Multitargeted Neuroprotective Strategies of Ethyl Pyruvate: From Molecular Mechanisms to Clinical Perspectives in CNS Disorders.

Ethyl pyruvate (EP), a simple aliphatic ester of pyruvic acid, is a potent neuroprotective compound with diverse properties, including anti-inflammatory, antioxidant, anti-apoptotic, and metabolic regulatory activities. Given the intricate nature of neurological disorders, the multi-target mechanism of action of EP offers significant therapeutic advantages. Preclinical studies across various models of central nervous system (CNS) injury have consistently shown that EP mitigates neuronal loss, preserves blood-brain barrier integrity, and promotes functional recovery. The therapeutic efficacy of EP is attributed to its multifaceted mechanisms of action. It modulates key signaling pathways, such as nuclear factor kappa B (NF-κB) and high mobility group box 1 (HMGB1), activates the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, and provides metabolic support. Specifically, EP suppresses neuroinflammation by preventing HMGB1 release through calcium chelation and by modulating NF-κB signaling via covalent modification of the p65 subunit and stabilization of IκB-α. Furthermore, it enhances endogenous antioxidant defenses by scavenging reactive oxygen species (ROS) and inducing Nrf2 translocation. EP also acts as a bioavailable pyruvate donor, restoring intracellular adenosine triphosphate and nicotinamide adenine dinucleotide levels under ischemic or oxidative stress conditions. Comparative studies with other pyruvate derivatives have highlighted the superior efficacy and safety of EP. Additionally, structural isosteres such as N,N-diisopropyl-2-oxopropanamide (DIPOPA) and N,N-diethyl-2-oxopropanamide (DEOPA) demonstrate even greater neuroprotective potency, primarily through enhanced NF-κB inhibition by suppressing IκB-α degradation. EP is a promising therapeutic candidate for addressing oxidative stress, inflammation, and metabolic dysregulation associated with CNS diseases. However, further research is necessary to optimize the appropriate dosage, evaluate its long-term efficacy, and facilitate its clinical translation.