Neuroprotective and antioxidant effects of digoxin derivative (BD-8) in an LPS-induced neuroinflammation model

Chronic neuroinflammation is a key factor in neurological and neuropsychiatric disorders, including depression and cognitive impairment. Persistent activation of microglia and astrocytes leads to the release of pro-inflammatory mediators and oxidative stress, contributing to neuronal damage. Therefore, therapies targeting central nervous system inflammation are of great interest. BD-8, a digoxin-derived cardiosteroid, has shown selectivity for the α2 isoform of Na⁺/K⁺-ATPase, expressed in peripheral and neuronal cells, particularly astrocytes, along with promising neuroprotective and anti-inflammatory effects. This study evaluated BD-8’s cytotoxicity in SH-SY5Y and BV-2 cells using the MTT assay, and its in vivo neuroprotective, anxiolytic, and antioxidant effects in rodent models. Wistar rats were used for systemic toxicity, while Swiss mice underwent LPS-induced neuroinflammation. Behavioral (Open Field test), biochemical, and oxidative stress markers were assessed in cortex and hippocampus. BD-8 showed lower cytotoxicity than digoxin and no adverse effects on cardiac, hepatic, or renal markers in vivo. It improved exploratory behavior and reduced LPS-induced sickness behavior. Additionally, BD-8 decreased lipid peroxidation and restored antioxidant enzyme activity (SOD, CAT, GPx). These findings highlight BD-8 as a promising therapeutic candidate for neuroinflammatory conditions.