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J147 treatment protects against traumatic brain injury by inhibiting neuronal endoplasmic reticulum stress potentially via the AMPK/SREBP-1 pathway.
Jin, Rong; Wang, Min; Shukla, Manish; Lei, Yuguo; An, Dong; Du, Jiwen; Li, Guohong.
Afiliación
  • Jin R; Department of Neurosurgery, Penn State Hershey Medical Center, Hershey, PA 17033, USA. Electronic address: Rjin@pennstatehealth.psu.edu.
  • Wang M; Department of Neurosurgery, Penn State Hershey Medical Center, Hershey, PA 17033, USA.
  • Shukla M; Department of Neurosurgery, Penn State Hershey Medical Center, Hershey, PA 17033, USA.
  • Lei Y; Department of Biomedical Engineering, Pennsylvania State University; University Park, PA, 16802, USA.
  • An D; Department of Neurosurgery, Penn State Hershey Medical Center, Hershey, PA 17033, USA.
  • Du J; Department of Neurosurgery, Penn State Hershey Medical Center, Hershey, PA 17033, USA.
  • Li G; Department of Neurosurgery, Penn State Hershey Medical Center, Hershey, PA 17033, USA. Electronic address: Guohongli@pennstatehealth.psu.edu.
Transl Res ; 274: 21-34, 2024 Sep 07.
Article en En | MEDLINE | ID: mdl-39245209
ABSTRACT
Endoplasmic reticulum (ER) stress is recognized as a crucial contributor to the progression of traumatic brain injury (TBI) and represents a potential target for therapeutic intervention. This study aimed to assess the potential of J147, a novel neurotrophic compound, in alleviating ER stress by modulating related signaling pathways, thereby promoting functional recovery in TBI. To this end, adult mice underwent controlled cortical impact (CCI) injury to induce TBI, followed by oral administration of J147 one-hour post-injury, with daily dosing for 3 to 7 days. Multiple behavioral assessments were conducted over 35 days, revealing a significant, dose-dependent improvement in neurofunctional recovery with J147 treatment. The neuropathological analysis demonstrated reduced acute neurodegeneration (observed at three days through FJC staining), enhanced long-term neuron survival (H&E and Nissl staining), and improved neuroplasticity (Golgi staining) at 35 days post-TBI. At the molecular level, TBIinduced AMP-activated protein kinase (AMPK) dephosphorylation, sterol regulatory element binding protein-1 (SREBP-1) activation, and upregulation of ER stress marker proteins, including phosphorylated eukaryotic initiation factor-2α (p-eIF2a), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP) in perilesional cortex neurons at three days post-injury. Notably, the J147 treatment significantly attenuated AMPK dephosphorylation, SERBP-1 activation, and expression of the ER stress markers. In summary, this study reveals the therapeutic promise of J147 in mitigating secondary brain damage associated with TBI and improving long-term functional recovery by modulating ER stress pathways.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Transl Res Asunto de la revista: MEDICINA / TECNICAS E PROCEDIMENTOS DE LABORATORIO Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Transl Res Asunto de la revista: MEDICINA / TECNICAS E PROCEDIMENTOS DE LABORATORIO Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos