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 <i>keap1</i>, were quantified. Expression levels of key downstream antioxidant genes (<i>sod1</i>, <i>sod2</i>, <i>catalase</i>, <i>glutathione peroxidase</i>, and <i>glutamate-cysteine ligase catalytic subunit</i>) 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.