Abstract
To evaluate the ameliorating effect of Modafinil on neuroinflammation, behavioral, and histopathological alterations in rats induced by propionic acid (PPA). Thirty male Wistar rats were used in the study, divided into 3 groups of ten subjects. One group served as a control, the subjects in the other two were given 250 mg/kg/day of PPA by intraperitoneal injection over the course of 5 days to induce autism. The experimental design was as follows: Group 1: Normal control (orally-fed control, n = 10); Group 2 (PPA + saline, n = 10): PPA and 1 ml/kg/day % 0.9 NaCl saline via oral gavage; Group 3 (PPA + Modafinil, n = 10) PPA and 30 mg/kg/day Modafinil (Modiodal tablets 100 mg, Cephalon) via oral gavage. All of the groups were investigated for behavioral, biochemical, and histological abnormality. Autism-like behaviors were reduced significantly in the rats treated with PPA. TNF-α, Nerve Growth Factor (NGF), IL-17, IL-2, and NF-KB levels as well as MDA levels and lactate were significantly higher in those treated with PPA compared to the control group. Using immunohistochemical methods, the number of neurons and GFAP immunoreactivity was significantly altered in PPA-treated rats compared to the control. Using Magnetic Resonance Spectroscopy (MRS), we found that lactate levels were significantly higher in the PPA-treated rats, while creatinine levels were significantly decreased. In the rats administered with Modafinil, behavior, neuroinflammation, and histopathological changes brought about by PPA were significantly reversed. Our results demonstrate the potential role of Modafinil in ameliorating PPA-induced neuroinflammation in rats.
Graphical Abstract
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
The datasets supporting the conclusions of this article are included within the article and its additional files.
References
Al-Owain M, Kaya N, Al-Shamrani H, Al-Bakheet A, Qari A, Al-Muaigl S, Ghaziuddin M (2013) Autism spectrum disorder in a child with propionic acidemia. JIMD Rep 7:63–66. https://doi.org/10.1007/8904_2012_143
Amirkhanloo F, Karimi G, Yousefi-Manesh H, Abdollahi A, Roohbakhsh A, Dehpour AR (2020) The protective effect of Modafinil on vincristine-induced peripheral neuropathy in rats: A possible role for TRPA1 receptors. Basic Clin Pharmacol Toxicol 127(5):405–418. https://doi.org/10.1111/bcpt.13454
Arenella M, Cadby G, De Witte W, Jones RM, Whitehouse AJ et al (2022) Potential role for immune-related genes in autism spectrum disorders: Evidence from genome-wide association meta-analysis of autistic traits. Autism 26(2):361–372. https://doi.org/10.1177/13623613211019547
Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah I, Van de Water J (2011) Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav Immun 25(1):40–45. https://doi.org/10.1016/j.bbi.2010.08.003
Béard E, Braissant O (2010) Synthesis and transport of creatine in the CNS: importance for cerebral functions. J Neurochem 115(2):297–313. https://doi.org/10.1111/j.1471-4159.2010.06935.x
Bhandari R, Kuhad A (2017) Resveratrol suppresses neuroinflammation in the experimental paradigm of autism spectrum disorders. Neurochem Int 103:8–23. https://doi.org/10.1016/j.neuint.2016.12.012
Boumezbeur F, Petersen KF, Cline GW, Mason GF, Behar KL, Shulman GI, Rothman DL (2010) The contribution of blood lactate to brain energy metabolism in humans measured by dynamic 13C nuclear magnetic resonance spectroscopy. J Neurosci 30(42):13983–13991. https://doi.org/10.1523/JNEUROSCI.2040-10.2010
Bradford MM (1976) A rapid sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254
Braunschweig D, Krakowiak P, Duncanson P, Boyce R, Hansen RL, Ashwood P, Hertz-Picciotto I, Pessah IN, Van de Water J (2013) Autism-specific maternal autoantibodies recognize critical proteins in developing brain. Transl Psychiatry 3(7):e277. https://doi.org/10.1038/tp.2013.50
Choi J, Lee S, Won J, Jin Y, Hong Y, Hur TY, Kim JH, Lee SR, Hong Y (2018) Pathophysiological and neurobehavioral characteristics of a propionic acid-mediated autism-like rat model. PLoS One 13(2):e0192925. https://doi.org/10.1371/journal.pone.0192925
Choi S, Kim JA, Li H, Jo SE, Lee H, Kim TH, Kim M, Kim SJ, Suh SH (2021) Anti-inflammatory and anti-fibrotic effects of modafinil in nonalcoholic liver disease. Biomed Pharmacother 144:112372. https://doi.org/10.1016/j.biopha.2021.112372
Cid-Jofré V, Moreno M, Sotomayor-Zárate R, Cruz G, Renard GM (2022) Modafinil Administration to Preadolescent Rat Impairs Non-Selective Attention, Frontal Cortex D2 Expression and Mesolimbic GABA Levels. Int J Mol Sci 23(12):6602. https://doi.org/10.3390/ijms23126602
Crowley T, Cryan JF, Downer EJ, O’Leary OF (2016) Inhibiting neuroinflammation: The role and therapeutic potential of GABA in neuro-immune interactions. Brain Behav Immun 54:260–277. https://doi.org/10.1016/j.bbi.2016.02.001
Cuevas-Olguin R, Roychowdhury S, Banerjee A, Garcia-Oscos F, Esquivel-Rendon E, Bringas ME, Kilgard MP, Flores G, Atzori M (2017) Cerebrolysin prevents deficits in social behavior, repetitive conduct, and synaptic inhibition in a rat model of autism. J Neurosci Res 95(12):2456–2468. https://doi.org/10.1002/jnr.24072
Dejban P, Eslami F, Rahimi N, Takzare N, Jahansouz M, Dehpour AR (2020) Involvement of nitric oxide pathway in the anti-inflammatory effect of modafinil on indomethacin-, stress-, and ethanol -induced gastric mucosal injury in rat. Eur J Pharmacol 887:173579. https://doi.org/10.1016/j.ejphar.2020.173579
Edmonson C, Ziats MN, Rennert OM (2014) Altered glial marker expression in autistic post-mortem prefrontal cortex and cerebellum. Mol Autism 5(1):3. https://doi.org/10.1186/2040-2392-5-3
El-Ansary A, Al-Ayadhi L (2014) GABAergic/glutamatergic imbalance relative to excessive neuroinflammation in autism spectrum disorders. J Neuroinflammation 11:189. https://doi.org/10.1186/s12974-014-0189-0
Erbas O, Erdogan MA, Khalilnezhad A, Gürkan FT, Yiğittürk G, Meral A, Taskiran D (2018) Neurobehavioral effects of long-term maternal fructose intake in rat offspring. Int J Dev Neurosci 69:68–79. https://doi.org/10.1016/j.ijdevneu.2018.07.001
Erbaş O, Sarac F, Aktuğ H, Peker G (2014) Detection of impaired cognitive function in rat with hepatosteatosis model and improving effect of GLP-1 analogs (exenatide) on cognitive function in hepatosteatosis. Scientific World Journal. 2014(11):946265. https://doi.org/10.1155/2014/946265
Finegold SM, Molitoris D, Song Y, Liu C, Vaisanen ML, Bolte E, McTeague M, Sandler R, Wexler H, Marlowe EM, Collins MD, Lawson PA, Summanen P, Baysallar M, Tomzynski TJ, Read E, Johnson E, Rolfe R, Nasir P, Shah H, Haake DA, Manning P, Kaul A (2002) Gastrointestinal microflora studies in late-onset autism. Clin Infect Dis 35(Suppl 1):S6–S16. https://doi.org/10.1086/341914
Frye RE, Melnyk S, Macfabe DF (2013) Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder. Transl Psychiatry 3(1):e220. https://doi.org/10.1038/tp.2012.143
Gerrard P, Malcolm R (2007) Mechanisms of modafinil: A review of current research. Neuropsychiatr Dis Treat 3(3):349–364
Han J, Chen D, Liu D, Zhu Y (2018) Modafinil attenuates inflammation via inhibiting Akt/NF-κB pathway in apoE-deficient mouse model of atherosclerosis. Inflammopharmacology 26(2):385–393. https://doi.org/10.1007/s10787-017-0387-3
Hemmer W, Wallimann T (1993) Functional aspects of creatine kinase in brain. Dev Neurosci 15(3–5):249–260. https://doi.org/10.1159/000111342
Hiremath GK, Najm IM (2007) Magnetic resonance spectroscopy in animal models of epilepsy. Epilepsia 48(Suppl 4):47–55. https://doi.org/10.1111/j.1528-1167.2007.01241.x
Hughes HK, Mills Ko E, Rose D, Ashwood P (2018) Immune Dysfunction and Autoimmunity as Pathological Mechanisms in Autism Spectrum Disorders. Front Cell Neurosci 12:405. https://doi.org/10.3389/fncel.2018.00405
Inglese M, Li BS, Rusinek H, Babb JS, Grossman RI, Gonen O (2003) Diffusely elevated cerebral choline and creatine in relapsing-remitting multiple sclerosis. Magn Reson Med 50(1):190–195. https://doi.org/10.1002/mrm.10481
Kim SA, Jang EH, Mun JY, Choi H (2019) Propionic acid induces mitochondrial dysfunction and affects gene expression for mitochondria biogenesis and neuronal differentiation in SH-SY5Y cell line. Neurotoxicology 75:116–122. https://doi.org/10.1016/j.neuro.2019.09.009
Lee P, Adany P, Choi IY (2017) Imaging based magnetic resonance spectroscopy (MRS) localization for quantitative neurochemical analysis and cerebral metabolism studies. Anal Biochem 529:40–47. https://doi.org/10.1016/j.ab.2017.01.007
Maier S, Düppers AL, Runge K, Dacko M, Lange T, Fangmeier T, Riedel A, Ebert D, Endres D, Domschke K, Perlov E, Nickel K, Tebartz van Elst L (2022) Increased prefrontal GABA concentrations in adults with autism spectrum disorders. Autism Res 15(7):1222–1236. https://doi.org/10.1002/aur.2740
Matsui T, Omuro H, Liu YF, Soya M, Shima T, McEwen BS, Soya H (2017) Astrocytic glycogen-derived lactate fuels the brain during exhaustive exercise to maintain endurance capacity. Proc Natl Acad Sci USA 114(24):6358–6363. https://doi.org/10.1073/pnas.1702739114
Matta SM, Hill-Yardin EL, Crack PJ (2019) The influence of neuroinflammation in Autism Spectrum Disorder. Brain Behav Immun 79:75–90. https://doi.org/10.1016/j.bbi.2019.04.037
Minzenberg MJ, Carter CS (2008) Modafinil: a review of neurochemical actions and effects on cognition. Neuropsychopharmacology 33(7):1477–14502. https://doi.org/10.1038/sj.npp.1301534
Ornell F, Valvassori SS, Steckert AV, Deroza PF, Resende WR, Varela RB, Quevedo J (2014) Modafinil effects on behavior and oxidative damage parameters in brain of wistar rats. Behav Neurol 2014:917246. https://doi.org/10.1155/2014/917246
Özkul B, Urfalı FE, Sever İH, Bozkurt MF, Söğüt İ, Elgörmüş ÇS, Erdogan MA, Erbaş O (2022) Demonstration of ameliorating effect of vardenafil through its anti-inflammatory and neuroprotective properties in autism spectrum disorder induced by propionic acid on rat model. Int J Neurosci 132(11):1150–1164. https://doi.org/10.1080/00207454.2022.2079507
Parracho HM, Bingham MO, Gibson GR, McCartney AL (2005) Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. J Med Microbiol 54(Pt 10):987–991. https://doi.org/10.1099/jmm.0.46101-0
Petrelli F, Pucci L, Bezzi P (2016) Astrocytes and Microglia and Their Potential Link with Autism Spectrum Disorders. Front Cell Neurosci 10:21. https://doi.org/10.3389/fncel.2016.00021
Puts NAJ, Wodka EL, Harris AD, Crocetti D, Tommerdahl M, Mostofsky SH, Edden RAE (2017) Reduced GABA and altered somatosensory function in children with autism spectrum disorder. Autism Res 10(4):608–619. https://doi.org/10.1002/aur.1691
Rasetti R, Mattay VS, Stankevich B, Skjei K, Blasi G, Sambataro F, Arrillaga-Romany IC, Goldberg TE, Callicott JH, Apud JA, Weinberger DR (2010) Modulatory effects of modafinil on neural circuits regulating emotion and cognition. Neuropsychopharmacology 35(10):2101–2109. https://doi.org/10.1038/npp.2010.83
Regenthal R, Koch H, Köhler C, Preiss R, Krügel U (2009) Depression-like deficits in rats improved by subchronic modafinil. Psychopharmacology 204(4):627–639. https://doi.org/10.1007/s00213-009-1493-8
Riske L, Thomas RK, Baker GB, Dursun SM (2017) Lactate in the brain: an update on its relevance to brain energy, neurons, glia and panic disorder. Ther Adv Psychopharmacol 7(2):85–89. https://doi.org/10.1177/2045125316675579
Rojas DC, Singel D, Steinmetz S, Hepburn S, Brown MS (2014) Decreased left perisylvian GABA concentration in children with autism and unaffected siblings. Neuroimage 86:28–34. https://doi.org/10.1016/j.neuroimage.2013.01.045
Saghazadeh A, Ataeinia B, Keynejad K, Abdolalizadeh A, Hirbod-Mobarakeh A, Rezaei N (2019) Anti-inflammatory cytokines in autism spectrum disorders: A systematic review and meta-analysis. Cytokine. 123:154740. https://doi.org/10.1016/j.cyto.2019.154740
Salari N, Rasoulpoor S, Rasoulpoor S, Shohaimi S, Jafarpour S, Abdoli N, Khaledi-Paveh B, Mohammadi M (2022) The global prevalence of autism spectrum disorder: a comprehensive systematic review and meta-analysis. Ital J Pediatr 48(1):112. https://doi.org/10.1186/s13052-022-01310-w
Santocchi E, Guiducci L, Fulceri F, Billeci L, Buzzigoli E, Apicella F, Calderoni S, Grossi E, Morales MA, Muratori F (2016) Gut to brain interaction in Autism Spectrum Disorders: a randomized controlled trial on the role of probiotics on clinical, biochemical and neurophysiological parameters. BMC Psychiatry 16:183. https://doi.org/10.1186/s12888-016-0887-5
Shultz SR, MacFabe DF, Ossenkopp KP, Scratch S, Whelan J, Taylor R, Cain DP (2008) Intracerebroventricular injection of propionic acid, an enteric bacterial metabolic end-product, impairs social behavior in the rat: implications for an animal model of autism. Neuropharmacology 54(6):901–911. https://doi.org/10.1016/j.neuropharm.2008.01.013
Shultz SR, Macfabe DF, Martin S, Jackson J, Taylor R, Boon F, Ossenkopp KP, Cain DP (2009) Intracerebroventricular injections of the enteric bacterial metabolic product propionic acid impair cognition and sensorimotor ability in the Long-Evans rat: further development of a rodent model of autism. Behav Brain Res 200(1):33–41. https://doi.org/10.1016/j.bbr.2008.12.023
Thomas RH, Meeking MM, Mepham JR, Tichenoff L, Possmayer F, Liu S, MacFabe DF (2012) The enteric bacterial metabolite propionic acid alters brain and plasma phospholipid molecular species: further development of a rodent model of autism spectrum disorders. J Neuroinflammation 9:153. https://doi.org/10.1186/1742-2094-9-153
Tiwari A, Khera R, Rahi S, Mehan S, Makeen HA, Khormi YH, Rehman MU, Khan A (2021) Neuroprotective Effect of α-Mangostin in the Ameliorating Propionic Acid-Induced Experimental Model of Autism in Wistar Rats. Brain Sci 11(3):288. https://doi.org/10.3390/brainsci11030288
Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA (2005) Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 57(1):67–81. https://doi.org/10.1002/ana.20315
Watts TJ (2008) The pathogenesis of autism. Clin Med Pathol. 1:99–103. https://doi.org/10.4137/cpath.s1143
Witters P, Debbold E, Crivelly K, Vande Kerckhove K, Corthouts K, Debbold B, Andersson H, Vannieuwenborg L, Geuens S, Baumgartner M, Kozicz T, Settles L, Morava E (2016) Autism in patients with propionic acidemia. Mol Genet Metab 119(4):317–321. https://doi.org/10.1016/j.ymgme.2016.10.009
Woodcock EA, Hillmer AT, Mason GF, Cosgrove KP (2019) Imaging Biomarkers of the Neuroimmune System among Substance Use Disorders: A Systematic Review. Mol Neuropsychiatry 5(3):125–146. https://doi.org/10.1159/000499621
Xiao YL, Fu JM, Dong Z, Yang JQ, Zeng FX, Zhu LX, He BC (2004) Neuroprotective mechanism of modafinil on Parkinson disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Acta Pharmacol Sin 25(3):301–305
Xie J, Huang L, Li X, Li H, Zhou Y, Zhu H, Pan T, Kendrick KM, Xu W (2017) Immunological cytokine profiling identifies TNF-α as a key molecule dysregulated in autistic children. Oncotarget 8(47):82390–82398. https://doi.org/10.18632/oncotarget.19326
Xiong X, Zuo Y, Cheng L, Yin Z, Hu T, Guo M, Han Z, Ge X, Li W, Wang Y, Wang D, Wang C, Zhang L, Zhang Y, Liu Q, Chen F, Lei P (2022) Modafinil Reduces Neuronal Pyroptosis and Cognitive Decline After Sleep Deprivation. Front Neurosci 16:816752. https://doi.org/10.3389/fnins.2022.816752
Yan YD, Chen YQ, Wang CY, Ye CB, Hu ZZ, Behnisch T, Huang ZL, Yang SR (2021) Chronic modafinil therapy ameliorates depressive-like behavior, spatial memory and hippocampal plasticity impairments, and sleep-wake changes in a surgical mouse model of menopause. Transl Psychiatry 11(1):116. https://doi.org/10.1038/s41398-021-01229-6
Yousefi-Manesh H, Rashidian A, Hemmati S, Shirooie S, Sadeghi MA, Zarei N, Dehpour AR (2019) Therapeutic effects of modafinil in ischemic stroke; possible role of NF-κB downregulation. Immunopharmacol and Immunotoxicol 41(5):558–564. https://doi.org/10.1080/08923973.2019.1669045
Zager A (2020) Modulating the immune response with the wake-promoting drug modafinil: A potential therapeutic approach for inflammatory disorders. Brain Behav Immun 88:878–886. https://doi.org/10.1016/j.bbi.2020.04.038
Zolkowska D, Andres-Mach M, Prisinzano TE, Baumann MH, Luszczki JJ (2015) Modafinil and its metabolites enhance the anticonvulsant action of classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model. Psychopharmacology (Berl) 232(14):2463–79. https://doi.org/10.1007/s00213-015-3884-3
Zürcher NR, Loggia ML, Mullett JE, Tseng C, Bhanot A, Richey L, Hightower BG, Wu C, Parmar AJ, Butterfield RI, Dubois JM, Chonde DB, Izquierdo-Garcia D, Wey HY, Catana C, Hadjikhani N, McDougle CJ, Hooker JM (2021) [11C]PBR28 MR-PET imaging reveals lower regional brain expression of translocator protein (TSPO) in young adult males with autism spectrum disorder. Mol Psychiatry 26(5):1659–1669. https://doi.org/10.1038/s41380-020-0682-z
Author information
Authors and Affiliations
Contributions
OE and EB drafted the manuscript and performed the analysis and interpretation of the statistical data together with other authors. VS designed the study. BO carried out the radiological imaging, performed the analysis and interpretation of the statistical data together with OE. BC and YU were involved in the design the study and the histopathological analysis. IS performed the biochemical analysis. All authors read, provided comments, and approved the final manuscript. The authors declare that all data was generated in house and that no paper mills were used.
Corresponding author
Ethics declarations
Ethics Approval
Demiroglu Science University Medical Ethics Committee approved all experiments and all procedures and processes in this study. Our study included animal subjects. We considered all ethical, scientific and legal values. Animals were looked after properly and used in minimum numbers (Demiroglu Science University, Approval number: 14210709).
Consent to Participate
Not applicable.
Consent for Publication
Not applicable.
Conflict of Interest
The authors all declare that they have no conflicts of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Bagcioglu, E., Solmaz, V., Erbas, O. et al. Modafinil Improves Autism-like Behavior in Rats by Reducing Neuroinflammation. J Neuroimmune Pharmacol 18, 9–23 (2023). https://doi.org/10.1007/s11481-023-10061-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11481-023-10061-2