Gamma-Benzylidene Digoxin Derivative Attenuates Neurotoxicity Response in a Murine Stroke Model

Stroke is a prevalent age-related disease globally, contributing significantly to neurological dysfunction, disability, and mortality rates. Despite its substantial healthcare burden, effective therapies remain limited. Na/K-ATPase (NKA), beyond its canonical role in ion homeostasis, emerges as a pivotal player in oxidative stress induction, implicating its potential as a therapeutic target. Here, we investigate the efficacy of the semi-synthetic cardiotonic steroid gamma-benzylidene digoxin-15 (BD-15) in ameliorating brain ischemia-induced damage. A total of 44 male Wistar albino rats were randomly assigned to four groups (n = 11/group). The animals were subjected to experimental brain ischemia induction and treated with BD-15. Behavioral assessments revealed a significant improvement in mobility and exploration in BD-15-treated rats compared to brain ischemia alone (P < 0.05). Histological analysis suggested a reduction in brain damage in BD-15-treated rats. Moreover, BD-15 administration attenuated oxidative stress, evidenced by decreased thiobarbituric acid reactive substances levels (TBARS) in the hippocampus and sensory-motor cortex in brain ischemia rats (P < 0.05). Additionally, BD-15 treatment mitigated changes in lipid composition, possibly via modulation of membrane integrity. BD-15 also significantly restored ionic homeostasis in brain ischemia rats, improving the activities of NKA, Ca²⁺-ATPase, Sarcoendoplasmic Reticulum Calcium ATPase, and Mg²⁺-ATPase activities in the hippocampus and sensory-motor cortex (P < 0.05). Notably, acetylcholinesterase activity in brain ischemia rats was improved after BD-15 treatment (P < 0.05), suggesting additional benefits in maintaining neurotransmission following ischemic injury. These findings suggest a multifaceted neuroprotective mechanism of BD-15 in brain ischemia pathology. Our results propose BD-15 as a promising therapeutic strategy for mitigating ischemia-induced neurotoxicity. Further clinical studies are necessary to validate these findings and explore the translational potential of BD-15 in human stroke management.