Abstract
Aim
The present research work aims at deciphering the involvement of nitric oxide pathway and its modulation by ( ±)catechin hydrate in experimental paradigm of autism spectrum disorders (ASD).
Method
An intracerebroventricular infusion of 4 μl of 1 M propanoic acid was given in the anterior region of the lateral ventricle to induce autism-like phenotype in male rats. Oral administration of ( ±)catechin hydrate (25, 50, and 100 mg/kg) was initiated from the 3rd day lasting till the 28th day. L-NAME (50 mg/kg) and L-arginine (800 mg/kg) were also given individually as well as in combination to explore the ability of ( ±)catechin hydrate to act via nitric oxide pathway. Behavior test for sociability, stereotypy, anxiety, depression, and novelty, repetitive, and perseverative behavior was carried out between the 14th and 28th day. On the 29th day, animals were sacrificed, and levels of mitochondrial complexes and oxidative stress parameters were evaluated. We also estimated the levels of neuroinflammatory and apoptotic markers such as TNF-α, IL-6, NF-κB, IFN-γ, HSP-70, and caspase-3. To evaluate the involvement of nitric oxide pathway, the levels of iNOS and homocysteine were estimated.
Results
Treatment with ( ±)catechin hydrate significantly ameliorated behavioral, biochemical, neurological, and molecular deficits. Hence, ( ±)catechin hydrate has potential to be used as neurotherapeutic agent in ASD targeting nitric oxide pathway-mediated oxidative and nitrosative stress responsible for behavioral, biochemical, and molecular alterations via modulating nitric oxide pathway.
Conclusion
The evaluation of the levels of iNOS and homocysteine conclusively establishes the role of nitric oxide pathway in causing behavioral, biochemical, and molecular deficits and the beneficial effect of ( ±)catechin hydrate in restoring these alterations.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
American Psychiatric Association (2013) Autism spectrum disorder. Curr Biol 15:R786–R790. https://doi.org/10.1016/j.cub.2005.09.033
Amodeo DA, Jones JH, Sweeney JA, Ragozzino ME (2012) Differences in BTBR T+ tf/J and C57BL/6J mice on probabilistic reversal learning and stereotyped behaviors. Behav Brain Res 227:64–72. https://doi.org/10.1016/j.bbr.2011.10.032
Antunes M, Biala G (2012) The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process 13:93–110. https://doi.org/10.1007/s10339-011-0430-z
Berman SB, Hastings TG (1999) Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria: implications for Parkinson’s disease. J Neurochem 73:1127–1137
Bhandari R, Kuhad A (2015) Neuropsychopharmacotherapeutic efficacy of curcumin in experimental paradigm of autism spectrum disorders. Life Sci 141:156–169. https://doi.org/10.1016/j.lfs.2015.09.012
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
Bhandari R, Paliwal JK, Kuhad A (2018) Naringenin and its nanocarriers as potential phytotherapy for autism spectrum disorders. J Funct Foods 47:361–375. https://doi.org/10.1016/j.jff.2018.05.065
Chang YC, Cole TB, Costa LG (2017) Behavioral phenotyping for autism spectrum disorders in mice. Curr Protoc Toxicol 2017:1–21. https://doi.org/10.1002/cptx.19
Chen C, Chang K, Lin R et al (2016) Nitric oxide pathway activity modulation alters the protective effects of (−)epigallocatechin-3-gallate on reserpine-induced impairment in rats. Behav Brain Res 305:198–211. https://doi.org/10.1016/j.bbr.2016.02.038
Cheruku SP, Ramalingayya GV, Chamallamudi MR et al (2018) Catechin ameliorates doxorubicin-induced neuronal cytotoxicity in in vitro and episodic memory deficit in in vivo in Wistar rats. Cytotechnology 70:245–259. https://doi.org/10.1007/s10616-017-0138-8
Choi J, Lee S, Won J et al (2018) Pathophysiological and neurobehavioral characteristics of a propionic acid-mediated autism-like rat model. PLoS ONE 13:e0192925. https://doi.org/10.1371/journal.pone.0192925
Claiborne A (1985) Catalase activity. In CRC Handbook of Methods for Oxygen Radical Research (ed. R. A. Greenwald), pp. 283–284. Florida: Boca Raton.Google Scholar
Dawson VL, Dawson TM (1996) Nitric oxide neurotoxicity. J Chem Neuroanat 10:179–190. https://doi.org/10.1016/0891-0618(96)00148-2
Delwing D, Delwing D, Bavaresco CS, Wyse ATS (2008) Protective effect of nitric oxide synthase inhibition or antioxidants on brain oxidative damage caused by intracerebroventricular arginine administration. Brain Res 1193:120–127. https://doi.org/10.1016/j.brainres.2007.11.052
Demirel I, Vumma R, Mohlin C et al (2012) Nitric oxide activates IL-6 production and expression in human renal epithelial cells. Am J Nephrol 36:524–530. https://doi.org/10.1159/000345351
Dhir A, Kulkarni SK (2007) Involvement of nitric oxide (NO) signaling pathway in the antidepressant action of bupropion, a dopamine reuptake inhibitor. Eur J Pharmacol 568:177–185. https://doi.org/10.1016/j.ejphar.2007.04.028
Ding-Zhou L, Marchand-Verrecchia C, Croci N et al (2002) L-NAME reduces infarction, neurological deficit and blood-brain barrier disruption following cerebral ischemia in mice. Eur J Pharmacol 457:137–146. https://doi.org/10.1016/S0014-2999(02)02686-9
Dubey M, Nagarkoti S, Awasthi D et al (2016) Nitric oxide-mediated apoptosis of neutrophils through caspase-8 and caspase-3-dependent mechanism. Cell Death Dis 7:e2348–e2412. https://doi.org/10.1038/cddis.2016.248
Dunham NW, Miya TS (1957) A note on a simple apparatus for detecting neurological deficit in rats and mice. J Am Pharm Assoc Am Pharm Assoc (baltim) 46:208–209
El-Ansary A, Al-Ayadhi L (2012) Neuroinflammation in autism spectrum disorders. J Neuroinflammation 9:1. https://doi.org/10.1186/1742-2094-9-265
Essa MM, Subash S, Braidy N et al (2013) Role of NAD+, oxidative stress, and tryptophan metabolism in autism spectrum disorders. Int J Tryptophan Res 6:15–28. https://doi.org/10.4137/IJTR.S11355
Ey E, Torquet N, Le Sourd AM et al (2013) The autism ProSAP1/Shank2 mouse model displays quantitative and structural abnormalities in ultrasonic vocalisations. Behav Brain Res 256:677–689. https://doi.org/10.1016/j.bbr.2013.08.031
Frye RE, Rose S, Chacko J, et al (2016) Modulation of mitochondrial function by the microbiome metabolite propionic acid in autism and control cell lines. Transl Psychiatry 6:e927. https://doi.org/10.1038/tp.2016.189
Frye RE, Rossignol DA (2014) Treatments for biomedical abnormalities associated with autism spectrum disorder. Front Pediatr 2:1–8. https://doi.org/10.3389/fped.2014.00066
Gao QH, Cai Q, Fan Y (2017) Beneficial effect of catechin and epicatechin on cognitive impairment and oxidative stress induced by extremely low frequency electromagnetic field. J Food Biochem 41:1–6. https://doi.org/10.1111/jfbc.12416
Gaur V, Kumar A (2010) Hesperidin pre-treatment attenuates NO-mediated cerebral ischemic reperfusion injury and memory dysfunction. Pharmacol Reports 62:635–648. https://doi.org/10.1016/S1734-1140(10)70321-2
Gorrindo P, Williams KC, Lee EB, Walker LS (2012) Gastrointestinal dysfunction in autism. Autism Res 5:101–108. https://doi.org/10.1002/aur.237.Gastrointestinal
Greco B, Managò F, Tucci V et al (2013) Autism-related behavioral abnormalities in synapsin knockout mice. Behav Brain Res 251:65–74. https://doi.org/10.1016/j.bbr.2012.12.015
Green LC, Wagner DA, Glogowski J et al (1982) Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem 126:131–138
Herman JP, Watson SJ (1987) The rat brain in stereotaxic coordinates (2nd edn). Trends Neurosci 10:439. https://doi.org/10.1016/0166-2236(87)90017-8
Jiang Z, Zhang J (2017) Catechin attenuates traumatic brain injury-induced blood–brain barrier damage and improves longer-term. 10:1269–1277. https://doi.org/10.1113/EP086520
Jollow DJ, Mitchell JR, Zampaglione N, Gillette JR (1974) Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence for 3,4-bromobenzene oxide as the hepatotoxic metabolite. Pharmacology 11:151–169
Kabitzke PA, Brunner D, He D et al (2018) Comprehensive analysis of two Shank3 and the Cacna1c mouse models of autism spectrum disorder. Genes, Brain Behav 17:4–22. https://doi.org/10.1111/gbb.12405
Kałuzna-Czaplińska J, Zurawicz E, Michalska M, Rynkowski J (2013) A focus on homocysteine in autism. Acta Biochim Pol 60:137–142
Karvat G, Kimchi T (2012) Systematic autistic-like behavioral phenotyping of 4 mouse strains using a novel wheel-running assay. Behav Brain Res 233:405–414. https://doi.org/10.1016/j.bbr.2012.05.028
Kim V, Hoeffer CA, Littman DR, Huh JR (2016) maternal IL-17a and autism. Science (80-) 351:933–939. https://doi.org/10.1126/science.aad0314.The
King TE (1967) [58] Preparation of succinate dehydrogenase and reconstitution of succinate oxidase. Methods Enzymol 10:322–331. https://doi.org/10.1016/0076-6879(67)10061-X
King TE, Howard RL (1967) [52] Preparations and properties of soluble NADH dehydrogenases from cardiac muscle. Methods Enzymol 10:275–294. https://doi.org/10.1016/0076-6879(67)10055-4
Kono Y (1978) Generation of superoxide radical during autoxidation of hydroxylamine and an assay for superoxide dismutase. Arch Biochem Biophys 186:189–195
Lee B, Sur B, Kwon S et al (2013) Chronic administration of catechin decreases depression and anxiety-like behaviors in a rat model using chronic corticosterone injections. Biomol Ther 21:313–322. https://doi.org/10.4062/biomolther.2013.004
Li Q, Han Y, Dy ABC, Hagerman RJ (2017) The gut microbiota and autism spectrum disorders. Front Cell Neurosci 11. https://doi.org/10.3389/fncel.2017.00120
Liu Y, Peterson DA, Kimura H, Schubert D (1997) Mechanism of cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction. J Neurochem 69:581–593
Lundblad C, Bentzer P (2007) Effects of l-arginine on cerebral blood flow, microvascular permeability, number of perfused capillaries, and brain water content in the traumatized mouse brain. Microvasc Res 74:1–8. https://doi.org/10.1016/j.mvr.2007.03.001
Macfabe D (2013) Autism: metabolism, mitochondria, and the microbiome. Glob Adv Heal Med 2:52–66. https://doi.org/10.7453/gahmj.2013.089
Macfabe DF (2012) Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders. Microb Ecol Health Dis 23. https://doi.org/10.3402/mehd.v23i0.19260
MacFabe DF, Cain DP, Rodriguez-Capote K et al (2007) Neurobiological effects of intraventricular propionic acid in rats: possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. Behav Brain Res 176:149–169. https://doi.org/10.1016/j.bbr.2006.07.025
MacFabe DF, Cain NE, Boon F et al (2011) Effects of the enteric bacterial metabolic product propionic acid on object-directed behavior, social behavior, cognition, and neuroinflammation in adolescent rats: relevance to autism spectrum disorder. Behav Brain Res 217:47–54. https://doi.org/10.1016/j.bbr.2010.10.005
Manios Y, Kolotourou M, Moschonis G et al (2005) Macronutrient intake, physical activity, serum lipids and increased body weight in primary schoolchildren in Istanbul. Pediatr Int 47:159–166. https://doi.org/10.1111/j.1442-200x.2005.02047.x
Mehta MV, Gandal MJ, Siegel SJ (2011) mGluR5-antagonist mediated reversal of elevated stereotyped, repetitive behaviors in the VPA model of autism. PLoS ONE 6:e26077. https://doi.org/10.1371/journal.pone.0026077
Moretti P, Bouwknecht JA, Teague R et al (2005) Abnormalities of social interactions and home-cage behavior in a mouse model of Rett syndrome. Hum Mol Genet 14:205–220. https://doi.org/10.1093/hmg/ddi016
Moy SS, Nadler JJ, Perez A et al (2004) Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice. Genes Brain Behav 3:287–302. https://doi.org/10.1111/j.1601-1848.2004.00076.x
Paquay JBG, Haenen GRMM, Stender G et al (2000) Protection against nitric oxide toxicity by tea. J Agric Food Chem 48:5768–5772. https://doi.org/10.1021/jf981316h
Park HJ, Lee J-Y, Chung M-Y et al (2011) Green tea extract suppresses NFκB activation and inflammatory responses in diet-induced obese rats with nonalcoholic steatohepatitis. J Nutr 142:57–63. https://doi.org/10.3945/jn.111.148544
Parohova J, Vrankova S, Barta A et al (2009) The cross-talk of nuclear factor kappab and nitric oxide in the brain. Act Nerv Super Rediviva 51:123–126
Pfeiffer S, Leopold E, Schmidt K et al (1996) Inhibition of nitric oxide synthesis by NG * nitro-L-arginine methyl ester. Br J Pharmacol 118:1433–1440
Raghavendra V, Chopra K, Kulkarni SK (1999) Brain renin angiotensin system (RAS) in stress-induced analgesia and impaired retention. Peptides 20:335–342
Ravindranath NH, Ravindranath MH (2011) Green tea catechins suppress NF-κB-mediated inflammatory responses: relevance to nutritional management of inflammation. Br J Nutr 105:1715–1717. https://doi.org/10.1017/s0007114510005611
Reygaert WC (2018) Green tea catechins: their use in treating and preventing infectious diseases. 2018:9105261
Sachdeva AK, Kuhad A, Chopra K (2011) Epigallocatechin gallate ameliorates behavioral and biochemical deficits in rat model of load-induced chronic fatigue syndrome. Brain Res Bull 86:165–172. https://doi.org/10.1016/j.brainresbull.2011.06.007
Sharma AC, Kulkarni SK (1992) Evaluation of learning and memory mechanisms employing elevated plus-maze in rats and mice. Prog Neuropsychopharmacol Biol Psychiatry 16:117–125
Shultz SR, MacFabe DF, Martin S et al (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 200:33–41. https://doi.org/10.1016/j.bbr.2008.12.023
Silva Santos LF, Stolfo A, Calloni C, Salvador M (2017) Catechin and epicatechin reduce mitochondrial dysfunction and oxidative stress induced by amiodarone in human lung fibroblasts. J Arrhythmia 33:220–225. https://doi.org/10.1016/j.joa.2016.09.004
Silverman JL, Tolu SS, Barkan CL, Crawley JN (2009) Repetitive self-grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP. Neuropsychopharmacology 35:976–989. https://doi.org/10.1038/npp.2009.201
Silverman JL, Yang M, Lord C, Crawley JN (2010) Behavioural phenotyping assays for mouse models of autism. Nat Rev Neurosci 11:490–502. https://doi.org/10.1038/nrn2851
Slattery DA, Cryan JF (2012) Using the rat forced swim test to assess antidepressant-like activity in rodents. Nat Protoc 7:1009–1014. https://doi.org/10.1038/nprot.2012.044
Sottocasa GL, Kuylenstierna B, Ernster L, Bergstrand A (1967) An electron-transport system associated with the outer membrane of liver mitochondria. A biochemical and morphological study. J Cell Biol 32:415–438
Sweeten TL, Posey DJ, Shankar S, McDougle CJ (2004) High nitric oxide production in autistic disorder: a possible role for interferon-γ. Biol Psychiatry 55:434–437. https://doi.org/10.1016/J.BIOPSYCH.2003.09.001
Teixeira MDA, Souza CM, Menezes APF et al (2013) Catechin attenuates behavioral neurotoxicity induced by 6-OHDA in rats. Pharmacol Biochem Behav 110:1–7. https://doi.org/10.1016/j.pbb.2013.05.012
Thomas A, Burant A, Bui N et al (2009) Marble burying reflects a repetitive and perseverative behavior more than novelty-induced anxiety. Psychopharmacology 204:361–373. https://doi.org/10.1007/s00213-009-1466-y
Van De Sande MMH, Van Buul VJ, Brouns FJPH (2014) Autism and nutrition: the role of the gut-brain axis. Nutr Res Rev 27:199–214. https://doi.org/10.1017/S0954422414000110
Water J Van De (2012) NIH public access. 25:40–45. https://doi.org/10.1016/j.bbi.2010.08.003.Elevated
Wei H, Zou H, Sheikh AM et al (2011) IL-6 is increased in the cerebellum of autistic brain and alters neural cell adhesion, migration and synaptic formation. J Neuroinflammation 8:52. https://doi.org/10.1186/1742-2094-8-52
Wills ED (1966) Mechanisms of lipid peroxide formation in animal tissues. Biochem J 99:667–676
Xie J, Huang L, Li X, et al (2017) Immunological cytokine profiling identifies TNF-α as a key molecule dysregulated in autistic children. Oncotarget 8(47):82390–82398
Xie Q, Nathan C (1994) The high-output nitric oxide pathway: role and regulation. J Leukoc Biol 56:576–582. https://doi.org/10.1002/jlb.56.5.576
Xu N, Li X, Zhong Y (2015) Inflammatory cytokines: potential biomarkers of immunologic dysfunction in autism spectrum disorders. Mediators Inflamm 2015:1–10. https://doi.org/10.1155/2015/531518
Yang M, Silverman JL, Crawley JN (2011) Automated three-chambered social approach task for mice. In: Current protocols in neuroscience. John Wiley & Sons, Inc., Hoboken
Young AMH, Campbell E, Lynch S et al (2011) Aberrant NF-kappaB expression in autism spectrum condition: a mechanism for neuroinflammation. Front Psychiatry 2:1–8. https://doi.org/10.3389/fpsyt.2011.00027
Yui K, Kawasaki Y, Yamada H, Ogawa S (2016) Oxidative stress and nitric oxide in autism spectrum disorder and other neuropsychiatric disorders. CNS Neurol Disord Drug Targets 15:587–596
Yuste JE, Tarragon E, Campuzano CM, Ros-Bernal F (2015) Implications of glial nitric oxide in neurodegenerative diseases. Front Cell Neurosci 9:1–13. https://doi.org/10.3389/fncel.2015.00322
Funding
Research grants sanctioned by the Department of Science and Technology (DST) to Dr. Anurag Kuhad file no. EMR/2017/003589 are fully acknowledged. Grants by UGC-NRC program of UIPS and DST-Purse grant of Panjab University are gratefully acknowledged. Grants of DST-FIST and UGC-CAS to the University Institute of Pharmaceutical Sciences (UIPS) are also acknowledged gratefully. AICTE-Post-graduate Fellowship to Mr. Rishab Mehta is also gratefully acknowledged.
Author information
Authors and Affiliations
Contributions
RB, AK, and RM conceived and designed the research study. RM did the experimental work and compiled and analyzed results. RM and RB wrote the manuscript. AK approved and revised the final draft.
Corresponding authors
Ethics declarations
Ethics approval
The experimental protocol was approved by the Institutional Animal Ethics Committee of Panjab University, Chandigarh (PU/45/99/CPCSEA /IAEC/2018/166) and was conducted under according to the guidelines given by Committee for the Purpose of Control and Supervision on Experiments on Animals (CPCSEA) for the use and care of experimental animals.
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Mehta, R., Bhandari, R. & Kuhad, A. Effects of catechin on a rodent model of autism spectrum disorder: implications for the role of nitric oxide in neuroinflammatory pathway. Psychopharmacology 238, 3249–3271 (2021). https://doi.org/10.1007/s00213-021-05941-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-021-05941-5