The Modulatory Role of Simvastatin / Dexamethasone Treatments in Lipopolysaccharide-Induced Neuroinflammation Model: Interplay of Efferocytosis, Apoptosis, and Oxidative Stress

Background: Neurodegenerative diseases are among the leading causes of morbidity and disability worldwide, representing a growing public health concern. Central to their pathogenesis are neuroinflammation and oxidative stress, both of which contribute to neuronal dysfunction and apoptosis. Efferocytosis, the process by which apoptotic cells are efficiently cleared by phagocytes, is essential for maintaining neural homeostasis and resolving inflammation. Impaired efferocytosis can exacerbate chronic inflammation, thereby promoting neuronal loss and disease progression. The present study aimed to investigate the interrelationship between efferocytosis, apoptosis, and oxidative stress in an experimentally induced neuroinflammatory model, and to evaluate the potential modulatory effects of two immunomodulatory agents—simvastatin and dexamethasone—administered individually or in combination. Methods: Seventy-five adult male albino mice were randomly allocated into five groups: a control group; a lipopolysaccharide (LPS)-treated group; a simvastatin-treated group; a dexamethasone-treated group; and a combined simvastatin–dexamethasone (SD) group. Behavioral assessments were conducted to evaluate neurofunctional performance. Brain tissues were examined for biochemical markers of oxidative stress and antioxidant defense. Histopathological and immunohistochemical evaluations, including NF-κB expression analysis, were performed to assess neuroinflammatory and apoptotic changes, as well as efferocytic activity. Results: Treatment with simvastatin and/or dexamethasone significantly alleviated LPS-induced neuroinflammation, oxidative damage, and neuronal apoptosis. Notably, the combined SD therapy exhibited the most pronounced neuroprotective effect, likely due to synergistic actions in suppressing NF-κB activation, mitigating oxidative stress, enhancing efferocytosis, and restoring neural integrity. Conclusion: These findings suggest that simvastatin and dexamethasone, particularly when used in combination, possess potent neuroprotective and anti-inflammatory properties that may offer therapeutic promise in the prevention and management of neurodegenerative disorders. Key words: Neuroinflammation; Lipopolysaccharide; Efferocytosis; Simvastatin; Dexamethasone