Scholarlink

<p>Metabolic stress induced by saturated fatty acids such as palmitic acid (PA) disrupts key signalling pathways involved in neuronal survival, differentiation, and plasticity. The Sonic Hedgehog (Shh) pathway, essential for neurogenesis and tissue regeneration, is particularly vulnerable to PA-mediated suppression. In this study, we investigated the therapeutic potential of purmorphamine, a smoothened (SMO) agonist, and lithium chloride (LiCl), a GSK3β inhibitor, in restoring metabolic stress-induced insulin resistance and Shh signalling in Neuro2A cells. For the induction of insulin resistance or metabolic stress model, N2a cells were treated with PA (200&#xa0;μM) for 24&#xa0;h and validated by stimulation with insulin (100&#xa0;nM) for various time periods 0, 5, 15, 30, 60, and 120&#xa0;min. A blunted response was observed on pAKT<sup>S473</sup> and pGSK3β<sup>S9</sup> levels, indicating the development of insulin resistance. Cells were co-treated with purmorphamine (1&#xa0;μM) or LiCl (10&#xa0;µM) for 24&#xa0;h alongside PA. PA exposure downregulated Shh components (PTCH1, SMO, Gli1) and transcriptional regulators (CREB, FOXO3), which further leads to reduced expression of neuroplasticity markers (BDNF, profilin1, SOX2) and compromised neurite outgrowth. Co-treatment with purmorphamine or LiCl significantly rescued these deficits, reinstating pathway activity and cellular function. Purmorphamine or LiCl also improved neurite outgrowth and restored the proliferative capacity of N2a cells. These findings highlight the role of GSK-3β and SMO signalling interactions in maintaining neuronal outgrowth and neuroplasticity.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Glycogen Synthase Kinase-3β Mediates Suppression of Neurite Outgrowth Through Sonic Hedgehog Signalling in Palmitic Acid-Exposed Neuro2A Cells

  • 期刊论文

  • 发表日期：

    2026年1月1日

查看全文
  • Pooja Singh,
  • Shonak Vrujlal Ambaliya,
  • Gajjar Shivam Kumar,
  • Shreyash Santosh Yadav,
  • Ashok Kumar Datusalia

摘要

Metabolic stress induced by saturated fatty acids such as palmitic acid (PA) disrupts key signalling pathways involved in neuronal survival, differentiation, and plasticity. The Sonic Hedgehog (Shh) pathway, essential for neurogenesis and tissue regeneration, is particularly vulnerable to PA-mediated suppression. In this study, we investigated the therapeutic potential of purmorphamine, a smoothened (SMO) agonist, and lithium chloride (LiCl), a GSK3β inhibitor, in restoring metabolic stress-induced insulin resistance and Shh signalling in Neuro2A cells. For the induction of insulin resistance or metabolic stress model, N2a cells were treated with PA (200 μM) for 24 h and validated by stimulation with insulin (100 nM) for various time periods 0, 5, 15, 30, 60, and 120 min. A blunted response was observed on pAKTS473 and pGSK3βS9 levels, indicating the development of insulin resistance. Cells were co-treated with purmorphamine (1 μM) or LiCl (10 µM) for 24 h alongside PA. PA exposure downregulated Shh components (PTCH1, SMO, Gli1) and transcriptional regulators (CREB, FOXO3), which further leads to reduced expression of neuroplasticity markers (BDNF, profilin1, SOX2) and compromised neurite outgrowth. Co-treatment with purmorphamine or LiCl significantly rescued these deficits, reinstating pathway activity and cellular function. Purmorphamine or LiCl also improved neurite outgrowth and restored the proliferative capacity of N2a cells. These findings highlight the role of GSK-3β and SMO signalling interactions in maintaining neuronal outgrowth and neuroplasticity.