Mehmet ÖZ, Durmuş Ali ASLANLAR, Hüseyin ERDAL, Erdem ARSLAN
Kastamonu Medical Journal - 2026;6(3):278-289
Aims: Systemic inflammation driven by lipopolysaccharide (LPS) induces neurobehavioral deficits, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and neurodegeneration-related alterations. N-acetylcysteine (NAC) is a potent antioxidant with emerging anti-inflammatory properties. This study investigated whether concurrent NAC treatment could attenuate LPS-induced neuromolecular and behavioral alterations in mice. Methods: Thirty-two male BALB/c mice were randomly assigned to Control, LPS, LPS+NAC, and NAC groups. Over nine consecutive days, subjects received daily intraperitoneal injections of LPS (0.25 mg/kg) and/or NAC (50 mg/kg). Anxiety- and depressive-like behaviors were evaluated using the open field, elevated plus maze, and forced swim tests. Systemic neuroendocrine markers (serum ACTH and cortisol) were quantified, alongside hippocampal Toll-like receptor 4 (TLR4), tumor necrosis factor-alpha (TNF-alpha), glutathione (GSH), brain-derived neurotrophic factor (BDNF), amyloid-beta (Abeta 1-42), and total Tau levels. Results: Repeated LPS administration induced marked anxiety- and depressive-like behaviors, accompanied by systemic HPA axis hyperactivity. In the hippocampus, LPS significantly upregulated the TLR4/TNF-alpha inflammatory cascade, depleted GSH and BDNF, and promoted the accumulation of Abeta 1-42 and Tau proteins. Concurrent NAC administration attenuated these behavioral deficits and normalized systemic ACTH and cortisol levels. Central assessments revealed that NAC significantly suppressed hippocampal TLR4 and TNF-alpha expression, restored GSH and BDNF levels, and mitigated Abeta 1-42 accumulation, although the reduction in total Tau did not reach statistical significance. Conclusion: NAC conferred significant protection against endotoxin-induced affective disturbances. By modulating hippocampal TLR4 and TNF-alpha levels, preserving neurotrophic support, and mitigating prolonged HPA axis hyper-reactivity, NAC may represent a potential therapeutic strategy for neuroinflammation-associated emotional dysfunctions.
