Generic placeholder image

CNS & Neurological Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Research Article

The Protective Role of L-carnitine on Psychosocial Stress-induced Changes in Gene Expression and Protein Levels of Matrix Metalloproteinases, Serum Corticosterone in a Rat Model

Author(s): Suzie Y. Rababa’h, Karem H. Alzoubi*, Hana Hammad, Laiali AlQuraan and Abeer M. Rababa’h

Volume 22, Issue 10, 2023

Published on: 20 October, 2022

Page: [1518 - 1525] Pages: 8

DOI: 10.2174/1871527322666221005130026

open access plus

Abstract

Background: Psychosocial stress (STS) is a common stress in modern societies. Chronic STS is associated with the impairment of a broad range of cognitive functions in humans and with prolonged abnormalities in memory. Matrix metalloproteinases (MMPs), a protein family of zinccontaining endopeptidases, are essential in neuro-inflammation and involved in neurodegenerative diseases. L-Car possessed neuroprotective, antioxidant, and anti-inflammatory properties and was shown to modulate MMPs.

Objective: The current study aimed to examine the protective effect of L-Carnitine (L-CAR) on STSinduced changes in serum corticosterone levels, MMP-2, -9, and -12 protein and mRNA expression in the hippocampus as a possible mechanism for L-CAR protective effect on STS-induced memory impairment.

Methods: The chronic STS and L-CAR (300 mg/kg/day, i.p) were simultaneously administered for 6 weeks to adult male Wistar rats. Serum corticosterone and protein levels of MMP-2, -9 and -12 were evaluated using ELISA. Real-Time PCR techniques were used to determine the mRNA levels of MMP-2, -9 and -12 in the hippocampus.

Results: The findings showed that serum corticosterone levels and MMP-2 and -9 protein levels were significantly increased (p<0.05) in the STS group compared to the control. Similarly, RT-PCR findings showed that the mRNA of those proteinases significantly increased (p<0.05) following the intruder method. On the other hand, the administration of L-CAR restored the alterations in corticosterone levels and MMPs gene and protein expression induced by chronic STS.

Conclusion: STS induced elevations in corticosterone and MMP-2 and -9 levels in the hippocampus. L-CAR, on the other hand, exhibited protective effects against the STS-induced changes in MMP-2 and -9.

Keywords: Psychosocial stress, L-carnitine, Gene, expression, Metalloproteinases, corticosterone, Hippocampus

[1]
Méndez-Cuesta LA, Márquez-Valadez B, Pérez-De la Cruz V, et al. Early changes in oxidative stress markers in a rat model of acute stress: effect of l-carnitine on the striatum. Basic Clin Pharmacol Toxicol 2011; 109(2): 123-9.
[http://dx.doi.org/10.1111/j.1742-7843.2011.00691.x] [PMID: 21371264]
[2]
Kim EJ, Pellman B, Kim JJ. Stress effects on the hippocampus: a critical review. Learn Mem 2015; 22(9): 411-6.
[http://dx.doi.org/10.1101/lm.037291.114] [PMID: 26286651]
[3]
Kim JJ, Song EY, Kim JJ, Song EY, Kosten TA. Stress effects in the hippocampus: Synaptic plasticity and memory. Stress 2006; 9(1): 1-11.
[http://dx.doi.org/10.1080/10253890600678004] [PMID: 16753928]
[4]
Quaedflieg CWEM, Schwabe L. Memory dynamics under stress. Memory 2018; 26(3): 364-76.
[http://dx.doi.org/10.1080/09658211.2017.1338299] [PMID: 28625108]
[5]
McEwen BS, Nasca C, Gray JD. Stress effects on neuronal structure: hippocampus, amygdala, and prefrontal cortex. Neuropsychopharmacology 2016; 41(1): 3-23.
[http://dx.doi.org/10.1038/npp.2015.171] [PMID: 26076834]
[6]
McEwen BS, Akil H. Revisiting the stress concept: implications for affective disorders. J Neurosci 2020; 40(1): 12-21.
[http://dx.doi.org/10.1523/JNEUROSCI.0733-19.2019] [PMID: 31896560]
[7]
Chu B, Marwaha K, Sanvictores T, Ayers D. Physiology, Stress ReactionStatPearls, StatPearls Publishing Copyright © 2021. Treasure Island, FL: StatPearls Publishing LLC 2021.
[8]
Rom O, Reznick AZ. The stress reaction: a historical perspective. Adv Exp Med Biol 2016; 905: 1-4.
[PMID: 26909884]
[9]
Chen X, Guo C, Kong J. Oxidative stress in neurodegenerative diseases. Neural Regen Res 2012; 7(5): 376-85.
[PMID: 25774178]
[10]
Peters A, McEwen BS, Friston K. Uncertainty and stress: Why it causes diseases and how it is mastered by the brain. Prog Neurobiol 2017; 156: 164-88.
[http://dx.doi.org/10.1016/j.pneurobio.2017.05.004] [PMID: 28576664]
[11]
Mahendra L, Austin RD, Kumar SS, Mahendra J, Felix A. Relationship between psychological stress, serum cortisol, expression of MMP-1 and chronic periodontitis in male police personnel. Int J Sci Eng Res 2012; 3: 2-5.
[12]
VanItallie TB. Stress: A risk factor for serious illness. Metabolism 2002; 51(6) (Suppl. 1): 40-5.
[http://dx.doi.org/10.1053/meta.2002.33191] [PMID: 12040540]
[13]
Schiavone S, Jaquet V, Trabace L, Krause KH. Severe life stress and oxidative stress in the brain: from animal models to human pathology. Antioxid Redox Signal 2013; 18(12): 1475-90.
[http://dx.doi.org/10.1089/ars.2012.4720] [PMID: 22746161]
[14]
Wingenfeld K, Wolf OT. Effects of cortisol on cognition in major depressive disorder, posttraumatic stress disorder and borderline personality disorder - 2014 Curt Richter Award Winner. Psychoneuroendocrinology 2015; 51: 282-95.
[http://dx.doi.org/10.1016/j.psyneuen.2014.10.009] [PMID: 25462901]
[15]
Wingenfeld K, Wolf OT. Stress, memory, and the hippocampus.In: The Hippocampus in clinical neuroscience. Karger Publishers 2014; Vol. 34: pp. 109-20.
[http://dx.doi.org/10.1159/000356423]
[16]
Beroun A, Mitra S, Michaluk P, Pijet B, Stefaniuk M, Kaczmarek L. MMPs in learning and memory and neuropsychiatric disorders. Cell Mol Life Sci 2019; 76(16): 3207-28.
[http://dx.doi.org/10.1007/s00018-019-03180-8] [PMID: 31172215]
[17]
Gardner J, Ghorpade A. Tissue inhibitor of metalloproteinase (TIMP)-1: The TIMPed balance of matrix metalloproteinases in the central nervous system. J Neurosci Res 2003; 74(6): 801-6.
[http://dx.doi.org/10.1002/jnr.10835] [PMID: 14648584]
[18]
Fernandez Machulsky N, Gagliardi J, Fabre B, et al. Matrix metalloproteinases and psychosocial factors in acute coronary syndrome patients. Psychoneuroendocrinology 2016; 63: 102-8.
[http://dx.doi.org/10.1016/j.psyneuen.2015.09.015] [PMID: 26431804]
[19]
Fujioka H, Dairyo Y, Yasunaga K-i, Emoto K. Neural functions of matrix metalloproteinases: plasticity, neurogenesis, and disease. Biochem Res Int 2012; 2012789083
[http://dx.doi.org/10.1155/2012/789083]
[20]
Jiang P, Li C, Xiang Z, Jiao B. Tanshinone IIA reduces the risk of Alzheimer’s disease by inhibiting iNOS, MMP-2 and NF-κBp65 transcription and translation in the temporal lobes of rat models of Alzheimer’s disease. Mol Med Rep 2014; 10(2): 689-94.
[http://dx.doi.org/10.3892/mmr.2014.2254] [PMID: 24859152]
[21]
Lin R, Yu K, Li X, et al. Electroacupuncture ameliorates post-stroke learning and memory through minimizing ultrastructural brain damage and inhibiting the expression of MMP-2 and MMP-9 in cerebral ischemia-reperfusion injured rats. Mol Med Rep 2016; 14(1): 225-33.
[http://dx.doi.org/10.3892/mmr.2016.5227] [PMID: 27177163]
[22]
Barichello T, Generoso JS, Michelon CM, et al. Inhibition of matrix metalloproteinases-2 and -9 prevents cognitive impairment induced by pneumococcal meningitis in Wistar rats. Exp Biol Med (Maywood) 2014; 239(2): 225-31.
[http://dx.doi.org/10.1177/1535370213508354] [PMID: 24419461]
[23]
Bobińska K, Szemraj J, Gałecki P, Talarowska M. The role of MMP genes in recurrent depressive disorders and cognitive functions. Acta Neuropsychiatr 2016; 28(4): 221-31.
[http://dx.doi.org/10.1017/neu.2015.72] [PMID: 26856768]
[24]
Car H, Michaluk P. Baclofen influences acquisition and MMP-2, MMP-9 levels in the hippocampus of rats after hypoxia. Pharmacol Rep 2012; 64(3): 536-45.
[http://dx.doi.org/10.1016/S1734-1140(12)70849-6] [PMID: 22814007]
[25]
Pettegrew JW, Levine J, McClure RJ. Acetyl-L-carnitine physical-chemical, metabolic, and therapeutic properties: relevance for its mode of action in Alzheimer’s disease and geriatric depression. Mol Psychiatry 2000; 5(6): 616-32.
[http://dx.doi.org/10.1038/sj.mp.4000805] [PMID: 11126392]
[26]
Chen N, Yang M, Zhou M, Xiao J, Guo J, He L. L‐carnitine for cognitive enhancement in people without cognitive impairment. Cochrane Data Sys Rev 2017; (3): 14651858
[http://dx.doi.org/10.1002/14651858.CD009374.pub3]
[27]
Ferreira GC, McKenna MC. l-Carnitine and Acetyl-l-carnitine Roles and Neuroprotection in Developing Brain. Neurochem Res 2017; 42(6): 1661-75.
[http://dx.doi.org/10.1007/s11064-017-2288-7] [PMID: 28508995]
[28]
Virmani A, Binienda Z. Role of carnitine esters in brain neuropathology. Mol Aspects Med 2004; 25(5-6): 533-49.
[http://dx.doi.org/10.1016/j.mam.2004.06.003] [PMID: 15363640]
[29]
Alesci S, De Martino MU, Mirani M, et al. l ‐Carnitine: a nutritional modulator of glucocorticoid receptor functions. FASEB J 2003; 17(11): 1-20.
[http://dx.doi.org/10.1096/fj.02-1024fje] [PMID: 12824292]
[30]
Kumaran S, Deepak B, Naveen B, Panneerselvam C. Effects of levocarnitine on mitochondrial antioxidant systems and oxidative stress in aged rats. Drugs R D 2003; 4(3): 141-7.
[http://dx.doi.org/10.2165/00126839-200304030-00001] [PMID: 12757399]
[31]
Singh S, Mishra A, Shukla S. Alcar exerts neuroprotective and pro-neurogenic effects by inhibition of glial activation and oxidative stress via activation of the wnt/β-catenin signaling in parkinsonian rats. Mol Neurobiol 2016; 53(7): 4286-301.
[http://dx.doi.org/10.1007/s12035-015-9361-5] [PMID: 26223802]
[32]
Rababaʹh SY. Alzoubi KH, Hammad HM, Alquraan L, El-Salem K. Memory impairment induced by chronic psychosocial stress is prevented by L-Carnitine. Drug Des Devel Ther 2019; 13: 4341-50.
[http://dx.doi.org/10.2147/DDDT.S225264] [PMID: 31908419]
[33]
Alzoubi KH, Rababa’h AM, Owaisi A, Khabour OF. L-carnitine prevents memory impairment induced by chronic REM-sleep deprivation. Brain Res Bull 2017; 131: 176-82.
[http://dx.doi.org/10.1016/j.brainresbull.2017.04.004] [PMID: 28433816]
[34]
Muthuswamy AD, Vedagiri K, Ganesan M, Chinnakannu P. Oxidative stress-mediated macromolecular damage and dwindle in antioxidant status in aged rat brain regions: Role of l-carnitine and dl-α-lipoic acid. Clin Chim Acta 2006; 368(1-2): 84-92.
[http://dx.doi.org/10.1016/j.cca.2005.12.010] [PMID: 16480704]
[35]
Tsakiris T, Angelogianni P, Tesseromatis C, Tsakiris S, Schulpis KH. Effect of L-carnitine administration on the modulated rat brain protein concentration, acetylcholinesterase, Na+K+-ATPase and Mg2+-ATPase activities induced by forced swimming. Br J Sports Med 2008; 42(5): 367-72.
[http://dx.doi.org/10.1136/bjsm.2007.039792] [PMID: 17984191]
[36]
Alkadhi KA, Alzoubi KH, Srivareerat M, Tran TT. Chronic psychosocial stress exacerbates impairment of synaptic plasticity in β-amyloid rat model of Alzheimer’s disease: prevention by nicotine. Curr Alzheimer Res 2011; 8(7): 718-31.
[http://dx.doi.org/10.2174/156720511797633188] [PMID: 21453245]
[37]
Alkadhi KA, Alzoubi KH, Aleisa AM, Tanner FL, Nimer AS. Psychosocial stress-induced hypertension results from in vivo expression of long-term potentiation in rat sympathetic ganglia. Neurobiol Dis 2005; 20(3): 849-57.
[http://dx.doi.org/10.1016/j.nbd.2005.05.020] [PMID: 16005635]
[38]
Gerges NZ, Stringer JL, Alkadhi KA. Combination of hypothyroidism and stress abolishes early LTP in the CA1 but not dentate gyrus of hippocampus of adult rats. Brain Res 2001; 922(2): 250-60.
[http://dx.doi.org/10.1016/S0006-8993(01)03181-X] [PMID: 11743957]
[39]
Khabour OF, Alzoubi KH, Alomari MA, Alzubi MA. Changes in spatial memory and BDNF expression to concurrent dietary restriction and voluntary exercise. Hippocampus 2010; 20(5): 637-45.
[PMID: 19530223]
[40]
van der Kooij MA, Fantin M, Rejmak E, et al. Role for MMP-9 in stress-induced downregulation of nectin-3 in hippocampal CA1 and associated behavioural alterations. Nat Commun 2014; 5(1): 4995.
[http://dx.doi.org/10.1038/ncomms5995] [PMID: 25232752]
[41]
Schoofs D, Preuß D, Wolf OT. Psychosocial stress induces working memory impairments in an n-back paradigm. Psychoneuroendocrinology 2008; 33(5): 643-53.
[http://dx.doi.org/10.1016/j.psyneuen.2008.02.004] [PMID: 18359168]
[42]
Khabour OF, Alzoubi KH, Abu Thiab TM, Al-Husein BA, Eissenberg T, Shihadeh AL. Changes in the expression and protein level of matrix metalloproteinases after exposure to waterpipe tobacco smoke. Inhal Toxicol 2015; 27(13): 689-93.
[http://dx.doi.org/10.3109/08958378.2015.1085471] [PMID: 26484568]
[43]
Rababa’h AM, Bsoul RW, Alkhatatbeh MJ, Alzoubi KH, Khabour OF. Waterpipe tobacco smoke distresses cardiovascular biomarkers in mice: alterations in protein expression of metalloproteinases, endothelin and myeloperoxidase. Inhal Toxicol 2019; 31(3): 99-106.
[http://dx.doi.org/10.1080/08958378.2019.1606366] [PMID: 31050300]
[44]
Bobińska K, Szemraj J, Czarny P, Gałecki P. Expression and activity of metalloproteinases in depression. Med Sci Monit 2016; 22: 1334-41.
[http://dx.doi.org/10.12659/MSM.895978] [PMID: 27098106]
[45]
Mahdavi R, Kolahi S, Attari VE, Mahdavi AM. L-Carnitine supplementation ameliorates serum tumor necrosis factor-alpha and matrix metalloproteinase-3 in knee osteoarthritis women. Bangladesh J Pharmacol 2017; 12(1): 28-34.
[http://dx.doi.org/10.3329/bjp.v12i1.30417]
[46]
Lee SR, Tsuji K, Lee SR, Lo EH. Role of matrix metalloproteinases in delayed neuronal damage after transient global cerebral ischemia. J Neurosci 2004; 24(3): 671-8.
[http://dx.doi.org/10.1523/JNEUROSCI.4243-03.2004] [PMID: 14736853]
[47]
Liao G, Wang Z, Lee E, et al. Enhanced expression of matrix metalloproteinase-12 contributes to Npc1 deficiency-induced axonal degeneration. Exp Neurol 2015; 269: 67-74.
[http://dx.doi.org/10.1016/j.expneurol.2015.04.004] [PMID: 25864931]

© 2024 Bentham Science Publishers | Privacy Policy