ProNGF/NGF Modulates Autophagy and Apoptosis through PI3K/Akt/mTOR and ERK Signaling Pathways following Cerebral...

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Autophagy and apoptosis are critical in cerebral ischemia-reperfusion (CIR) injury.
• The specific roles of proNGF and mature NGF in CIR-induced autophagy and apoptosis are not fully understood.
• Understanding these mechanisms is crucial for developing post-stroke neurological rehabilitation strategies.

Purpose of the Study:

• To investigate the mechanisms by which proNGF and mature NGF influence autophagy and apoptosis in CIR.
• To elucidate the signaling pathways involved in NGF-mediated neuronal protection or damage following CIR.
• To evaluate the therapeutic potential of NGF and proNGF in a CIR model.

Main Methods:

• Utilized PC12 cell lines and male Sprague-Dawley (SD) rats to simulate CIR.
• Analyzed the expression and transformation of proNGF to NGF during reperfusion.
• Investigated the effects of proNGF and NGF on autophagy and apoptosis via Western blotting and pathway analysis (PI3K/Akt/mTOR, ERK).
• Assessed neurological deficits in CIR rats treated with recombinant NGF and proNGF.

Main Results:

• ProNGF is the dominant form of NGF within 24 hours of reperfusion, while mature NGF is produced later.
• Mature NGF protects neurons from CIR-induced autophagic and apoptotic damage by activating PI3K/Akt/mTOR and ERK pathways.
• ProNGF exacerbates neuronal damage by promoting ERK-mediated autophagy and affecting apoptosis-related proteins.
• Treatment with NGF improved neurological deficits in CIR rats, whereas proNGF worsened them.

Conclusions:

• NGF exhibits differential effects on neuronal survival post-CIR, with mature NGF being neuroprotective and proNGF being neurotoxic.
• The PI3K/Akt/mTOR and ERK signaling pathways are key mediators of NGF's effects on autophagy and apoptosis in CIR.
• Targeting NGF/proNGF balance holds promise for therapeutic interventions in post-stroke neurological rehabilitation.