Targeting chemobrain: from experimental models to therapeutic discovery

Area of Science:

• Neuroscience
• Oncology
• Pharmacology

Background:

• Chemotherapy-induced cognitive impairment (CICI) affects many cancer survivors, diminishing quality of life.
• Currently, no FDA-approved treatments exist for CICI.
• Chemotherapy agents induce neuroinflammation, oxidative stress, and mitochondrial dysfunction, disrupting brain function.

Purpose of the Study:

• To summarize the mechanisms underlying CICI.
• To highlight a multi-model discovery pipeline for CICI research.
• To discuss emerging therapeutic strategies for mitigating CICI.

Main Methods:

• Review of preclinical evidence from rodent and complementary models (Drosophila, zebrafish, C. elegans).
• Analysis of key molecular pathways implicated in CICI, including PARP1 activation, NAD depletion, COX-2 signaling, and adenosine A2A receptor dysregulation.
• Evaluation of therapeutic strategies targeting redox balance, mitochondrial function, and neuroinflammation.

Main Results:

• Chemotherapeutic agents trigger oxidative stress, DNA damage, mitochondrial dysfunction, and neuroinflammation.
• These disruptions affect synaptic plasticity and neurogenesis.
• Conserved mechanisms of CICI are observed across diverse model organisms.

Conclusions:

• CICI is a significant challenge for cancer survivors with no current FDA-approved therapies.
• Understanding conserved molecular pathways is crucial for developing effective treatments.
• Targeting redox balance, mitochondrial function, and neuroinflammation shows promise for mitigating chemotherapy-related cognitive decline.