Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Oxidative Stress Research
• Pharmacology

Background:

• Alzheimer's disease (AD) is characterized by oxidative stress (OS), mitochondrial dysfunction, and reduced levels of antioxidants like all-trans retinoic acid (ATRA) and Nrf2.
• Histone acetylation homeostasis is disrupted in AD, suggesting a role for epigenetic modifications in the disease.
• Investigating novel therapeutic strategies targeting redox homeostasis is crucial for AD treatment.

Purpose of the Study:

• To determine if vorinostat (VOR), a histone deacetylase inhibitor, and ATRA can synergistically or differentially regulate redox homeostasis.
• To evaluate the neuroprotective effects of ATRA and VOR against OS-induced damage in mouse hippocampal neurons (HT22 cells).

Main Methods:

• HT22 cells were pre-treated with ATRA and/or VOR, followed by exposure to hydrogen peroxide (H₂O₂) to induce OS.
• Assessed lipid peroxidation, mitochondrial oxidation, apoptosis, DNA fragmentation, Nrf2 expression, and antioxidant response enzymes using various assays (ELISA, comet assay, TUNEL, flow cytometry, Western blot).

Main Results:

• ATRA and VOR pre-treatments significantly attenuated H₂O₂-induced apoptosis, necrosis, and DNA damage.
• Both ATRA and VOR increased Nrf2 protein levels and downstream antioxidant enzymes (HO-1, SOD).
• While H₂O₂ increased Nrf2 expression, nuclear Nrf2 activity was impaired, suggesting dysfunctional Nrf2 pathway signaling in OS.

Conclusions:

• ATRA and VOR, independently or in combination, protect neuronal cells from OS through distinct pathways.
• These compounds hold potential for reducing OS in early Alzheimer's disease pathogenesis and progression.
• Targeting both ATRA and VOR-mediated pathways may be a promising therapeutic strategy for AD.