A hyperpolarization-activated cyclic nucleotide-gated channel inhibitor mitigates brain mitochondrial oxidative...

The effects of ivabradine, a hyperpolarization-activated cyclic nucleotide-gated channel blocker, on doxorubicin-induced chemobrain remain unclear. This study aimed to investigate whether ivabradine mitigates doxorubicin-induced chemobrain by improving cognitive function, hippocampal synaptic plasticity, and mitochondrial function, while reducing oxidative stress, inflammation, and blood-brain barrier (BBB) disruption in male rats.

Twenty-four male rats were randomly assigned to one of four groups: control-vehicle treated, control-ivabradine treated, doxorubicin-vehicle treated, and doxorubicin-ivabradine treated. Control-rats received normal saline, while doxorubicin-treated rats were given doxorubicin (3 mg/kg/day) intraperitoneally on days 0, 4, 8, 15, 22, and 29. Ivabradine (10 mg/kg) was given orally from day 0 to day 29. On day 30, cognitive function was evaluated using the novel object location (NOL) test. Following euthanasia, hippocampal synaptic plasticity, mitochondrial function, BBB integrity, brain oxidative stress and inflammation were assessed.

Doxorubicin treatment led to impaired performance in the NOL test, reduced hippocampal synaptic plasticity, disruption of mitochondrial function and BBB integrity, alongside increased oxidative stress and inflammation in the brain. Ivabradine reduced the level of mitochondrial reactive oxygen species (ROS), but did not significantly improve NOL performance or synaptic plasticity in doxorubicin-treated rats. However, ivabradine partially restored hippocampal dendritic spine morphology and reduced oxidative stress and inflammation in the brain.

Doxorubicin-induced chemobrain resulted in cognitive impairment and brain pathologies. Ivabradine reduced mitochondrial ROS and alleviated oxidative stress and inflammation in the brain, but did not improve cognitive function or synaptic plasticity. Higher doses of ivabradine may be required for more effective neuroprotection in chemobrain.