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<p>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 (<i>n</i> = 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 (<i>P</i> &lt; 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 (<i>P</i> &lt; 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, Ca<sup>2+</sup>-ATPase, Sarcoendoplasmic Reticulum Calcium ATPase, and Mg<sup>2+</sup>-ATPase activities in the hippocampus and sensory-motor cortex (<i>P</i> &lt; 0.05). Notably, acetylcholinesterase activity in brain ischemia rats was improved after BD-15 treatment (<i>P</i> &lt; 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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年7月12日

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  • Bruno de Souza Gonçalves,
  • Carla P. dos Santos,
  • Matheus V. Machado,
  • Marina M. Toledo,
  • Hélio B. dos Santos,
  • Ralph G. Thomé,
  • Grazielle A. S. Maia,
  • Cristiane Q. Tilelli,
  • Luciana E. D. de Carvalho,
  • Hérica L. Santos,
  • Vanessa F. Cortes,
  • Maira C. Lima,
  • Leandro A. Barbosa,
  • José A. F. P. Villar

摘要

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.