The Protective Effects of Pioglitazone Against Cognitive Impairment
Caused by L-methionine Administration in a Rat Model

Karem   H.   Alzoubi; Omar    F.   Khabour; Mahmoud       Alfaqih; Murad       Tashtoush; Sayer   I.    Al-Azzam; Nizar    M.   Mhaidat; Nasr       Alrabadi

doi:10.2174/1871527320666210809122523

Abstract

Purpose: Accumulating evidence indicates that elevated levels of methionine are associated with cognitive decline, including loss of memory. The exact mechanisms behind this observation are not completely understood but could be related to an increase in oxidative stress markers in hippocampal tissues. The above increase in oxidative stress could be directly caused by an increase in the blood levels of methionine (hypermethioninemia) or one of its metabolites, such as homocysteine. Pioglitazone is a drug primarily used for the treatment of type 2 diabetes mellitus. Several reports showed that using pioglitazone protects against cognitive decline observed in Alzheimer's disease. Pioglitazone has antioxidant properties independent of its hypoglycemic effects. Taken together, we hypothesized that pioglitazone protects against memory loss triggered by elevated levels of methionine through lowering oxidative stress in the hippocampus.

Methods: To test this hypothesis, we used chronic administration of L-methionine in a rat model. Spatial learning and memory were evaluated in the model using a radial arm water maze (RAWM). The levels of several markers related to oxidative stress were measured in hippocampal tissues recovered from experimental rats.

Results: Current results showed that administration of L-methionine was associated with a significant loss of short- and long-term memory and an increase in blood homocysteine levels. The above memory changes were associated with an increase in lipid peroxidation and a decrease in the activity of catalase and glutathione peroxidase antioxidant enzymes in the hippocampus. The combined treatment of pioglitazone with L-methionine protected rat model from memory loss. It also prevented changes observed in lipid peroxidation and changes in the activity of catalase and glutathione peroxidase enzymes.

Conclusion: Current findings indicate that pioglitazone is a viable therapeutic option that protects against cognitive changes observed upon administration of L-methionine.

Keywords: Pioglitazone, L-methionine, memory, learning, hippocampus, maze, oxidative stress.

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[1] 
Hondorp ER, Matthews RG. Methionine. Ecosal Plus  2006; 2(1)
[http://dx.doi.org/10.1128/ecosalplus.3.6.1.7] [PMID: 26443567] 
[2] 
Fang CC, Feng L, Jiang WD, et al. Effects of dietary methionine on growth performance, muscle nutritive deposition, muscle fibre growth and type I collagen synthesis of on-growing grass carp (Ctenopharyngodon idella). Br J Nutr  2020; 1-16.
[http://dx.doi.org/10.1017/S0007114520002998] [PMID: 32718370] 
[3] 
Ligthart-Melis GC, Engelen MPKJ, Simbo SY, et al. Metabolic consequences of supplemented methionine in a clinical context. J Nutr  2020; 150(Suppl. 1): 2538S-47S.
[http://dx.doi.org/10.1093/jn/nxaa254] [PMID: 33000166] 
[4] 
Børsheim E, Bui QU, Tissier S, Kobayashi H, Ferrando AA, Wolfe RR. Effect of amino acid supplementation on muscle mass, strength and physical function in elderly. Clin Nutr  2008; 27(2): 189-95.
[http://dx.doi.org/10.1016/j.clnu.2008.01.001] [PMID: 18294740] 
[5] 
Sanchez-Roman I, Barja G. Regulation of longevity and oxidative stress by nutritional interventions: Role of methionine restriction. Exp Gerontol  2013; 48(10): 1030-42.
[http://dx.doi.org/10.1016/j.exger.2013.02.021] [PMID: 23454735] 
[6] 
Stadtman ER. Methionine oxidation and aging. Biochimica et Biophysica Acta (BBA)-. Proteins and Proteomics  2005; 1703(2): 135-40.
[http://dx.doi.org/10.1016/j.bbapap.2004.08.010] 
[7] 
Vuaden FC, Savio LE, Piato AL, et al. Long-term methionine exposure induces memory impairment on inhibitory avoidance task and alters acetylcholinesterase activity and expression in zebrafish (Danio rerio). Neurochem Res  2012; 37(7): 1545-53.
[http://dx.doi.org/10.1007/s11064-012-0749-6] [PMID: 22437435] 
[8] 
Alzoubi KH, Khabour OF, Al-Azzam SI, Tashtoush MH, Mhaidat NM. Metformin eased cognitive impairment induced by chronic L-methionine administration: Potential role of oxidative stress. Curr Neuropharmacol  2014; 12(2): 186-92.
[http://dx.doi.org/10.2174/1570159X11666131120223201] [PMID: 24669211] 
[9] 
Young SN, Shalchi M. The effect of methionine and S-adenosylmethionine on S-adenosylmethionine levels in the rat brain. J Psychiatry Neurosci  2005; 30(1): 44-8.
[PMID: 15644997] 
[10] 
Zhang N. Role of methionine on epigenetic modification of DNA methylation and gene expression in animals. Anim Nutr  2018; 4(1): 11-6.
[http://dx.doi.org/10.1016/j.aninu.2017.08.009] [PMID: 30167479] 
[11] 
Mastroeni D, Grover A, Delvaux E, Whiteside C, Coleman PD, Rogers J. Epigenetic mechanisms in Alzheimer’s disease. Neurobiol Aging  2011; 32(7): 1161-80.
[http://dx.doi.org/10.1016/j.neurobiolaging.2010.08.017] [PMID: 21482442] 
[12] 
Tyagi N, Moshal KS, Sen U, et al. H2S protects against methionine-induced oxidative stress in brain endothelial cells. Antioxid Redox Signal  2009; 11(1): 25-33.
[http://dx.doi.org/10.1089/ars.2008.2073] [PMID: 18837652] 
[13] 
Towfighi A, Markovic D, Ovbiagele B. Pronounced association of elevated serum homocysteine with stroke in subgroups of individuals: A nationwide study. J Neurol Sci  2010; 298(1-2): 153-7.
[http://dx.doi.org/10.1016/j.jns.2010.07.013] [PMID: 20810133] 
[14] 
Dimopoulos N. Association of cognitive impairment with plasma levels of folate, vitamin B12 and homocysteine in the elderly. in vivo  2006; 20(6B): 895-9.
[15] 
Alzoubi KH, Mhaidat NM, Obaid EA, Khabour OF. Caffeine prevents memory impairment induced by hyperhomocysteinemia. J Mol Neurosci  2018; 66(2): 222-8.
[http://dx.doi.org/10.1007/s12031-018-1158-3] [PMID: 30140995] 
[16] 
Perna AF, Ingrosso D, De Santo NG. Homocysteine and oxidative stress. Amino Acids  2003; 25(3-4): 409-17.
[http://dx.doi.org/10.1007/s00726-003-0026-8] [PMID: 14661100] 
[17] 
Tyagi N, Sedoris KC, Steed M, Ovechkin AV, Moshal KS, Tyagi SC. Mechanisms of homocysteine-induced oxidative stress. Am J Physiol Heart Circ Physiol  2005; 289(6): H2649-56.
[http://dx.doi.org/10.1152/ajpheart.00548.2005] [PMID: 16085680] 
[18] 
Alzoubi KH, Khabour OF, Al-Awad RM, Aburashed ZO. Every-other day fasting prevents memory impairment induced by high fat-diet: Role of oxidative stress. Physiol Behav  2021; 229: 113263.
[http://dx.doi.org/10.1016/j.physbeh.2020.113263] [PMID: 33246002] 
[19] 
Mayyas F, Alzoubi KH, Al-Taleb Z. Impact of high fat/high salt diet on myocardial oxidative stress. Clin Exp Hypertens  2017; 39(2): 126-32.
[http://dx.doi.org/10.1080/10641963.2016.1226894] [PMID: 28287889] 
[20] 
Kumar P, Kaundal RK, More S, Sharma SS. Beneficial effects of pioglitazone on cognitive impairment in MPTP model of Parkinson’s disease. Behav Brain Res  2009; 197(2): 398-403.
[http://dx.doi.org/10.1016/j.bbr.2008.10.010] [PMID: 18983875] 
[21] 
Pathan AR, Viswanad B, Sonkusare SK, Ramarao P. Chronic administration of pioglitazone attenuates intracerebroventricular streptozotocin induced-memory impairment in rats. Life Sci  2006; 79(23): 2209-16.
[http://dx.doi.org/10.1016/j.lfs.2006.07.018] [PMID: 16904700] 
[22] 
Prakash A, Kumar A. Role of nuclear receptor on regulation of BDNF and neuroinflammation in hippocampus of β-amyloid animal model of Alzheimer’s disease. Neurotox Res  2014; 25(4): 335-47.
[http://dx.doi.org/10.1007/s12640-013-9437-9] [PMID: 24277156] 
[23] 
Alzoubi KH, Shatnawi A, Al-Qudah MA, Alfaqih MA. Edaravone prevents memory impairment in an animal model of post-traumatic distress. Behav Pharmacol  2019; 30(2 and 3-Spec Issue): 201-7.
[http://dx.doi.org/10.1097/FBP.0000000000000479] [PMID: 30829662] 
[24] 
Alzoubi KH, Shatnawi AF, Al-Qudah MA, Alfaqih MA. Vitamin C attenuates memory loss induced by post-traumatic stress like behavior in a rat model. Behav Brain Res  2020; 379: 112350.
[http://dx.doi.org/10.1016/j.bbr.2019.112350] [PMID: 31711893] 
[25] 
Bird CM, Burgess N. The hippocampus and memory: Insights from spatial processing. Nat Rev Neurosci  2008; 9(3): 182-94.
[http://dx.doi.org/10.1038/nrn2335] [PMID: 18270514] 
[26] 
Michiels C, Raes M, Toussaint O, Remacle J. Importance of Se-glutathione peroxidase, catalase, and Cu/Zn-SOD for cell survival against oxidative stress. Free Radic Biol Med  1994; 17(3): 235-48.
[http://dx.doi.org/10.1016/0891-5849(94)90079-5] [PMID: 7982629] 
[27] 
Davies MH, Birt DF, Schnell RC. Direct enzymatic assay for reduced and oxidized glutathione. J Pharmacol Methods  1984; 12(3): 191-4.
[http://dx.doi.org/10.1016/0160-5402(84)90059-7] [PMID: 6536823] 
[28] 
Ellinger GM. A chemical approach to the nutritional availability of methionine in food proteins. In: Annales de la nutrition et de l’alimentation. JSTOR 1978.
[29] 
Martínez Y, Li X, Liu G, et al. The role of methionine on metabolism, oxidative stress, and diseases. Amino Acids  2017; 49(12): 2091-8.
[http://dx.doi.org/10.1007/s00726-017-2494-2] [PMID: 28929442] 
[30] 
Galizia I. S-adenosyl methionine (SAMe) for depression in adults. Cochrane Database of Systematic Reviews 2016.
[31] 
Mora SI, García-Román J, Gómez-Ñañez I, García-Román R. Chronic liver diseases and the potential use of S-adenosyl-L-methionine as a hepatoprotector. Eur J Gastroenterol Hepatol  2018; 30(8): 893-900.
[http://dx.doi.org/10.1097/MEG.0000000000001141] [PMID: 29683981] 
[32] 
Tapia-Rojas C, Lindsay CB, Montecinos-Oliva C, et al. Is L-methionine a trigger factor for Alzheimer’s-like neurodegeneration?: Changes in Aβ oligomers, tau phosphorylation, synaptic proteins, Wnt signaling and behavioral impairment in wild-type mice. Mol Neurodegener  2015; 10(1): 62.
[http://dx.doi.org/10.1186/s13024-015-0057-0] [PMID: 26590557] 
[33] 
El-Dessouki AM, Galal MA, Awad AS, Zaki HF. Neuroprotective effects of simvastatin and cilostazol in l-methionine-induced vascular dementia in rats. Mol Neurobiol  2017; 54(7): 5074-84.
[http://dx.doi.org/10.1007/s12035-016-0051-8] [PMID: 27544235] 
[34] 
Fayez AM, Elnoby AS. Neuroprotective effects of zafirlukast, piracetam and their combination on L-Methionine-induced vascular dementia in rats. 2019; 33(6): 634-48.
[http://dx.doi.org/10.1111/fcp.12473] 
[35] 
Kalani A, Chaturvedi P, Kalani K, Kamat PK, Chaturvedi P. A high methionine, low folate and vitamin B6/B12 containing diet can be associated with memory loss by epigenetic silencing of netrin-1. Neural Regen Res  2019; 14(7): 1247-54.
[http://dx.doi.org/10.4103/1673-5374.251333] [PMID: 30804256] 
[36] 
Nuru M, Muradashvili N, Kalani A, Lominadze D, Tyagi N. High methionine, low folate and low vitamin B6/B12 (HM-LF-LV) diet causes neurodegeneration and subsequent short-term memory loss. Metab Brain Dis  2018; 33(6): 1923-34.
[http://dx.doi.org/10.1007/s11011-018-0298-z] [PMID: 30094804] 
[37] 
Bilginoglu A. Cardiovascular protective effect of pioglitazone on oxidative stress in rats with metabolic syndrome. J Chin Med Assoc  2019; 82(6): 452-6.
[http://dx.doi.org/10.1097/JCMA.0000000000000103] [PMID: 30932940] 
[38] 
Khasabova IA, Khasabov SG, Olson JK, et al. Pioglitazone, a PPARγ agonist, reduces cisplatin-evoked neuropathic pain by protecting against oxidative stress. Pain  2019; 160(3): 688-701.
[http://dx.doi.org/10.1097/j.pain.0000000000001448] [PMID: 30507781] 
[39] 
Paciello F, Fetoni AR, Rolesi R, et al. Pioglitazone represents an effective therapeutic target in preventing oxidative/inflammatory cochlear damage induced by noise exposure. Front Pharmacol  2018; 9: 1103.
[http://dx.doi.org/10.3389/fphar.2018.01103] [PMID: 30349478] 
[40] 
Medić B, Stojanović M, Rovčanin B, et al. Pioglitazone attenuates kidney injury in an experimental model of gentamicin-induced nephrotoxicity in rats. Sci Rep  2019; 9(1): 13689.
[http://dx.doi.org/10.1038/s41598-019-49835-1] [PMID: 31548602] 
[41] 
Soliman E, Behairy SF, El-Maraghy NN, Elshazly SM. PPAR-γ agonist, pioglitazone, reduced oxidative and endoplasmic reticulum stress associated with L-NAME-induced hypertension in rats. Life Sci  2019; 239: 117047.
[http://dx.doi.org/10.1016/j.lfs.2019.117047] [PMID: 31730865] 
[42] 
Zakaria A, Rady M, Mahran L, Abou-Aisha K. Pioglitazone attenuates lipopolysaccharide-induced oxidative stress, dopaminergic neuronal loss and neurobehavioral impairment by activating Nrf2/ARE/HO-1. Neurochem Res  2019; 44(12): 2856-68.
[http://dx.doi.org/10.1007/s11064-019-02907-0] [PMID: 31713708] 
[43] 
Xia P, Pan Y, Zhang F, et al. Pioglitazone Confers Neuroprotection Against Ischemia-Induced Pyroptosis due to its Inhibitory Effects on HMGB-1/RAGE and Rac1/ROS Pathway by Activating PPAR-ɤ. Cell Physiol Biochem  2018; 45(6): 2351-68.
[http://dx.doi.org/10.1159/000488183] [PMID: 29554649] 
[44] 
Bonato JM, Bassani TB, Milani H, Vital MABF, de Oliveira RMW. Pioglitazone reduces mortality, prevents depressive-like behavior, and impacts hippocampal neurogenesis in the 6-OHDA model of Parkinson’s disease in rats. Exp Neurol  2018; 300: 188-200.
[http://dx.doi.org/10.1016/j.expneurol.2017.11.009] [PMID: 29162435] 
[45] 
Kunisawa K, Nakashima N, Nagao M, Nomura T, Kinoshita S, Hiramatsu M. Betaine prevents homocysteine-induced memory impairment via matrix metalloproteinase-9 in the frontal cortex. Behav Brain Res  2015; 292: 36-43.
[http://dx.doi.org/10.1016/j.bbr.2015.06.004] [PMID: 26057356] 
[46] 
Li JG, Barrero C, Merali S, Praticò D. Genetic absence of ALOX5 protects from homocysteine-induced memory impairment, tau phosphorylation and synaptic pathology. Hum Mol Genet  2017; 26(10): 1855-62.
[http://dx.doi.org/10.1093/hmg/ddx088] [PMID: 28334897] 
[47] 
Zhao H, Ji ZH, Liu C, Yu XY. Neuroprotection and mechanisms of atractylenolide III in preventing learning and memory impairment induced by chronic high-dose homocysteine administration in rats. Neuroscience  2015; 290: 485-91.
[http://dx.doi.org/10.1016/j.neuroscience.2015.01.060] [PMID: 25662510] 
[48] 
Díaz-Leines S, Peñaloza-López YR, Serrano-Miranda TA, Flores-Ávalos B, Vidal-Ixta MT, Jiménez-Herrera B. Evaluation of psychoacoustic tests and P300 event-related potentials in elderly patients with hyperhomocysteinemia. Acta Otorrinolaringol Esp  2013; 64(4): 265-72.
[http://dx.doi.org/10.1016/j.otoeng.2013.08.008] [PMID: 23527990] 
[49] 
Licking N, Murchison C, Cholerton B, et al. Homocysteine and cognitive function in Parkinson’s disease. Parkinsonism Relat Disord  2017; 44: 1-5.
[http://dx.doi.org/10.1016/j.parkreldis.2017.08.005] [PMID: 28807493] 
[50] 
Logan S, Pharaoh GA, Marlin MC, et al. Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes. Mol Metab  2018; 9: 141-55.
[http://dx.doi.org/10.1016/j.molmet.2018.01.013] [PMID: 29398615] 
[51] 
Soto M, Cai W, Konishi M, Kahn CR. Insulin signaling in the hippocampus and amygdala regulates metabolism and neurobehavior. Proc Natl Acad Sci USA  2019; 116(13): 6379-84.
[http://dx.doi.org/10.1073/pnas.1817391116] [PMID: 30765523] 

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DOI https://dx.doi.org/10.2174/1871527320666210809122523	Print ISSN 1871-5273
Publisher Name Bentham Science Publisher	Online ISSN 1996-3181

CNS & Neurological Disorders - Drug Targets

The Protective Effects of Pioglitazone Against Cognitive Impairment Caused by L-methionine Administration in a Rat Model

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