Antibiotic Abuse Induced Histopathological and Neurobehavioral Disorders in Mice

Author(s): Ahmed Mohamed Nabil Helaly*, Yomna Ahmed El-Attar, Mahmoud Khalil, Doaa Shams El-Din Ahmed Ghorab, Adel Mahmoud El- Mansoury

Journal Name: Current Drug Safety

Volume 14 , Issue 3 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Introduction: Antibiotic abuse is a common phenomenon in Egypt as medications are prescribed without supervision. It is suggested that the excess use of antibiotics modifies the gut microbiota and plays a role in the development of neurological and psychiatric disorders.

Objective: The aim of the present study was to use bulb-c mice as models for curam (amoxicillin /clavulanic acid) abuse compared to the locally acting neomycin model, then restoring the probiotic balance to look at the possible effects on the animal brains.

Methods: The results showed early excitable brains demonstrated by S100b immunohistochemistry in both cortexes and hippocampuses of neomycin-treated mice. Staining with PAS stain showed no suggested neurodegenerative changes. Treatment with probiotics improved the S100b immunohistochemistry profile of the curam group partially but failed to overcome the neuroinflammatory reaction detected by hematoxylin and eosin stain. Curam was possibly blamed for the systemic effects.

Results: The neurobehavioral tests showed delayed impairment in the open field test for the curam group and impaired new object recognition for the neomycin group. These tests were applied by video recording. The neurobehavioral decline developed 14 days after the end of the 3-week antibiotic course. Unfortunately, curam abuse induced animal fatalities.

Conclusion: Antibiotic abuse has a neurotoxic effect that works by both local and more prominent systemic mechanisms. It can be said that antibiotic abuse is a cofactor behind the rise of neuropsychiatric diseases in Egypt.

Keywords: Antibiotic abuse, microbiota, curam, neomycin, S100b, PAS stain, gut-brain axis.

Zyoud SH, Abu Taha A, Araj KF, et al. Parental knowledge, attitudes, and practices regarding antibiotic use for acute upper respiratory tract infections in children: A cross-sectional study in Palestine. BMC Pediatr 2015; 15: 176.
Edwards DJ, Richman PB, Bradley K, Eskin B, Mandell M. Parental use and misuse of antibiotics: Are there differences in urban vs. suburban settings? Acad Emerg Med 2002; 9(1): 22-6.
[] [PMID: 11772665]
Ahmed AGE, Ahmed SMB, Kolkailah DAAA, et al. Pattern of antibiotic abuse- a population-based study in Cairo. Egypt J Chest Dis Tuberc 2013; 62: 189-95.
Li J, Song X, Yang T, et al. A systematic review of antibiotic prescription associated with upper respiratory tract infections in china. Medicine (Baltimore) 2016; 95(19): e3587.
[ 1097/MD.0000000000003587] [PMID: 27175658]
AlRahabi MK, Abuong ZA. Antibiotic abuse during endodontic treatment in private dental centers. Saudi Med J 2017; 38(8): 852-6.
[] [PMID: 28762439]
Mostafa S, Miller BJ. Antibiotic-associated psychosis during treatment of urinary tract infections: A systematic review. J Clin Psychopharmacol 2014; 34(4): 483-90.
[] [PMID: 24911441]
Kass J S, Shandera W X. Nervous system effects of antituberculosis therapy. CNS Drugs 2010; 34(24): 655-67.
Foster BJA. Gut feeling: Bacteria and the brain. Cerebrum 2013; 9: 1-14.
Toribio-Mateas M. Harnessing the power of microbiome assessment tools as part of neuroprotective nutrition and lifestyle medicine interventions. Microorganisms 2018; 6(2): pii:E35.
Haroon E, Raison CL, Miller AH. Psychoneuroimmunology meets neuropsychopharmacology: Translational implications of the impact of inflammation on behavior. Neuropsychopharmacology 2012; 37(1): 137-62.
[] [PMID: 21918508]
Louveau A, Smirnov I, Keyes TJ, et al. Structural and functional features of central nervous system lymphatic vessels. Nature 2015; 523(7560): 337-41.
[] [PMID: 26030524]
Golubeva AV, Crampton S, Desbonnet L, et al. Prenatal stress-induced alterations in major physiological systems correlate with gut microbiotacomposition in adulthood. Psychoneuroendocrinology 2015; 60: 58-74.
Daneman R, Rescigno M. The gut immune barrier and the blood-brain barrier: Are they so different? Immunity 2009; 31(5): 722-35.
Ridaura V, Belkaid Y. Gut microbiota: The link to your second brain. Cell 2015; 161(2): 193-4.
[ 2015.03.033] [PMID: 25860600]
Messaoudi M, Lalonde R, Violle N, et al. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br J Nutr 2011; 105(5): 755-64.
[ 1017/S0007114510004319] [PMID: 20974 015]
Liu WH, Chuang HL, Huang YT, et al. Alteration of behavior and monoamine levels attributable to Lactobacillus plantarum PS128 in germ-free mice. Behav Brain Res 2016; 298(Pt B): 202-9.
[] [PMID: 26522841]
Bercik P, Park AJ, Sinclair D, et al. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterol Motil 2011; 23(12): 1132-9.
[] [PMID: 21988661]
Gelber RH. The activity of amoxicillin plus clavulanic acid against Mycobacterium leprae in mice. J Infect Dis 1991; 163(6): 1374-7.
[] [PMID: 2037803]
Hölter SM, Einicke J, Sperling B, et al. Tests for anxiety-related behavior in mice. Curr Protoc Mouse Biol 2015; 5(4): 291-309.
Takao K, Miyakawa T. Light/dark transition test for mice. J Vis Exp 2006; 1(1): 104.
[PMID: 18704188]
Biala M A G. The novel objects recognition memory. Neurobiology, test procedure, and its modifications. Cogn Process 2012; 13(2): 93-110.
Hillman H, Deutsch K. Area changes in slices of rat brain during preparation for histology or electron microscopy. J Microsc 1978; 114(1): 77-84.
[ tb00117.x] [PMID: 361964]
Bancroft JD, Layton C. The Hematoxylin and eosin Theory and practice of histological techniques. 7th ed. Philadelphia: Churchill Livingstone of El Sevier 2013; pp. 173-214.
Sheehan DC, Hrapchak BB. Theory and practice of histotechnology. 2nd ed. Columbus, OH: Battelle Memorial Institute 1987.
Hicks D, Dell’Orto P, Falzon M, et al. Immunohistochemical performance of estrogen and progesterone receptor antibodies on the dako omnis staining platform: Evaluation in multicenter studies. Appl Immunohistochem Mol Morphol 2017; 25(5): 313-9.
[] [PMID: 26657878]
Bruce-Keller AJ, Salbaum JM, Luo M, et al. Obese-type gut microbiota induce neurobehavioral changes in the absence of obesity. Biol Psychiatry 2015; 77(7): 607-15.
[] [PMID: 25173628]
Wang CH, Gu JY, Zhang XL, et al. Venlafaxine ameliorates the depression-like behaviors and hippocampal S100B expression in a rat depression model. Behav Brain Funct 2016; 12(1): 1-10.
[] [PMID: 26729018]
Collins SM, Surette M, Bercik P. The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol 2012; 10(11): 735-42.
[] [PMID: 23000955]
Holzer P, Reichmann F, Farzi A. Neuropeptide Y, Peptide YY and pancreatic polypeptide in the gut-brain axis. Neuropeptides 2012; 46(6): 261-74.
[] [PMID: 22979996]
Cryan JF, Dinan TG. Mind-altering microorganisms: The impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci 2012; 13(10): 701-12.
[] [PMID: 22968153]
Atli O, Demir-Ozkay U, Ilgin S, Aydin TH, Akbulut EN, Sener E. Evidence for neurotoxicity associated with amoxicillin in juvenile rats. Hum Exp Toxicol 2016; 35(8): 866-76.
[ 10.1177/0960327115607948] [PMID: 26429924]
Dinan TG, Cryan JF. Melancholic microbes: A link between gut microbiota and depression? Neurogastroenterol Motil 2013; 25(9): 713-9.
[] [PMID: 23910373]
Steenbergen L, Sellaro R, van Hemert S, Bosch JA, Colzato LS. A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain Behav Immun 2015; 48: 258-64.
[] [PMID: 25862297]
Akkasheh G, Kashani-Poor Z, Tajabadi-Ebrahimi M, et al. Clinical and metabolic response to probiotic administration in patients with major depressive disorder: A randomized, double-blind, placebo-controlled trial. Nutrition 2016; 32(3): 315-20.
[ 10.1016/j.nut.2015.09.003] [PMID: 26706022]
Bravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci USA 2011; 108(38): 16050-5.
[ 1102999 108] [PMID: 21876150]

open access plus

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Published on: 17 September, 2019
Page: [199 - 208]
Pages: 10
DOI: 10.2174/1574886314666190612130921

Article Metrics

PDF: 37
PRC: 1