Chlorogenic Acid Alleviates the Detrimental Effects of Concurrent Hyperglycemia and Chronic Stress on Brain Homeostasis by Modulating Antioxidative Defense in Adult Zebrafish

Oxidative stress is a key contributor to diabetes-related cognitive decline and is intensified by diabetes distress (DD), the psychological burden of disease management. DD lowers brain levels of nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor that regulates antioxidant defense. This study examined whether chlorogenic acid (CGA), a polyphenolic NRF2 activator, could counteract oxidative and astroglial dysfunctions in adult zebrafish subjected to chronic unpredictable mild stress (CUMS) combined with dextrose, a model mimicking DD. Zebrafish were treated with CGA (50, 100, or 200 mg/kg), and the levels of NRF2 protein and mRNA, along with its regulator keap1, were quantified. Expression levels of key downstream antioxidant genes (sod1, sod2, catalase, glutathione peroxidase, and glutamate-cysteine ligase catalytic subunit) were assessed alongside glutathione (GSH) content and superoxide dismutase (SOD) and catalase activities. Astroglial integrity was evaluated via glial fibrillary acidic protein (GFAP) levels in the whole brain and stress-sensitive regions. CGA increased total brain NRF2 protein, its mRNA, and those of its downstream effectors. At 200 mg/kg, CGA restored GSH levels, boosted antioxidant enzyme activities, and mitigated DD-associated reductions in GFAP and NRF2 in stress-vulnerable areas. These findings identify NRF2 as a promising target to protect brain health under diabetic conditions.