Protective Effects of Astaxanthin on Triple Whammy-Induced Acute Kidney Injury via Antioxidant, Anti-inflammatory and Anti-Apoptotic Mechanisms

Abstract

The triple whammy combination (diuretics, ACE inhibitors, and NSAIDs) can cause acute kidney injury (AKI). Astaxanthin is known for its antioxidant, anti-inflammatory, and anti-apoptotic properties, which may offer nephroprotection. This study aimed to evaluate the prophylactic effect of astaxanthin in a triple whammy-induced AKI rat model. Thirty rats were divided into 6 groups: Normal control, triple whammy (negative control), N-acetylcysteine (positive control), and 3 astaxanthin-treated groups (0.4, 1.6 and 2.4 mg/kg body weight). Oral treatment was given for 7 days before the administration of the triple whammy combination for 2 days. Blood and urine samples were collected to assess renal biomarkers, and histopathological evaluation was performed. Antioxidant activity was tested using the DPPH radical scavenging assay. Molecular docking was used to analyze astaxanthin’s binding affinity to inflammatory (NF-κB) and apoptotic (caspase-3) targets. Triple whammy administration significantly increased serum creatinine, urea, proteinuria, and histological damage. Astaxanthin, especially at 1.6 mg/kg, significantly reduced these biomarkers and improved renal structure compared to both negative and N-acetylcysteine-treated groups. DPPH assay showed strong antioxidant activity for both astaxanthin (IC₅₀ = 24.2 µg/mL) and N-acetylcysteine (IC₅₀ = 3.7 µg/mL). In silico analysis demonstrated higher binding affinity of astaxanthin to caspase-3 (–7.5 kcal/mol) and NF-κB (–6.6 kcal/mol) than N-acetylcysteine. In conclusion, astaxanthin demonstrates superior nephroprotective efficacy, as evidenced by improved renal biomarkers and histological structure, potent antioxidant capacity, and strong predicted interactions with key inflammatory and apoptotic targets. These findings highlight astaxanthin’s potential as a promising prophylactic agent against AKI, warranting further mechanistic and translational studies. HIGHLIGHTS Astaxanthin, particularly at 1.6 mg/kg, significantly reduced serum creatinine and urea levels in a rat model of “triple whammy”-induced kidney injury. Astaxanthin demonstrated potent free radical scavenging activity in DPPH assay (IC₅₀ = 24.2 µg/mL). Molecular docking revealed that astaxanthin has higher binding affinities to caspase-3 and NF-κB than N-acetylcysteine, suggesting potential to modulate apoptosis and inflammation. GRAPHICAL ABSTRACT

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