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Digoxin Derivative BD-8 Attenuates Oxidative Stress and Neuroinflammation in an LPS-Induced Experimental Model
Vitória Karolina Brandão Souza1, Davi Azevedo Ferreira2, Antônio Pereira Ribeiro Arantes3
1Instituto de Ciências Biológicas, Department of Pharmacology, Federal University of Goiás, Goiânia, 74690-612, GO, Brazil.
Abstract:
Chronic neuroinflammation contributes to neuronal damage through oxidative stress and inflammatory mediators, highlighting the need for novel therapeutic strategies. This study evaluated the cytotoxicity and neuroprotective effects of BD-8, a digoxin-derived cardiosteroid, in vitro and in vivo. BD-8 showed lower cytotoxicity than digoxin, with CC₅₀ values of 7.4 µM in SH-SY5Y cells and 8.5 µM in BV-2 cells, while digoxin presented a CC₅₀ of 33 nM in SH-SY5Y cells. In vivo, BD-8 did not alter cardiac, hepatic, or renal biochemical markers, supporting its systemic safety profile. In the open-field test, BD-8 prevented LPS-induced locomotor impairment, significantly increasing total crossings at 0.56 mg/kg (62.07 ± 3.269; P < 0.05) and 1.12 mg/kg (66.31 ± 5.282; P < 0.001) compared to the LPS group. BD-8 also reduced lipid peroxidation levels in the cortex at 0.56 mg/kg (14.38 ± 0.5568; P < 0.001) and 1.12 mg/kg (13.94 ± 0.8372; P < 0.001), and in the hippocampus at 1.12 mg/kg (14.04 ± 0.5223; P < 0.001). Additionally, BD-8 modulated antioxidant enzyme activities, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), in both the cortex and hippocampus and reduced IL-6 levels in these brain regions without altering BDNF (Brain Derived Neurotrophic Factor) levels. These findings support BD-8 as a promising candidate for neuroinflammatory disorders.
Insights
BD-8, a digoxin derivative, demonstrates neuroprotective effects against chronic neuroinflammation with lower cytotoxicity than digoxin. This study supports BD-8 as a potential therapeutic agent for neuroinflammatory disorders.
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- Chronic neuroinflammation is a key driver of neuronal damage via oxidative stress and inflammatory mediators.
- Novel therapeutic strategies are crucial for managing neuroinflammatory conditions.
- Digoxin-derived cardiosteroids are being explored for therapeutic potential.
Purpose of the Study:
- To evaluate the cytotoxicity and neuroprotective effects of BD-8, a digoxin derivative.
- To assess the in vitro and in vivo safety and efficacy of BD-8 in models of neuroinflammation.
- To investigate BD-8's impact on oxidative stress markers and inflammatory mediators in the brain.
Main Methods:
- Cytotoxicity was assessed using CC₅₀ values in SH-SY5Y and BV-2 cell lines.
- In vivo safety was evaluated by monitoring cardiac, hepatic, and renal biochemical markers.
- Neuroprotective effects were studied using the LPS-induced neuroinflammation model in an open-field test, measuring locomotor activity, lipid peroxidation, antioxidant enzyme activities (SOD, CAT, GPx), and IL-6 levels.
Main Results:
- BD-8 exhibited significantly lower cytotoxicity compared to digoxin (CC₅₀ > 7 µM for BD-8 vs. 33 nM for digoxin in SH-SY5Y cells).
- In vivo studies showed no adverse effects of BD-8 on cardiac, hepatic, or renal function.
- BD-8 treatment attenuated LPS-induced locomotor impairment, reduced cortical and hippocampal lipid peroxidation, modulated antioxidant enzyme activities, and decreased IL-6 levels without affecting BDNF.
Conclusions:
- BD-8 possesses a favorable safety profile and demonstrates significant neuroprotective effects in vitro and in vivo.
- BD-8 mitigates neuroinflammation by reducing oxidative stress and inflammatory mediators.
- BD-8 represents a promising therapeutic candidate for treating neuroinflammatory disorders.
