Abstract
Cadmium (Cd), is a heavy metal reported to be associated with oxidative stress and inflammation. In this paper, we investigated the possible protective effects of carvacrol against Cd-induced neurotoxicity in rats. Adult male Sprague Dawley rats were treated orally with Cd (25 mg/kg body weight) and with carvacrol (25 and 50 mg/kg body weight) for 7 days. Carvacrol decreased the levels of malondialdehyde (MDA), glial fibrillary acidic protein (GFAP) and monoamine oxidase (MAO), and significantly increased the levels of glutathione (GSH) and activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in brain tissue. Additionally, carvacrol alleviated the in levels of inflammation and apoptosis related proteins involving p38 mitogen-activated protein kinase (p38 MAPK), cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB), B-cell lymphoma-3 (Bcl-3), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), myeloperoxidase (MPO), prostaglandin E2 (PGE2), neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS), cysteine aspartate specific protease-3 (caspase-3) and Bcl-2 associated X protein (Bax) in the Cd-induced neurotoxicity. Carvacrol also decreased the mRNA expression of matrix metalloproteinases (MMP9 and MMP13), as well as 8-hydroxy-2′-deoxyguanosine (8 − OHdG) level, a marker of oxidative DNA damage. Collectively, our findings indicated that carvacrol has a beneficial effect in ameliorating the Cd-induced neurotoxicity in the brain of rats.
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References
Abdel Moneim AE, Bauomy AA, Diab MMS, Shata MTM, Al-Olayan EM, El-Khadragy MF (2014) The Protective Effect of Physalis peruviana L. Against Cadmium-Induced Neurotoxicity in Rats. Biol Trace Elem Res 160:392–399
Adefegha SA, Oboh G, Omojokun OS, Adefegha OM (2016) Alterations of Na+/K+-ATPase, cholinergic and antioxidant enzymes activity by protocatechuic acid in cadmium-induced neurotoxicity and oxidative stress in Wistar rats. Biomed Pharmacother 83:559–568
Aebi H (1984) [13] Catalase in vitro. Methods Enzymol 105:121–126
Afifi OK, Embaby AS (2016) Histological Study on the Protective Role of Ascorbic Acid on Cadmium Induced Cerebral Cortical Neurotoxicity in Adult Male Albino Rats. J Microscopy Ultrastructure 4:36–45
Akinyemi AJ, Adeniyi PA (2018) Effect of Essential Oils from Ginger (Zingiber officinale) and Turmeric (Curcuma longa) Rhizomes on Some Inflammatory Biomarkers in Cadmium Induced Neurotoxicity in Rats. J Toxicol 2018: 4109491
Al Olayan EM, Aloufi AS, AlAmri OD, El-Habit OH, Abdel Moneim AE (2020) Protocatechuic acid mitigates cadmium-induced neurotoxicity in rats: Role of oxidative stress, inflammation and apoptosis. Sci Total Environ 723:137969
Al omairi NE, Radwan OK, Alzahrani YA, Kassab RB (2018) Neuroprotective efficiency of Mangifera indica leaves extract on cadmium-induced cortical damage in rats. Metab Brain Dis 33:1121–1130
Alnahdi HS, Sharaf IA (2019) Possible prophylactic effect of omega-3 fatty acids on cadmium-induced neurotoxicity in rats’ brains. Environ Sci Pollut Res 26:31254–31262
Alvi AM, Al Kury LT, Alattar A, Ullah I, Muhammad AJ, Alshaman R, et al (2021) Carveol attenuates seizure severity and neuroinflammation in pentylenetetrazole-kindled epileptic rats by regulating the Nrf2 signaling pathway. Oxidative med cell longev 2021:9966663
Ashok A, Rai NK, Tripathi S, Bandyopadhyay S (2015) Exposure to As-, Cd-, and Pb-Mixture Induces Aβ, Amyloidogenic APP Processing and Cognitive Impairments via Oxidative Stress-Dependent Neuroinflammation in Young Rats. Toxicol Sci 143:64–80
Barnwal P, Vafa A, Afzal SM, Shahid A, Hasan SK, Alpashree et al (2017) Benzo(a)pyrene induces lung toxicity and inflammation in mice: prevention by carvacrol. Hum Exp Toxicol 37:752–761
Ben P, Zhang Z, Zhu Y, **ong A, Gao Y, Mu J et al (2016) l-Theanine attenuates cadmium-induced neurotoxicity through the inhibition of oxidative damage and tau hyperphosphorylation. Neurotoxicology 57:95–103
Brkic M, Balusu S, Libert C, Vandenbroucke RE (2015) Friends or foes: Matrix metalloproteinases and their multifaceted roles in neurodegenerative diseases. Mediators Inflamm 2015:620581
Bytyqi-Damoni A, Kestane A, Taslimi P, Tuzun B, Zengin M, Bilgicli HG et al (2020) Novel carvacrol based new oxypropanolamine derivatives: Design, synthesis, characterization, biological evaluation, and molecular docking studies. J Mol Struct 1202:127297
Caglayan C, Temel Y, Kandemir FM, Yildirim S, Kucukler S (2018) Naringin protects against cyclophosphamide-induced hepatotoxicity and nephrotoxicity through modulation of oxidative stress, inflammation, apoptosis, autophagy, and DNA damage. Environ Sci Pollut Res 25:20968–20984
Caglayan C, Kandemir FM, Darendelioğlu E, Yıldırım S, Kucukler S, Dortbudak MB (2019a) Rutin ameliorates mercuric chloride-induced hepatotoxicity in rats via interfering with oxidative stress, inflammation and apoptosis. J Trace Elem Med Biol 56:60–68
Caglayan C, Kandemir FM, Yildirim S, Kucukler S, Eser G (2019b) Rutin protects mercuric chloride-induced nephrotoxicity via targeting of aquaporin 1 level, oxidative stress, apoptosis and inflammation in rats. J Trace Elem Med Biol 54:69–78
Çelik H, Kucukler S, Çomaklı S, Caglayan C, Özdemir S, Yardım A et al (2020a) Neuroprotective effect of chrysin on isoniazid-induced neurotoxicity via suppression of oxidative stress, inflammation and apoptosis in rats. Neurotoxicology 81:197–208
Çelik H, Kucukler S, Çomaklı S, Özdemir S, Caglayan C, Yardım A et al (2020b) Morin attenuates ifosfamide-induced neurotoxicity in rats via suppression of oxidative stress, neuroinflammation and neuronal apoptosis. NeuroToxicolgy 76: 126–137
Cho K-H, Kim D-C, Yoon CS, Ko WM, Lee SJ, Sohn JH et al (2016) Anti-neuroinflammatory effects of citreohybridonol involving TLR4-MyD88-mediated inhibition of NF-кB and MAPK signaling pathways in lipopolysaccharide-stimulated BV2 cells. Neurochem Int 95:55–62
Ciesielski T, Bellinger DC, Schwartz J, Hauser R, Wright RO (2013) Associations between cadmium exposure and neurocognitive test scores in a cross-sectional study of US adults. Environ Health 12:13
Cui Z-w, **e Z-x, Wang B-f, Zhong Z-h, Chen X-y, Sun Y-h et al (2015) Carvacrol protects neuroblastoma SH-SY5Y cells against Fe2+-induced apoptosis by suppressing activation of MAPK/JNK-NF-κB signaling pathway. Acta Pharmacol Sin 36:1426–1436
Eldutar E, Kandemir FM, Kucukler S, Caglayan C (2017) Restorative effects of Chrysin pretreatment on oxidant–antioxidant status, inflammatory cytokine production, and apoptotic and autophagic markers in acute paracetamol-induced hepatotoxicity in rats: An experimental and biochemical study. 31:e21960
Govil N, Chaudhary S, Waseem M, Parvez S (2012) Postnuclear Supernatant: An In Vitro Model for Assessing Cadmium-Induced Neurotoxicity. Biol Trace Elem Res 146:402–409
Graille M, Wild P, Sauvain J-J, Hemmendinger M, Guseva Canu I, Hopf NB (2020) Urinary 8-OHdG as a Biomarker for Oxidative Stress: A Systematic Literature Review and Meta-Analysis. International Journal of Molecular Sciences; 21
Gulcin İ, Alwasel SH (2022) Metal Ions, Metal Chelators and Metal Chelating Assay as Antioxidant Method.Processes;10
Hakimi Z, Salmani H, Marefati N, Arab Z, Gholamnezhad Z, Beheshti F et al (2020) Protective Effects of Carvacrol on Brain Tissue Inflammation and Oxidative Stress as well as Learning and Memory in Lipopolysaccharide-Challenged Rats. Neurotox Res 37:965–976
Kandemir FM, Yildirim S, Kucukler S, Caglayan C, Darendelioglu E, Dortbudak MB (2020) Protective effects of morin against acrylamide-induced hepatotoxicity and nephrotoxicity: A multi-biomarker approach. Food Chem Toxicol 138:111190
Kandemir FM, Caglayan C, Darendelioğlu E, Küçükler S, İzol E, Kandemir Ö (2021) Modulatory effects of carvacrol against cadmium-induced hepatotoxicity and nephrotoxicity by molecular targeting regulation. Life Sci 277:119610
Kim KS, Lim H-J, Lim JS, Son JY, Lee J, Lee BM et al (2018) Curcumin ameliorates cadmium-induced nephrotoxicity in Sprague-Dawley rats. Food Chem Toxicol 114:34–40
Kucukler S, Darendelioglu E, Caglayan C, Ayna A, Yildirim S, Kandemir FM (2020) Zingerone attenuates vancomycin-induced hepatotoxicity in rats through regulation of oxidative stress, inflammation and apoptosis. Life Sci 259:118382
Lawrence RA, Burk RF (1976) Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun 71:952–958
Li M, Pi H, Yang Z, Reiter RJ, Xu S, Chen X et al (2016) Melatonin antagonizes cadmium-induced neurotoxicity by activating the transcription factor EB-dependent autophagy–lysosome machinery in mouse neuroblastoma cells. J Pineal Res 61:353–369
Liu B, Yu H, Baiyun R, Lu J, Li S, Bing Q et al (2018) Protective effects of dietary luteolin against mercuric chloride-induced lung injury in mice: Involvement of AKT/Nrf2 and NF-κB pathways. Food Chem Toxicol 113:296–302
Livak KJ, Schmittgen TD (2001) Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2–∆∆CT Method. Methods 25:402–408
López E, Figueroa S, Oset-Gasque MJ, González MP (2003) Apoptosis and necrosis: two distinct events induced by cadmium in cortical neurons in culture. Br J Pharmacol 138:901–911
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
Manouchehrabadi M, Farhadi M, Azizi Z, Torkaman-Boutorabi A (2020) Carvacrol Protects Against 6-Hydroxydopamine-Induced Neurotoxicity in In Vivo and In Vitro Models of Parkinson’s Disease. Neurotox Res 37:156–170
Martelli A, Rousselet E, Dycke C, Bouron A, Moulis JM (2006) Cadmium toxicity in animal cells by interference with essential metals. Biochimie 88:1807–1814
Mehana E-SE, Khafaga AF, El-Blehi SS (2019) The role of matrix metalloproteinases in osteoarthritis pathogenesis: An updated review. Life Sci 234:116786
Naeem K, Tariq Al Kury L, Nasar F, Alattar A, Alshaman R, Shah FA et al (2021) Natural Dietary Supplement, Carvacrol, Alleviates LPS-Induced Oxidative Stress, Neurodegeneration, and Depressive-Like Behaviors via the Nrf2/HO-1 Pathway. J Inflamm Res 14:1313–1329
Ojo OA, Ajiboye BO, Oyinloye BE, Ojo AB, Olarewaju OI (2014a) Protective effect of Irvingia gabonensis stem bark extract on cadmium-induced nephrotoxicity in rats. Interdisciplinary Toxicol 7:208–214
Ojo OA, Oyinloye BE, Ajiboye BO, Onikanni SA (2014b) Neuroprotective mechanism of ethanolic extract of Irvingia gabonensis stem bark against cadmium-induced neurotoxicity in rats. Journal of Advances in Medicine Medical Research 5793–5805
Oyinloye BE, Ajiboye BO, Ojo OA, Musa HM, Onikanni SA, Ojo AA (2016) Ameliorative potential of Aframomum melegueta extract in cadmium-induced hepatic damage and oxidative stress in male Wistar rats. J Appl Pharm Sci 6:1–6
Phuagkhaopong S, Ospondpant D, Kasemsuk T, Sibmooh N, Soodvilai S, Power C et al (2017) Cadmium-induced IL-6 and IL-8 expression and release from astrocytes are mediated by MAPK and NF-κB pathways. Neurotoxicology 60:82–91
Placer ZA, Cushman LL, Johnson BC (1966) Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. Anal Biochem 16:359–364
Rogers JT, Venkataramani V, Washburn C, Liu Y, Tummala V, Jiang H et al (2016) A role for amyloid precursor protein translation to restore iron homeostasis and ameliorate lead (Pb) neurotoxicity. J Neurochem 138:479–494
Rosenberg GA (2009) Matrix metalloproteinases and their multiple roles in neurodegenerative diseases. Lancet Neurol 8:205–216
Sedlak J, Lindsay RH (1968) Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem 25:192–205
Sharifi-Rad M, Varoni EM, Iriti M, Martorell M, Setzer WN, del (2018) Carvacrol and human health: A comprehensive review. Phytother Res 32:1675–1687ContrerasM
Sun Y, Oberley LW, Li Y (1988) A simple method for clinical assay of superoxide dismutase. Clin Chem 34:497–500
Taslimi P, Caglayan C, Gulcin İ (2017) The impact of some natural phenolic compounds on carbonic anhydrase, acetylcholinesterase, butyrylcholinesterase, and α-glycosidase enzymes: An antidiabetic, anticholinergic, and antiepileptic study. J Biochem Mol Toxicol 31:e21995
Unsal C, Kanter M, Aktas C, Erboga M (2013) Role of quercetin in cadmium-induced oxidative stress, neuronal damage, and apoptosis in rats. Toxicol Ind Health 31:1106–1115
Wang B, Du Y (2013) Cadmium and Its Neurotoxic Effects. Oxidative Medicine and Cellular Longevity 2013: 898034
Wang P, Luo Q, Qiao H, Ding H, Cao Y, Yu J et al (2017) The Neuroprotective Effects of Carvacrol on Ethanol-Induced Hippocampal Neurons Impairment via the Antioxidative and Antiapoptotic Pathways. Oxidative Medicine and Cellular Longevity; 2017: 4079425
Yardım A, Kucukler S, Özdemir S, Çomaklı S, Caglayan C, Kandemir FM et al (2021) Silymarin alleviates docetaxel-induced central and peripheral neurotoxicity by reducing oxidative stress, inflammation and apoptosis in rats. Gene 769:145239
Zare Mehrjerdi F, Niknazar S, Yadegari M, Akbari FA, Pirmoradi Z, Khaksari M (2020) Carvacrol reduces hippocampal cell death and improves learning and memory deficits following lead-induced neurotoxicity via antioxidant activity. Naunyn Schmiedebergs Arch Pharmacol 393:1229–1237
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MOY, HÇ and AG designed the research. AG and TD conducted experiments. AG, TD, and ES analyzed data. MOY and CC wrote the manuscript. All authors read and approved the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.
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Yıldız, M.O., Çelik, H., Caglayan, C. et al. Neuroprotective effects of carvacrol against cadmium-induced neurotoxicity in rats: role of oxidative stress, inflammation and apoptosis. Metab Brain Dis 37, 1259–1269 (2022). https://doi.org/10.1007/s11011-022-00945-2
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DOI: https://doi.org/10.1007/s11011-022-00945-2