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

Pooja Singh1, Shonak Vrujlal Ambaliya1, Gajjar Shivam Kumar1

  • 1Laboratory of Molecular NeuroTherapeutics, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Raebareli, U.P, Lucknow, 226002, India.

Molecular Neurobiology
|May 9, 2026
PubMed

Insights

Palmitic acid causes metabolic stress, impairing neuronal function. Purmorphamine and lithium chloride treatments restored insulin signalling, Sonic Hedgehog pathway activity, and neuronal outgrowth in Neuro2A cells.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Metabolic stress from saturated fatty acids, like palmitic acid (PA), disrupts neuronal survival and plasticity.
  • The Sonic Hedgehog (Shh) pathway is crucial for neurogenesis but is vulnerable to PA-induced suppression.

Purpose of the Study:

  • To investigate purmorphamine and lithium chloride (LiCl) as potential therapeutics against PA-induced metabolic stress and insulin resistance in Neuro2A cells.
  • To assess the impact of these compounds on Shh signalling and neuronal plasticity markers.

Main Methods:

  • Neuro2A cells were treated with PA to induce metabolic stress and insulin resistance, validated by insulin stimulation.
  • Cells were co-treated with purmorphamine (SMO agonist) or LiCl (GSK3β inhibitor) alongside PA.
  • Shh pathway components, transcriptional regulators, neuroplasticity markers, and neurite outgrowth were analyzed.

Main Results:

  • PA treatment induced insulin resistance and downregulated Shh signalling components (PTCH1, SMO, Gli1) and key regulators (CREB, FOXO3).
  • PA exposure reduced neuroplasticity markers (BDNF, profilin1, SOX2) and impaired neurite outgrowth.
  • Co-treatment with purmorphamine or LiCl significantly rescued these deficits, restoring pathway activity, cellular function, and neurite outgrowth.

Conclusions:

  • Purmorphamine and LiCl can counteract palmitic acid-induced metabolic stress and insulin resistance in neuronal cells.
  • GSK-3β and SMO signalling pathways are critical targets for maintaining neuronal outgrowth and neuroplasticity.
  • These findings suggest therapeutic potential for purmorphamine and LiCl in neurological conditions associated with metabolic dysfunction.
Keywords:
GSK3βInsulin resistanceLithium chlorideNeurite outgrowthPalmitic acidSonic hedgehog signaling

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