- Isoproterenol induces oxidative imbalance, neuroinflammation, behavioural dysfunction, hippocampal and cortical structural alterations, reduced SIRT6, TRAP1 and BDNF, increased GFAP.
- Dapagliflozin attenuates molecular, cellular and functional alterations by reducing oxidative and inflammatory stress and restoring neurotrophic and stress-responsive protein expression.
- Bile salt-stabilised nanovesicular dapagliflozin enhances drug delivery, producing superior redox restoration, inflammation suppression, protein normalisation and neuronal and behavioural preservation.
J Biochem Mol Toxicol. 2026 Nov;40(11):e71134. doi: 10.1002/jbt.71134.
ABSTRACT
Sustained β-adrenergic stimulation represents a pharmacologically relevant stressor capable of inducing systemic oxidative and inflammatory injury that extends to the central nervous system. Isoproterenol (ISO), a synthetic catecholamine, is widely used to model catecholaminergic injury in experimental settings. Dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, exhibits pleiotropic antioxidant and anti-inflammatory properties; however, its effects on catecholamine-induced brain injury remain poorly defined. In the present study, we investigated the pharmacological effects of dapagliflozin and a bile salt-stabilized dapagliflozin-loaded nanovesicular formulation in an ISO-induced model of catecholaminergic brain injury in rats. ISO administration resulted in marked oxidative imbalance, neuroinflammatory activation, behavioral dysfunction, and structural alterations in hippocampal and cortical regions. These changes were accompanied by reduced expression of stress-responsive and neurotrophic proteins, including SIRT6, TRAP1, and BDNF, along with enhanced astroglial activation as indicated by increased GFAP immunoreactivity. Treatment with dapagliflozin attenuated these molecular, cellular, and functional alterations, while the nanovesicular formulation produced a more pronounced improvement of redox balance, suppression of inflammatory responses, normalization of protein expression, and preservation of neuronal architecture and behavior. Collectively, these findings demonstrate that dapagliflozin mitigates catecholaminergic brain injury through attenuation of oxidative and inflammatory stress, with enhanced efficacy achieved via formulation-assisted drug delivery, without implying a distinct pharmacodynamic mechanism.
PMID:42893416 | DOI:10.1002/jbt.71134
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