Tenuigenin activates the IRS1/Akt/mTOR signaling by blocking PTPN1 to inhibit autophagy and improve locomotor recovery in spinal cord injury

  • J Ethnopharmacol. 2023 Jun 22;116841. doi: 10.1016/j.jep.2023.116841.
Li'e Zang  1 ,  Dewang Fu  2 ,  Fan Zhang  3 ,  Ning Li  4 ,  Xue Ma  5
Affiliations
  • 1. Department of Neurology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, Liaoning, PR China. Electronic address: [email protected].
  • 2. Department of Urology Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, Liaoning, PR China. Electronic address: [email protected].
  • 3. Department of Neurology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, Liaoning, PR China. Electronic address: [email protected].
  • 4. Department of Neurology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, Liaoning, PR China. Electronic address: [email protected].
  • 5. Department of Emergency, The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121002, Liaoning, PR China. Electronic address: [email protected].
PMID: 37355079 DOI: 10.1016/j.jep.2023.116841
Abstract

Ethnopharmacological relevance: Tenuigenin (TEN) is a main pharmacologically active component of Polygala tenuifolia Willd. (Polygalaceae), which has shown neuroprotective functions in Alzheimer's disease. Moreover, TEN also demonstrated an anti-oxidative impact in an in vitro model of Parkinson's disease, reducing damage and loss of dopaminergic neurons.

Aim: This work focuses on the impact of TEN on locomotor recovery following spinal cord injury (SCI) and underpinning molecules involved.

Methods: A rat model of SCI was generated, and the rats were treated with TEN, oe-PTPN1 (PTP non-receptor type 1), a protein kinase B (Akt)/mammalian target of rapamycin (mTOR) antagonist LY294002, or an Autophagy inhibitor 3-methyladenine (3-MA). Subsequently, locomotor function was detected. Pathological changes and neuronal activity in the spinal cord tissues were analyzed by hematoxylin and eosin staining, Nissl staining, and TUNEL assays. Protein expression of Beclin-1 and microtubule associated protein 1 light chain 3 beta (LC3B)-II/LC3B-I, PTPN1, IRS1, mTOR, and phosphorylated Akt (p-Akt) was analyzed by western blot assays. The LC3B expression was further examined by immunofluorescence staining.

Results: Treatment with TEN restored the locomotor function of SCI rats, reduced the cavity area and cell Apoptosis, upregulated growth-associated protein 43 and neurofilament 200, and decreased the Beclin-1 and LC3B-II/LC3B-I levels in the spinal cord. TEN suppressed PTPN1 protein level, while PTPN1 suppressed IRS1 protein to reduce the p-Akt and mTOR levels. Either PTPN1 overexpression or LY294002 treatment blocked the promoting effect of TEN on SCI recovery. However, treatment with 3-MA suppressed Autophagy, which consequently rescued the locomotor function and reduced neuron loss induced by PTPN1.

Conclusion: This study demonstrates that TEN suppresses Autophagy to promote function recovery in SCI rats by blocking PTPN1 and rescuing the IRS1/Akt/mTOR signaling.

Keywords
Akt/mTOR; Autophagy; IRS1; PTPN1; Spinal cord injury; Tenuigenin.
Products