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

doi:10.66235/kumj.1944317

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

Abstract

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.

Keywords

Supporting Institution

This research was supported by the Aksaray University Scientific Research Projects Coordination Unit. Grant number: 2024-022.

Project Number

2023-011

Ethical Statement

Ethical approval for the protocol was obtained from the Local Animal Experiment Ethics Committee of Aksaray University (Aksaray, Türkiye). (Decision Number: 2023-011, Approval date: December 19, 2023)

References

da Silva AAF, Fiadeiro MB, Bernardino LI, Fonseca CSP, Baltazar GMF, Cristóvão ACB. Lipopolysaccharide-induced animal models for neuroinflammation - An overview. J Neuroimmunol. 2024;387:578273. doi:10.1016/j.jneuroim.-2023.578273
Allendorf DH, Franssen EH, Brown GC. Lipopolysaccharide activates microglia via neuraminidase 1 desialylation of Toll-like Receptor 4. J Neurochem. 2020;155(4):403-416. doi:10.1111/jnc.15024
Zamyatina A, Heine H. Lipopolysaccharide Recognition in the Crossroads of TLR4 and Caspase-4/11 Mediated Inflammatory Pathways. Front Immunol. 2020;11:585146. doi:10.3389/fimmu.2020.585146
Ishijima T, Nakajima K. Inflammatory cytokines TNFα, IL-1β, and IL-6 are induced in endotoxin- stimulated microglia through different signaling cascades. Sci Prog. 2021;104(4):368504211054985. doi:10.1177/00368504211054985
Miyata S. Glial functions in the blood-brain communication at the circumventricular organs. Front Neurosci. 2022;16:991779. doi:10.3389/fnins.2022.991779
Sun Y, Koyama Y, Shimada S. Inflammation From Peripheral Organs to the Brain: How Does Systemic Inflammation Cause Neuroinflammation? Front Aging Neurosci. 2022;14:903455. doi:10.3389/fnagi.2022.903455
Geloso MC, Zupo L, Corvino V. Crosstalk between peripheral inflammation and brain: Focus on the responses of microglia and astrocytes to peripheral challenge. Neurochem Int. 2024;180:105872. doi:10.1016/j.neuint.2024.105872
Wu A, Zhang J. Neuroinflammation, memory, and depression: new approaches to hippocampal neurogenesis. J Neuroinflammation. 2023;20(1):283. doi:10.1186/s12974-023-02964-x

Domínguez-Rivas E, Ávila-Muñoz E, Schwarzacher SW, Zepeda A. Adult hippocampal neurogenesis in the context of lipopolysaccharide-induced neuroinflammation: A molecular, cellular and behavioral review. Brain Behav Immun. 2021;97:286-302. doi:10.1016/j.bbi.2021.06.014
Öz M, Erdal H. A TNF-α inhibitor abolishes sepsis-induced cognitive impairment in mice by modulating acetylcholine and nitric oxide homeostasis, BDNF release, and neuroinflammation. Behav Brain Res. 2024;466:114995. doi:10.1016/j.bbr.-2024.114995
Jamali-Raeufy N, Alizadeh F, Mehrabi Z, Mehrabi S, Goudarzi M. Acetyl-L-carnitine confers neuroprotection against lipopolysaccharide (LPS) -induced neuroinflammation by targeting TLR4/NFκB, autophagy, inflammation and oxidative stress. Metab Brain Dis. 2021;36(6):1391-1401. doi:10.1007/s11011-021-00715-6
Sharma V, Sharma P, Singh TG. Mechanistic insights on TLR-4 mediated inflammatory pathway in neurodegenerative diseases. Pharmacol Rep. 2024;76(4):679-692. doi:10.1007/s43440-024-00613-5
Wang CS, McCarthy CI, Guzikowski NJ, Kavalali ET, Monteggia LM. Brain-derived neurotrophic factor scales presynaptic calcium transients to modulate excitatory neurotransmission. Proc Natl Acad Sci U S A. 2024;121(17):e2303664121. doi:10.1073/pnas.2303664121
Chakraborty S, Shankaranarayana Rao BS, Tripathi SJ. The neuroprotective effects of N-acetylcysteine in psychiatric and neurodegenerative disorders: From modulation of glutamatergic transmission to restoration of synaptic plasticity. Neuropharmacology. 2025;278:110527. doi:10.1016/j.-neuropharm.2025.110527
Santus P, Signorello JC, Danzo F, Lazzaroni G, Saad M, Radovanovic D. Anti-Inflammatory and Anti-Oxidant Properties of N-Acetylcysteine: A Fresh Perspective. J Clin Med. 2024;13(14):4127. doi:10.3390/jcm13144127
Sakai M, Yu Z, Taniguchi M, et al. N-Acetylcysteine Suppresses Microglial Inflammation and Induces Mortality Dose-Dependently via Tumor Necrosis Factor-α Signaling. Int J Mol Sci. 2023;24(4):3798. doi:10.3390/ijms24043798
Pan X, Su Z, Huang Z, Chen Y, Li X, Zheng X. N-acetylcysteine (NAC) ameliorates ethanol-induced oxidative stress, neuroinflammation, and cognitive dysfunction in APP/PS1 mouse model. Transl Psychiatry. 2025;15(1):435. doi:10.1038/s41398-025-03496-z
Chinnathambi S, Adithyan A, Chandrashekar M, Rangappa N. Tau and Amyloid beta causes microglial activation in Alzheimer’s disease. Adv Clin Chem. 2025;128:83-107. doi:10.1016/bs.acc.2025.06.002
Kim MW, Choe K, Park JS, et al. Pharmacological Inhibition of Spleen Tyrosine Kinase Suppressed Neuroinflammation and Cognitive Dysfunction in LPS-Induced Neurodegeneration Model. Cells. 2022;11(11):1777. doi:10.3390/cells11111777
Costa M, Bernardi J, Fiuza T, Costa L, Brandão R, Pereira ME. N-acetylcysteine protects memory decline induced by streptozotocin in mice. Chem Biol Interact. 2016;253:10-17. doi:10.1016/j.cbi.2016.04.026
Öz M, Nurullahoğlu Atalık KE, Aslanlar DA. The effects of donepezil on anxiety- and depression-like behaviors in diabetic rats and the role of nitric oxide modulators. KMJ. 2023;3(1):12-17. doi:10.51271/KMJ-0088
Aslanlar DA, Vişneci EF, Oz M, Nurullahoglu Atalik KE. N-acetylcysteine ameliorates chemotherapy-induced impaired anxiety and depression-like behaviors by regulating inflammation, oxidative and cholinergic status, and BDNF release. Behav Brain Res. 2024;458:114740. doi:10.1016/j.bbr.2023.114740
Li S, Zhu Z, Lan T, et al. Levomilnacipran ameliorates lipopolysaccharide-induced depression-like behaviors and suppressed the TLR4/Ras signaling pathway. Int Immunopharmacol. 2023;122:110595. doi:10.1016/j.intimp.-2023.110595
Bawadood AS, Al-Abbasi FA, Alghamdi AM, et al. Fustin alleviates lipopolysaccharide-induced anxiety-depression-like performances by modulation of oxidative stress/neuroinflammatory markers/ NF-κB/caspase-3/BDNF expression in rodents. Eur Rev Med Pharmacol Sci. 2024;28(1):419-432. doi:10.26355/eurrev_202401_34931
Liu Y, Rao B, Zhou F. Static and dynamic functional connectivity alterations in mice with LPS-induced depression: A 9.4T fMRI study using independent component and graph theory analyses. J Psychiatr Res. 2026;197:86-96. doi:10.1016/j.jpsychires.-2026.02.043
Mahdirejei HA, Peeri M, Azarbayjani MA, Fattahi Masrour F. Fluoxetine combined with swimming exercise synergistically reduces lipopolysaccharide-induced depressive-like behavior by normalizing the HPA axis and brain inflammation in mice. Pharmacol Biochem Behav. 2023;232:173640. doi:10.1016/j.pbb.2023.173640
Guo M, Pei WJ, Liu L, Chen K, Cheng Y, Piao XL. Neuroprotective effects of gypenosides on LPS-induced anxiety and depression-like behaviors. Int Immunopharmacol. 2024;143(Pt 1):113367. doi:10.1016/j.intimp.2024.113367
Han QQ, Shen SY, Liang LF, Chen XR, Yu J. Complement C1q/C3-CR3 signaling pathway mediates abnormal microglial phagocytosis of synapses in a mouse model of depression. Brain Behav Immun. 2024;119:454-464. doi:10.1016/j.bbi.2024.04.018
Avci H, Yıldızhan K. The effect of selenium on cadmium-induced neurotoxicity model in rats: The role of TRPM2 cation channel. Kastamonu Medical Journal. 2026;6(2):169-175. doi:10.66235/kumj.1887610
Bolshakov AP, Tret’yakova LV, Kvichansky AA, Gulyaeva NV. Glucocorticoids: Dr. Jekyll and Mr. Hyde of Hippocampal Neuroinflammation. Biochemistry (Mosc). 2021;86(2):156-167. doi:10.1134/S0006297921020048
Correia AS, Cardoso A, Vale N. Oxidative Stress in Depression: The Link with the Stress Response, Neuroinflammation, Serotonin, Neurogenesis and Synaptic Plasticity. Antioxidants (Basel). 2023;12(2):470. doi:10.3390/antiox12020470
Guan Z, Fang J. Peripheral immune activation by lipopolysaccharide decreases neurotrophins in the cortex and hippocampus in rats. Brain Behav Immun. 2006;20(1):64-71. doi:10.1016/j.bbi.2005.04.005
Meng J, Wei P, Yang H, et al. Levistilide A from Ligusticum chuanxiong alleviates LPS-induced depression- and anxiety-like behaviors by promoting mitophagy through the SIRT3/PINK1/Parkin pathway. J Ethnopharmacol. 2026;361:121146. doi:10.1016/j.jep.2025.121146
Li Z, Wang H, Yin Y. Peripheral inflammation is a potential etiological factor in Alzheimer’s disease. Rev Neurosci. 2024;35(1):99-120. doi:10.1515/revneuro-2023-0049
Chakraborty S, Tripathi SJ, Srikumar BN, Raju TR, Shankaranarayana Rao BS. N-acetyl cysteine ameliorates depression-induced cognitive deficits by restoring the volumes of hippocampal subfields and associated neurochemical changes. Neurochem Int. 2020;132:104605. doi:10.1016/j.neuint.-2019.104605
Lomeli N, Pearre DC, Lepe J, et al. N-acetylcysteine prevents cisplatin-induced cognitive impairments in an ovarian cancer rat model. Cancer Lett. 2024;611:217405. doi:10.1016/j.canlet.2024.217405
Chakraborty S, Tripathi SJ, Raju TR, Shankaranarayana Rao BS. Mechanisms underlying remediation of depression-associated anxiety by chronic N-acetyl cysteine treatment. Psychopharmacology (Berl). 2020;237(10):2967-2981. doi:10.1007/s00213-020-05585-x
Zhong Y, Guan J, Ma Y, et al. Role of Imaging Modalities and N-Acetylcysteine Treatment in Sepsis-Associated Encephalopathy. ACS Chem Neurosci. 2023;14(11):2172-2182. doi:10.1021/acschemneuro.3c00180
Firouzjaei Y, Hajizadeh Moghaddam A, Sohabatzadeh F, Khanjani Jelodar S, Farhadi M. Neuroprotective effects of plasma-activated N-acetylcysteine against streptozotocin-induced behavioral deficits in rats: Attenuation of oxidative stress and cholinergic dysfunction. Ecotoxicol Environ Saf. 2026;309:119619. doi:10.1016/j.ecoenv.2025.119619
Afşar E. Effect of the hypothalamic serotonin on body weight change in the context of brain insulin resistance in Alzheimer’s disease. Kastamonu Medical Journal. 2026;6(2):120-126. doi:10.66235/kumj.1853640
Bai H, Chen H, Du S, et al. N-Acetylcysteine Mitigates Ketamine Neurotoxicity in Young Rats by Modulating ROS-Mediated Pyroptosis and Ferroptosis. Mol Neurobiol. 2025;62(7):9416-9429. doi:10.1007/s12035-025-04860-2
Dorcas Aremu T, Ramírez Ortega D, Blanco Ayala T, et al. Modulation of Brain Kynurenic Acid by N-Acetylcysteine Prevents Cognitive Impairment and Muscular Weakness Induced by Cisplatin in Female Rats. Cells. 2024;13(23):1989. doi:10.3390/cells13231989

Details

Primary Language

English

Subjects

Physiopathology

Journal Section

Research Article

Authors

Mehmet Öz ^*
0000-0003-4167-2623
Türkiye

Durmuş Ali Aslanlar
0000-0002-6932-2767
Türkiye

Hüseyin Erdal
0000-0003-0786-5077
Türkiye

Erdem Arslan
0000-0002-4992-5915
Türkiye

Publication Date

September 27, 2026

Submission Date

May 4, 2026

Acceptance Date

July 31, 2026

Published in Issue

Year 2026 Volume: 6 Number: 3

DOI

https://doi.org/10.66235/kumj.1944317

IZ

https://izlik.org/JA99BJ92TK

Cite

RIS / Bibtex

APA

Öz, M., Aslanlar, D. A., Erdal, H., & Arslan, E. (2026). Attenuation of systemic inflammation-induced behavioral deficits and neuromolecular alterations by N-acetylcysteine in a rodent model. Kastamonu Medical Journal, 6(3), 278-289. https://doi.org/10.66235/kumj.1944317

AMA

1.Öz M, Aslanlar DA, Erdal H, Arslan E. Attenuation of systemic inflammation-induced behavioral deficits and neuromolecular alterations by N-acetylcysteine in a rodent model. Kastamonu Medical Journal. 2026;6(3):278-289. doi:10.66235/kumj.1944317

Chicago

Öz, Mehmet, Durmuş Ali Aslanlar, Hüseyin Erdal, and Erdem Arslan. 2026. “Attenuation of Systemic Inflammation-Induced Behavioral Deficits and Neuromolecular Alterations by N-Acetylcysteine in a Rodent Model”. Kastamonu Medical Journal 6 (3): 278-89. https://doi.org/10.66235/kumj.1944317.

EndNote

Öz M, Aslanlar DA, Erdal H, Arslan E (September 1, 2026) Attenuation of systemic inflammation-induced behavioral deficits and neuromolecular alterations by N-acetylcysteine in a rodent model. Kastamonu Medical Journal 6 3 278–289.

IEEE

[1]M. Öz, D. A. Aslanlar, H. Erdal, and E. Arslan, “Attenuation of systemic inflammation-induced behavioral deficits and neuromolecular alterations by N-acetylcysteine in a rodent model”, Kastamonu Medical Journal, vol. 6, no. 3, pp. 278–289, Sept. 2026, doi: 10.66235/kumj.1944317.

ISNAD

Öz, Mehmet - Aslanlar, Durmuş Ali - Erdal, Hüseyin - Arslan, Erdem. “Attenuation of Systemic Inflammation-Induced Behavioral Deficits and Neuromolecular Alterations by N-Acetylcysteine in a Rodent Model”. Kastamonu Medical Journal 6/3 (September 1, 2026): 278-289. https://doi.org/10.66235/kumj.1944317.

JAMA

1.Öz M, Aslanlar DA, Erdal H, Arslan E. Attenuation of systemic inflammation-induced behavioral deficits and neuromolecular alterations by N-acetylcysteine in a rodent model. Kastamonu Medical Journal. 2026;6:278–289.

MLA

Öz, Mehmet, et al. “Attenuation of Systemic Inflammation-Induced Behavioral Deficits and Neuromolecular Alterations by N-Acetylcysteine in a Rodent Model”. Kastamonu Medical Journal, vol. 6, no. 3, Sept. 2026, pp. 278-89, doi:10.66235/kumj.1944317.

Vancouver

1.Mehmet Öz, Durmuş Ali Aslanlar, Hüseyin Erdal, Erdem Arslan. Attenuation of systemic inflammation-induced behavioral deficits and neuromolecular alterations by N-acetylcysteine in a rodent model. Kastamonu Medical Journal. 2026 Sep. 1;6(3):278-89. doi:10.66235/kumj.1944317