GSK2606414 attenuates PERK/p-eIF2α/ATF4/CHOP axis and augments mitochondrial function to mitigate high glucose...

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Diabetic peripheral neuropathy (DPN) is caused by neuronal dysfunction and apoptosis under high glucose conditions.
• The unfolded protein response (UPR) pathway, particularly PERK (protein kinase RNA (PKR)-like ER kinase), plays a critical role in cell fate during endoplasmic reticulum stress (ER stress).

Purpose of the Study:

• To investigate the role of the PERK inhibitor GSK2606414 in high glucose-induced neurotoxicity.
• To evaluate the protective effects of GSK2606414 against ER stress and apoptosis in neuroblastoma (N2A) cells.

Main Methods:

• N2A cells were treated with high glucose (30 mM) and the PERK inhibitor GSK2606414.
• UPR activation markers (GRP78, p-PERK, p-eIF2α, ATF-4, CHOP) and apoptotic proteins (Bax, caspase 3, Bcl-2) were analyzed.
• Mitochondrial function and ER stress markers were assessed using immunofluorescence and protein level analysis.

Main Results:

• High glucose activated the UPR pathway, increasing GRP78, p-PERK, p-eIF2α, ATF-4, and CHOP expression.
• PERK activation led to increased mitochondrial superoxide production and decreased Mfn-2 levels.
• GSK2606414 treatment attenuated high glucose-induced neuronal apoptosis by inhibiting the PERK-eIF2α-ATF4-CHOP axis, reducing Bax and caspase 3, and increasing Bcl-2.

Conclusions:

• High glucose induces ER stress and apoptosis in neuronal cells via PERK activation.
• The PERK inhibitor GSK2606414 demonstrates neuroprotective effects against high glucose-induced toxicity.
• GSK2606414 holds potential for therapeutic intervention in diabetic peripheral neuropathy.