N-Acetylcysteine Prevents Sleep Deprivation-induced Memory Deficit in Juvenile Rats Through the Suppression of BDNF, Cortisol, Acetylcholine Levels, and Inflammatory Cytokines Expressions
Abstract
BACKGROUND: Sleep deprivation (SD) affects 20–30% of children and is known to impair cognitive functions, particularly memory. Despite its impact, there is currently no standardized treatment. Evidence from both adult animal and human suggests that N-acetylcysteine (NAC) possesses neuroprotective properties. This study was conducted to evaluate the effects of NAC on memory deficits induced by SD in juvenile rats.
METHODS: Juvenile Sprague-Dawley rats were subjected to SD using the modified multiple platform method. NAC was administered intraperitoneally at doses of 100 mg/kgBW or 500 mg/kgBW. Y-maze and novel object recognition (NOR) tests were used for neurobehavioral assessment. Biochemical analyses were conducted to measure cortisol, brain-derived neurotrophic factor (BDNF), and acetylcholine (ACh) levels, using enzyme-linked immunosorbent assay (ELISA). Acetylcholine esterase (AChE) activity was measured by colorimetric method. Western blot analysis was performed to examine cAMP response element-binding protein (CREB) and phosphorylated CREB (p-CREB). Additionally, cytokine mRNA expressions were evaluated using polymerase chain reaction (PCR).
RESULTS: Spontaneous alteration and discrimination ratio were decreased in SD group without treatment compared to the normal group (p<0.05). Similarly, BDNF was also decreased compared with normal group (p<0.05). Cortisol level and mRNA expression of TNF-α were increased significantly compared with normal group (p<0.05) along with a slight increase of ACh activity. Interestingly, NAC treatment mainly at the dose of 500 mg/kgBW prevented those pathological features significantly.
CONCLUSION: NAC might prevent the SD-induced memory deficits by suppressing the inflammatory markers, activity of AChE, cortisol, and enhancing the level of BDNF.
KEYWORDS: SD, NAC, memory, AChE, cortisol, inflammatory markers, BDNF
Full Text:
PDFReferences
Atrooz F, Liu H, Kochi C, Salim S. Early life sleep deprivation: Role of oxido-inflammatory processes. Neuroscience. 2019; 406: 22-37, CrossRef.
Verschuren O, Gorter JW, Pritchard-Wiart L. Sleep: An underemphasized aspect of health and development in neurorehabilitation. Early Human Dev. 2017; 113: 120-8, CrossRef.
Himelfarb M, Shatkin JP. Pediatric insomnia. Psychiatr Clin. 2024; 47(1): 121-34, CrossRef.
Empitu MA, Kadariswantiningsih IN, Thaha M, Nugroho CW, Putri EAC, El Hakim Z, et al. Determiner of poor sleep quality in chronic kidney disease patients links to elevated diastolic blood pressure, hs-CRP, and blood-count-based inflammatory predictors. Indones Biomed J. 2019; 11(1): 100-6, CrossRef.
Wright Jr KP, Drake AL, Frey DJ, Fleshner M, Desouza CA, Gronfier C, et al. Influence of sleep deprivation and circadian misalignment on cortisol, inflammatory markers, and cytokine balance. Brain Behav Immun. 2015; 47: 24-34, CrossRef.
Raina N. Sleep deprivation affects brain acetylcholinesterase activity and cognitive ability in young and aged rats. Sch Acad J Biosci. 2021; 12: 405-10, CrossRef.
Chanana P, Kumar A. An insight into mechanisms underlying sleep deprivation induced cognitive dysfunction. J Sleep Disord Ther. 2017; 6(1): 1000258, CrossRef.
Costa M, Bernardi J, Costa L, Fiuza T, Brandão R. N-acetyl cysteine decreases mice brain acetyl cholinesterase activity: An in vitro kinetic study. 2015; 5: 1, CrossRef.
Faghfouri AH, Zarezadeh M, Tavakoli-Rouzbehani OM, Radkhah N, Faghfuri E, Kord-Varkaneh H, et al. The effects of N-acetylcysteine on inflammatory and oxidative stress biomarkers: A systematic review and meta-analysis of controlled clinical trials. Eur J Pharmacol. 2020; 884: 173368, CrossRef.
Garner JM, Chambers J, Barnes AK, Datta S. Changes in brain-derived neurotrophic factor expression influence sleep-wake activity and homeostatic regulation of rapid eye movement sleep. Sleep. 2018; 41(2): zsx194, CrossRef.
Hajali V, Sheibani V, Ghazvini H, Ghadiri T, Valizadeh T, Saadati H, et al. Effect of castration on the susceptibility of male rats to the sleep deprivation-induced impairment of behavioral and synaptic plasticity. Neurobiol Learn Mem. 2015; 123: 140-8, CrossRef.
Azogu I, de la Tremblaye PB, Dunbar M, Lebreton M, LeMarec N, Plamondon H. Acute sleep deprivation enhances avoidance learning and spatial memory and induces delayed alterations in neurochemical expression of GR, TH, DRD1, pCREB and Ki67 in rats. Behav Brain Res. 2015; 279: 177-90, CrossRef.
Yuste JE, Tarragon E, Campuzano CM, Ros-Bernal F. Implications of glial nitric oxide in neurodegenerative diseases. Front Cell Neurosci. 2015; 9: 322, CrossRef.
Hope BT, Michael GJ, Knigge KM, Vincent SR. Neuronal NADPH diaphorase is a nitric oxide synthase. Proc Natl Acad Sci USA. 1991; 88(7): 2811-4, CrossRef.
Ooi SL, Green R, Pak SC. N‐acetylcysteine for the treatment of psychiatric disorders: A review of current evidence. Biomed Res Int. 2018; 2018: 2469486, CrossRef.
Prasada JS, Kumar M, Rastogi T, Bhattacharya S. Effect of N-acetyl cysteine on some behavioral and oxidative stress parameters in sleep deprived mice. Int J Recent Trend Sci Technol. 2016; 19(3): 404-9.
Nor N, Nawi A, Wan Ahmad W, Noordin L. Sleep deprivation models in rodents. Jurnal Sains Kesihatan Malaysia. 2021; 19(2): 29-38, CrossRef.
Olonode ET, Aderibigbe AO, Adeoluwa OA, Eduviere AT, Ben-Azu B. Morin hydrate mitigates rapid eye movement sleep deprivation-induced neurobehavioural impairments and loss of viable neurons in the hippocampus of mice. Behav Brain Research. 2019; 356: 518-25, CrossRef.
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: 10-7, CrossRef.
Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976; 72(1-2): 248-54, CrossRef.
Nolan T, Hands RE, Bustin SA. Quantification of mRNA using real-time RT-PCR. Nat Protoc. 2006; 1(3): 1559-82, CrossRef.
Damgaard MV, Treebak JT. Protocol for qPCR analysis that corrects for cDNA amplification efficiency. STAR Protoc. 2022; 3(3): 101515, CrossRef.
Ott SR, Elphick MR. New techniques for whole-mount NADPH-diaphorase histochemistry demonstrated in insect ganglia. J Histochem Cytochem. 2003; 51(4): 523-32, CrossRef.
Antunes M, Biala G. The novel object recognition memory: Neurobiology, test procedure, and its modifications. Cogn Process. 2012; 13: 93-110, CrossRef.
Gonzalez‐Zulueta M, Dawson VL, Dawson TM. Histochemical analysis of nitric oxide synthase by NADPH diaphorase staining. Curr Protoc Toxicol. 2001: Chapter 10: Unit 10.6, CrossRef.
Tuan LH, Lee LJ. Microglia-mediated synaptic pruning is impaired in sleep-deprived adolescent mice. Neurobiol Dis. 2019: 130: 104517, CrossRef.
Sulaman BA, Kudlak T, Eban-Rothschild A. Dopamine's reach: Unlocked by sleep loss. Neuron. 2024; 112(1): 4-6, CrossRef.
da Costa M, Bernardi J, Costa L, Fiuza T, Brandão R, Ribeiro MF, et al. N-acetylcysteine treatment attenuates the cognitive impairment and synaptic plasticity loss induced by streptozotocin. Chem Biol Interact. 2017; 272: 37-46, CrossRef.
Rahardjo TM. Propofol effect on stress response and free radicals in patient during surgery and sedation procedure. Indones Biomed J. 2015; 7(3): 147-52, CrossRef.
Song HT, Sun XY, Yang TS, Zhang LY, Yang JL, Bai J. Effects of sleep deprivation on serum cortisol level and mental health in servicemen. Int J Psychophysiol. 2015; 96(3): 169-75, CrossRef.
Abdel-Wahab WM, Moussa FI. Neuroprotective effect of N-acetylcysteine against cisplatin-induced toxicity in rat brain by modulation of oxidative stress and inflammation. Drug Des Devel Ther. 2019: 13: 1155-62, CrossRef.
Tsarouchas TM, Wehner D, Cavone L, Munir T, Keatinge M, Lambertus M, et al. Dynamic control of proinflammatory cytokines Il-1β and Tnf-α by macrophages in zebrafish spinal cord regeneration. Nat Commun. 2018; 9(1): 4670, CrossRef.
Wang Y, Che M, Xin J, Zheng Z, Li J, Zhang S. The role of IL-1β and TNF-α in intervertebral disc degeneration. Biomed Pharmacother. 2020: 131: 110660, CrossRef.
Xue R, Wan Y, Sun X, Zhang X, Gao W, Wu W. Nicotinic mitigation of neuroinflammation and oxidative stress after chronic sleep deprivation. Front Immunol. 2019: 10: 2546, CrossRef.
Liu H, Huang X, Li Y, Xi K, Han Y, Mao H, et al. TNF signaling pathway-mediated microglial activation in the PFC underlies acute paradoxical sleep deprivation-induced anxiety-like behaviors in mice. Brain Behav Immun. 2022; 100: 254-66, CrossRef.
Roy K, Chauhan G, Kumari P, Wadhwa M, Alam S, Ray K, et al. Phosphorylated delta sleep inducing peptide restores spatial memory and p-CREB expression by improving sleep architecture at high altitude. Life Sci. 2018; 209: 282-90, CrossRef.
Alkadhi K, Zagaar M, Alhaider I, Salim S, Aleisa A. Neurobiological consequences of sleep deprivation. Curr Neuropharmacol. 2013; 11(3): 231-49, CrossRef.
Yoo JM, Lee BD, Sok DE, Ma JY, Kim MR. Neuroprotective action of N-acetyl serotonin in oxidative stress-induced apoptosis through the activation of both TrkB/CREB/BDNF pathway and Akt/Nrf2/Antioxidant enzyme in neuronal cells. Redox Niol. 2017; 11: 592-9, CrossRef.
Arent CO, Valvassori SS, Steckert AV, Resende WR, Dal-Pont GC, Lopes-Borges J, et al. The effects of n-acetylcysteine and/or deferoxamine on manic-like behavior and brain oxidative damage in mice submitted to the paradoxal sleep deprivation model of mania. J Psychiatr. Res. 2015; 65: 71-9, CrossRef.
Rogóż Z, Kamińska K, Lech MA, Lorenc-Koci E. N-acetylcysteine and aripiprazole improve social behavior and cognition and modulate brain BDNF levels in a rat model of schizophrenia. Int J Mol Sci. 2022; 23(4): 2125, CrossRef.
DOI: https://doi.org/10.18585/inabj.v17i2.3445
Copyright (c) 2025 The Prodia Education and Research Institute
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Indexed by:
The Prodia Education and Research Institute
