and T. Malm",
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Loppi, S, Kolosowska, N, Kärkkäinen, O, Korhonen, P, Huuskonen, M, Grubman, A, Dhungana, H, Wojciechowski, S, Pomeshchik, Y, Giordano, M, Kagechika, H, White, A, Auriola, S, Koistinaho, J, Landreth, G, Hanhineva, K, Kanninen, K & Malm, T 2018, 'HX600, a synthetic agonist for RXR-Nurr1 heterodimer complex, prevents ischemia-induced neuronal damage' Brain, Behavior, and Immunity, vol. 73, pp. 670-681. https://doi.org/10.1016/j.bbi.2018.07.021

HX600, a synthetic agonist for RXR-Nurr1 heterodimer complex, prevents ischemia-induced neuronal damage. / Loppi, S.; Kolosowska, N.; Kärkkäinen, O.; Korhonen, P.; Huuskonen, M.; Grubman, A.; Dhungana, H.; Wojciechowski, S.; Pomeshchik, Y.; Giordano, M.; Kagechika, H.; White, A.; Auriola, S.; Koistinaho, J.; Landreth, G.; Hanhineva, K.; Kanninen, K.; Malm, T.

In: Brain, Behavior, and Immunity, Vol. 73, 01.10.2018, p. 670-681.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - HX600, a synthetic agonist for RXR-Nurr1 heterodimer complex, prevents ischemia-induced neuronal damage

AU - Loppi, S.

AU - Kolosowska, N.

AU - Kärkkäinen, O.

AU - Korhonen, P.

AU - Huuskonen, M.

AU - Grubman, A.

AU - Dhungana, H.

AU - Wojciechowski, S.

AU - Pomeshchik, Y.

AU - Giordano, M.

AU - Kagechika, H.

AU - White, A.

AU - Auriola, S.

AU - Koistinaho, J.

AU - Landreth, G.

AU - Hanhineva, K.

AU - Kanninen, K.

AU - Malm, T.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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.

AB - 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.

KW - Metabolic profiling

KW - Microglia

KW - Neuroinflammation

KW - Nuclear receptors

KW - Stroke

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U2 - 10.1016/j.bbi.2018.07.021

DO - 10.1016/j.bbi.2018.07.021

M3 - Article

VL - 73

SP - 670

EP - 681

JO - Brain, Behavior, and Immunity

JF - Brain, Behavior, and Immunity

SN - 0889-1591

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