Ursolic acid attenuates LPS-induced cognitive dysfunction through the modulation of oxidative stress, neuroinflammation, and hippocampal synaptic plasticity.
BACKGROUND Neuroinflammation and oxidative stress play vital roles in the pathogenesis of neurodegenerative diseases characterized by cognitive decline. Ursolic acid (UA), a natural pentacyclic triterpenoid compound with reported anti-inflammatory and antioxidant properties, has been suggested as a potential neuroprotective agent. PURPOSE This study was conducted to clarify whether UA attenuates lipopolysaccharide (LPS)-induced neurotoxicity through redox regulation, mitochondrial protection, and modulation of neurotrophic signaling. STUDY DESIGN An in vivo mouse model of LPS-induced neuroinflammation and cognitive impairment was used to evaluate the neuroprotective effects of UA. METHODS Mice were administered LPS (10 µg/µl) via intracerebroventricular injection to induce neuroinflammation and cognitive impairment and were subsequently treated with UA (50 or 100 mg/kg, intraperitoneally). Behavioral tests were performed to assess learning and memory. Oxidative stress markers in hippocampal tissues were analyzed, together with inflammatory mediators and brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB)-cAMP response element-binding protein (CREB) signaling by western blot. Glial activation was examined by immunofluorescence, and hippocampal ultrastructure was evaluated using transmission electron microscopy and serial section-based three-dimensional electron microscopy. RESULTS UA treatment improved LPS-induced learning and memory deficits, reduced oxidative damage, and restored antioxidant enzyme activities in the hippocampus in a dose-related manner. The higher dose (UA2, 100 mg/kg) generally exerted a stronger restorative effect than the lower dose (UA1, 50 mg/kg). It also suppressed microglial overactivation and nuclear factor kappa B-mediated inflammatory signaling along with reducing the expression of proinflammatory mediators. UA also restored hippocampal BDNF-TrkB-CREB signaling, which is essential for synaptic plasticity and memory formation. Ultrastructural analyses revealed preservation of neuronal and synaptic architecture and normalization of mitochondrial morphology, with reduced mitochondrial fragmentation and mitochondria-on-a-string dynamics. CONCLUSION UA mitigates LPS-induced cognitive deficits by modulating oxidative and inflammatory signaling, reactivating BDNF-TrkB-CREB signaling, and stabilizing mitochondrial homeostasis. These findings emphasize the therapeutic potential of UA as a natural redox-modulating neuroprotective agent for inflammation-associated cognitive dysfunction.