Co-Supplementation of Policosanol and Atorvastatin Attenuates High-Cholesterol and High-Galactose Diet-Induced Ocular and Brain Damage and Improves Cognitive Health in Zebrafish

Objectives: This study compares the effects of policosanol (PCO), atorvastatin (ATV), and their combination (ATV + PCO) on high-cholesterol and high-galactose diet (HCHG)-induced adverse events in the eyes and brain, as well as cognitive behavior, in zebrafish. Methodology: Adult zebrafish (n = 42/group) were fed for 22 weeks with HCHG, or HCHG co-supplemented with PCO, ATV, or ATV + PCO. Corneal clouding was assessed in all the groups, while retina and brain tissue were collected for histological and immunohistochemical analyses. Cognitive behavior across the groups was analyzed using the open field test, and memory impairment was assessed using electric pulse (passive avoidance) response tests. Results: After 22 weeks of feeding, the highest corneal clouding, with an opacity index of 1.1 ± 0.16, was observed in the HCHG group, which was substantially reduced by 2.2-fold and 1.9-fold by the supplementation of PCO and ATV + PCO, respectively. The ocular histological analysis revealed a significant 3.9-fold and 2.1-fold lower reactive oxygen species (ROS) generation in the retina of PCO- and ATV + PCO-supplemented zebrafish, compared with the HCHG-fed zebrafish. Consistently, brain histology suggests substantially lower ROS generation and apoptosis in the tectum opticum (TeO) and periventricular gray zone (PGZ) of the PCO and ATV + PCO groups than in the HCHG group. Likewise, PCO and ATV + PCO supplementation substantially prevented HCHG-induced senescence and demyelination in the brain. HCHG-induced cognitive impairment, marked by a reduced swimming speed, distance, and geotaxis swimming pattern (bottom dwelling), was substantially improved with co-supplementation of PCO and ATV + PCO. Furthermore, the PCO- and ATV + PCO-supplemented groups showed reduced confusion and higher escape capacity in response to electric pulses during the passive avoidance test. Conclusions: PCO and ATV + PCO supplementation provided a beneficial effect against HCHG-induced ocular and brain damage by mitigating oxidative stress, apoptosis, senescence, and demyelination, and simultaneously improving cognitive and memory decline in zebrafish.