DOI: 10.66235/kumj.1944317 ISSN: 2757-9336

Attenuation of systemic inflammation-induced behavioral deficits and neuromolecular alterations by N-acetylcysteine in a rodent model

Mehmet Öz, Durmuş Ali Aslanlar, Hüseyin Erdal, Erdem Arslan
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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-α), glutathione (GSH), brain-derived neurotrophic factor (BDNF), amyloid-beta (Aβ 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-α inflammatory cascade, depleted GSH and BDNF, and promoted the accumulation of Aβ 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-α expression, restored GSH and BDNF levels, and mitigated Aβ 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-α levels, preserving neurotrophic support, and mitigating prolonged HPA axis hyper-reactivity, NAC may represent a potential therapeutic strategy for neuroinflammation-associated emotional dysfunctions.

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