Anti-inflammatory Action of BT75, a Novel RARα Agonist, in Cultured Microglia and in an Experimental Mouse Model of Alzheimer’s Disease

Zhang, Xiuli; Subbanna, Shivakumar; Williams, Colin R. O.; Canals‐Baker, Stefanie; Smiley, John F.; Wilson, Donald A.; Das, Bhaskar C.; Saito, Mariko

doi:10.1007/s11064-023-03888-x

Cited by 6 publications

(4 citation statements)

References 73 publications

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“…ATRA inhibits expression of TNFα and iNOS in primary rat microglia activated by LPS or Aβ ( Dheen et al, 2005 ) and attenuates neuroinflammation induced by ethanol in adult rat brain by modulating SIRT1 and NF-κB ( Priyanka et al, 2018 ). Our previous studies also indicate that BT75 is a potent anti-inflammatory agent in SIM-A9 microglial cell line activated with LPS ( Zhang et al, 2023 ). Since excessive or chronic neuroinflammation has been implicated in ethanol-induced neurodegeneration ( Chastain and Sarkar, 2014 ; Pascual et al, 2017 ; Zhang et al, 2018 ; Saito et al, 2019 ; Kane and Drew, 2021 ), anti-inflammatory action of BD75 may exert neuroprotection of PV and SST neurons.…”

Section: Discussionmentioning

confidence: 73%

Effects of retinoic acid receptor α modulators on developmental ethanol-induced neurodegeneration and neuroinflammation

et al. 2023

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Ethanol exposure in neonatal mice induces acute neurodegeneration followed by long-lasting glial activation and GABAergic cell deficits along with behavioral abnormalities, providing a third trimester model of fetal alcohol spectrum disorders (FASD). Retinoic acid (RA), the active form of vitamin A, regulates transcription of RA-responsive genes and plays essential roles in the development of embryos and their CNS. Ethanol has been shown to disturb RA metabolism and signaling in the developing brain, which may be a cause of ethanol toxicity leading to FASD. Using an agonist and an antagonist specific to RA receptor α (RARα), we studied how RA/RARα signaling affects acute and long-lasting neurodegeneration and activation of phagocytic cells and astrocytes caused by ethanol administered to neonatal mice. We found that an RARα antagonist (BT382) administered 30 min before ethanol injection into postnatal day 7 (P7) mice partially blocked acute neurodegeneration as well as elevation of CD68-positive phagocytic cells in the same brain area. While an RARα agonist (BT75) did not affect acute neurodegeneration, BT75 given either before or after ethanol administration ameliorated long-lasting astrocyte activation and GABAergic cell deficits in certain brain regions. Our studies using Nkx2.1-Cre;Ai9 mice, in which major GABAergic neurons and their progenitors in the cortex and the hippocampus are labeled with constitutively expressed tdTomato fluorescent protein, indicate that the long-lasting GABAergic cell deficits are mainly caused by P7 ethanol-induced initial neurodegeneration. However, the partial reduction of prolonged GABAergic cell deficits and glial activation by post-ethanol BT75 treatment suggests that, in addition to the initial cell death, there may be delayed cell death or disturbed development of GABAergic cells, which is partially rescued by BT75. Since RARα agonists including BT75 have been shown to exert anti-inflammatory effects, BT75 may rescue GABAergic cell deficits by reducing glial activation/neuroinflammation.

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Section: Discussionmentioning

confidence: 73%

Effects of retinoic acid receptor α modulators on developmental ethanol-induced neurodegeneration and neuroinflammation

et al. 2023

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“…Sanjay et al (2022) obtiveram resultados promissores ao utilizarem fármacos anti-inflamatórios, onde observaram a mudança do fenótipo M1, para M2, caracterizado pela atividade anti-inflamatória. Dessa forma, verificou-se que a supressão de neuroinflamação através da modulação da polarização microglial pode tornar-se um potencial alvo terapêutico (COMPANYS-ALEMANY et al, 2022;JIE et al, 2022;NI et al, 2023;SANJAY et al, 2022;ZHANG et al, 2023).…”

Section: Resultsunclassified

Uso De Fármacos Anti-Inflamatórios Na Supressão Da Neuroinflamação Na Doença De Alzheimer: Uma Revisão Integrativa

Miranda,

SCHIEWE,

NIETO

et al. 2024

Anais Do I Congresso Nacional Multidisciplinar Em Ciências Da Saúde on-Line

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JOÃO ALFREDO SCHIEWE; EDUARDO APARECIDO DA SILVA NIETO; HERON BITTENCOURT; IVO ILVAN KERPPERS RESUMO Justificativa: A doença de Alzheimer (DA) é uma doença neurodegenerativa que cursa com disfunções na memória e cognição. É descrita pela presença do acúmulo de peptídeo beta amiloide em placas, as quais promovem neurotoxicidade e ativação da micróglia com aumento da liberação de citocinas que incitam inflamação. Esses fatores podem exacerbar a inflamação e aumentar a progressão da doença de Alzheimer. Assim, a neuroinflamação pode tornar-se um alvo terapêutico promissor no tratamento da DA, Objetivos: Discorrer acerca do uso de drogas anti-inflamatórias na supressão da neuroinflamação no tratamento da DA. Método: Foi realizada uma revisão integrativa da literatura, com busca na base de dado Pubmed, usando os seguintes descritores padronizados pelo Medical Subject Headings (MeSH): "Anti-inflammatory agents", "Alzheimer Disease" e "Neuroinflammation", combinados com o operador booleano "AND". A amostra foi composta por dez artigos científicos originais que versavam sobre os temas de interesse. Resultados: Os dados observados em relação a supressão da neuroinflamação em modelos humanos e murinos foram favoráveis. Analisou-se o direcionamento de alvos terapêuticos na neuroinflamação, com destaque para a polarização do fenótipo microglial e a supressão de vias inflamatórias. Conclusão: Observou-se que o uso de

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“…Fifth, chronic neuroinflammation in microglia upregulates the expression of CYP26, an enzyme involved in ATRA degradation, implying that chronic neuroinflammation, as observed in AD, is associated with reduced hippocampal ATRA levels [71]. Treatment with ATRA or a RARα agonist exerts potent anti-inflammatory effects [68,[71][72][73]. Finally, ATRA plays a non-genomic role in homeostatic plasticity by balancing excitatory and inhibitory synaptic strength, mediated by postsynaptic calcium-dependent regulation of ATRA synthesis [74][75][76][77].…”

Section: The Role Of Atra In Ad Animal Modelsmentioning

confidence: 99%

The Contribution of Hippocampal All-Trans Retinoic Acid (ATRA) Deficiency to Alzheimer’s Disease: A Narrative Overview of ATRA-Dependent Gene Expression in Post-Mortem Hippocampal Tissue

Almaguer,

Hindle,

Lawrence

2023

Antioxidants

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There is accumulating evidence that vitamin A (VA) deficiency contributes to the pathogenesis and progression of Alzheimer’s disease (AD). All-trans retinoic acid (ATRA), a metabolite of VA in the brain, serves distinct roles in the human hippocampus. Agonists of retinoic acid receptors (RAR), including ATRA, promote activation of the non-amyloidogenic pathway by enhancing expression of α-secretases, providing a mechanistic basis for delaying/preventing amyloid beta (Aβ) toxicity. However, whether ATRA is actually deficient in the hippocampi of patients with AD is not clear. Here, using a publicly available human transcriptomic dataset, we evaluated the extent to which ATRA-sensitive genes are dysregulated in hippocampal tissue from post-mortem AD brains, relative to age-matched controls. Consistent with ATRA deficiency, we found significant dysregulation of many ATRA-sensitive genes and significant upregulation of RAR co-repressors, supporting the idea of transcriptional repression of ATRA-mediated signaling. Consistent with oxidative stress and neuroinflammation, Nrf2 and NfkB transcripts were upregulated, respectively. Interestingly, transcriptional targets of Nrf2 were not upregulated, accompanied by upregulation of several histone deacetylases. Overall, our investigation of ATRA-sensitive genes in the human hippocampus bolsters the scientific premise of ATRA depletion in AD and that epigenetic factors should be considered and addressed as part of VA supplementation.

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Anti-inflammatory Action of BT75, a Novel RARα Agonist, in Cultured Microglia and in an Experimental Mouse Model of Alzheimer’s Disease

Cited by 6 publications

References 73 publications

Effects of retinoic acid receptor α modulators on developmental ethanol-induced neurodegeneration and neuroinflammation

Effects of retinoic acid receptor α modulators on developmental ethanol-induced neurodegeneration and neuroinflammation

Uso De Fármacos Anti-Inflamatórios Na Supressão Da Neuroinflamação Na Doença De Alzheimer: Uma Revisão Integrativa

The Contribution of Hippocampal All-Trans Retinoic Acid (ATRA) Deficiency to Alzheimer’s Disease: A Narrative Overview of ATRA-Dependent Gene Expression in Post-Mortem Hippocampal Tissue

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