Clearing the fog: The potential of plasmalogens in mitigating chemotherapy-induced cognitive impairment. — The Association Specialists
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Clearing the fog: The potential of plasmalogens in mitigating chemotherapy-induced cognitive impairment. (22035)

Isobel T Thomas-Bland 1 2 , John Mamo 1 2 , Ryu Takechi 1 2 , Yu Yu 1 3 , Tim Rosenow 4 , Virginie Lam 1 2
  1. Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
  2. Curtin School of Population Health Perth, Curtin University, Perth, Western Australia, Australia
  3. Curtin School of Medicine, Curtin University, Perth, Western Australia, Australia
  4. National Imaging Facility at Centre for Microscopy Characterisation and Analysis, University of Western Australia, Perth, Western Australia, Australia

Chemotherapy-induced cognitive impairment, often called ‘chemobrain’, is a devastating neurocognitive sequela of chemotherapy that adversely impacts up to 70% of breast cancer survivors. Pre-clinical investigations postulate that chemobrain arises from several neurotoxic mechanisms, including exaggerated circulating pro-inflammatory cytokines, elevated oxidative stress, chronic neuroinflammation, and, subsequently, neurovascular breakdown, impairing myelin homeostasis and neuroplasticity.

The recognition of interventional adjunct therapeutics with pleiotropic effects to target the implicated neuropathological effects remains unfulfilled and is critical in preventing chemobrain. Plasmalogens are neuroprotective in several neurodegenerative conditions, likely attributed to their pivotal role in cell signalling and potent antioxidant and anti-inflammatory properties.

To induce chemobrain, C57BL/J6 mice were administered 2.0 mg/kg of doxorubicin once weekly for four weeks. Mice received either standard or 2%w/w of plasmalogen-supplemented chow for four weeks. Post-chemotherapy, cognitive function was assessed, followed by in vivo magnetic resonance imaging to determine volumetric alterations and white matter anomalies. Ex vivo confocal immunomicroscopy was used to determine blood-brain barrier permeability, neuroinflammation, oxidative stress and neuronal death.

Doxorubicin-treated mice developed significant spatial memory and learning impairments, accompanied by reduced hippocampal atrophy, heightened neuroinflammation and substantive neuronal loss. Plasmalogen co-supplementation in doxorubicin-treated mice substantially restored cognitive function in conjunction with ‘restoration’ of volumetric alterations in specific regions of interest, compared to controls. Revival of cognition was associated with a marked reduction in blood-brain barrier permeability, microglia and astrocyte activation, and oxidative stress. Overall, our findings identify plasmalogens as an effective therapeutic agent for preventing and reversing chemobrain and restoring brain health, enabling potential clinical translation.