Repurposing Imeglimin for Chemotherapy-Induced Cognitive Impairment: Targeting Mitochondrial Dysfunction and Neuroinflammation.

Chemotherapy-induced cognitive impairment, known as chemo brain, is a severe side effect of cancer treatment that may cause severe memory, attention, executive skills, and cognitive learning damage. There are several underpinning factors of CICI comprising several pathways, such as oxidative stress, impaired mitochondrial function, neural inflammation, insulin resistance, and decreased neurogenesis. Due to its remarkable neuroprotective properties, imeglimin-a new class of antidiabetic medication - looks potentially promising as a treatment method for chemo brain-associated cognitive disorders. Imeglimin affects mitochondrial bioenergetics, playing a role in enhanced mitochondrial O2 uptake, increased membrane potentials and diminished oxidative stress. This is exceptionally important in the chemo brain context, as the chemotherapeutic agents such as cisplatin and doxorubicin commonly cause mitochondrial damage and oxidative stress in neurons of the brain. Also, by functioning as an antioxidant, imeglimin enhances redox homeostasis, thereby protecting against neuronal apoptosis and regular synaptic activity. Neuroinflammation, another significant activity in CICI, is fueled by microglial activation and cytokine production. The anti-inflammatory activity of imeglimin is associated with its ability to suppress NF-κB signaling and reduce the levels of pro-inflammatory cytokine TNF-α and IL-6. Such outcomes suggest that imeglimin might ameliorate the neuroinflammatory responses associated with chemotherapy. In addition, imeglimin enhances insulin sensitivity and modulates brain glucose metabolism, which associates it with the modern concept of chemo brain as "type 3 diabetes". Enhancing insulin signaling is one of the mechanisms by which imeglimin may increase synaptic plasticity and improve cognitive resilience. Moreover, Imeglimin exhibits multiple mitochondrial and anti-inflammatory actions that may hold potential for mitigating chemobrain-related pathology. However, its therapeutic application in this context remains hypothetical and warrants dedicated preclinical and clinical evaluation. This review discusses these possible mechanisms and emphasises the need for more preclinical and clinical trials to support its role in reducing the cognitive effects of chemotherapy. Unlike prior descriptive chemobrain reviews, this article applies a hypothesis-driven translational framework to critically assess Imeglimin's mechanistic plausibility, pharmacological constraints, and unmet validation gaps in chemotherapy-induced cognitive impairment.