Kouchmeshky Azita, Whiting Andrew, McCaffery Peter
School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
Department of Chemistry, Science Laboratories, Durham University, Durham, United Kingdom.
Front Neurosci. 2024 Sep 10;18:1422294. doi: 10.3389/fnins.2024.1422294. eCollection 2024.
Retinoic acid (RA) was first recognised to be important for the central nervous system (CNS) in its developmental regulatory role and, given this action, it has been proposed in the adult CNS to regulate plasticity and promote regeneration. These types of roles have included support of neurogenesis, induction of neurite outgrowth, and protection from neuronal death. These functions are predominantly mediated by the retinoic acid receptor (RAR) transcription factor, and hence agonists for the RARs have been tested in a variety of models of neurodegeneration. This present study employs several models less explored for the action of RAR agonists to reverse neurodegeneration.
A series of assays are used in which neuronal cells are placed under the types of stress that have been linked to neurodegeneration, in particular amyotrophic lateral sclerosis (ALS), and the neuroprotective influence of a new potent agonist for RAR, ellorarxine, is tested out. In these assays, neuronal cells were subjected to excitotoxic stress induced by glutamate, proteostasis disruption caused by epoxomicin, and oxidative stress leading to stress granule formation triggered by sodium arsenite.
Ellorarxine effectively reversed neuronal death in excitotoxic and proteostasis disruption assays and mitigated stress granule formation induced by sodium arsenite. This study also highlights for the first time the novel observation of RAR modulation of stress granules, although it is unknown whether this change in stress granules will be neuroprotective or potentially regenerative. Furthermore, the distribution of RAR agonists following intraperitoneal injection was assessed in mice, revealing preferential accumulation in the central nervous system, particularly in the spinal cord, compared to the liver. Gene expression studies in the spinal cord demonstrated that ellorarxine induces transcriptional changes at a low dose (0.01 mg/kg).
These findings underscore the therapeutic potential of RAR agonists, such as ellorarxine, for ALS and potentially other neurodegenerative diseases.
视黄酸（RA）最初被认为在中枢神经系统（CNS）的发育调节中起重要作用，鉴于此作用，有人提出在成年中枢神经系统中它可调节可塑性并促进再生。这些作用类型包括支持神经发生、诱导神经突生长以及保护神经元免于死亡。这些功能主要由视黄酸受体（RAR）转录因子介导，因此RAR激动剂已在多种神经退行性疾病模型中进行了测试。本研究采用了几种较少探索RAR激动剂逆转神经退行性变作用的模型。
使用了一系列试验，将神经元细胞置于与神经退行性变相关的应激类型下，特别是肌萎缩侧索硬化症（ALS），并测试一种新型强效RAR激动剂埃洛拉辛的神经保护作用。在这些试验中，神经元细胞受到谷氨酸诱导的兴奋性毒性应激、环氧霉素引起的蛋白稳态破坏以及亚砷酸钠引发的导致应激颗粒形成的氧化应激。
埃洛拉辛在兴奋性毒性和蛋白稳态破坏试验中有效逆转了神经元死亡，并减轻了亚砷酸钠诱导的应激颗粒形成。本研究还首次突出了RAR对应激颗粒调节的新观察结果，尽管尚不清楚应激颗粒的这种变化是否具有神经保护作用或潜在的再生作用。此外，评估了小鼠腹腔注射RAR激动剂后的分布情况，结果显示与肝脏相比，其在中枢神经系统中，特别是脊髓中优先积累。脊髓中的基因表达研究表明，埃洛拉辛在低剂量（0.01 mg/kg）时即可诱导转录变化。
这些发现强调了RAR激动剂，如埃洛拉辛，对ALS以及潜在的其他神经退行性疾病的治疗潜力。
