Mechanisms of Calcineurin Inhibitor-Induced Neurotoxicity: A Systematic Literature Review

Calcineurin inhibitors (CNIs) are extensively employed in immunosuppressive treatment yet are linked to notable neurotoxic adverse effects, which remain inadequately comprehended despite their clinical importance. This systematic literature review seeks to integrate available findings on the processes responsible for CNI-induced neurotoxicity, while identifying deficiencies in present understanding and examining possible approaches for neuroprotection. We performed an extensive examination of published research, with particular attention to four critical aspects: the neuroprotective properties of CNIs, their neurotoxic adverse effects, the function of calcineurin in neurological disorders, and the mechanisms underlying CNI activity. The review indicates that CNI-induced neurotoxicity stems from intricate interactions among impaired calcium signaling, oxidative stress, blood-brain barrier impairment, and modified synaptic plasticity, where calcineurin inhibition serves as a pivotal mechanism in these phenomena. It is noteworthy that although CNIs show neuroprotective effects in specific situations, their application in clinical settings is frequently constrained by neurological side effects that depend on dosage, such as cognitive deficits, convulsions, and damage to white matter. The results underscore the twofold aspect of CNIs, in which their advantages in suppressing immunity are offset by substantial risks of neurotoxicity, demanding vigilant oversight in treatment. Additional studies are required to clarify exact molecular processes and create specific treatments to reduce neurotoxicity while preserving immunosuppressive effects. This review establishes a basic structure for subsequent research on improving the safety of CNIs in clinical settings.