Abstract
To explore the protective efficacy of α-lipoic acid (ALA) against Cd-prompted neurotoxicity, young male New Zealand rabbits (Oryctolagus cuniculus) were divided randomly into four groups. Group 1 (control) received demineralized water. Group 2 (Cd) administered cadmium chloride (CdCl2) 3 mg/kg bwt. Group 3 (ALA) administered ALA 100 mg/kg bwt. Group 4 (Cd + ALA) administered ALA 1 h after Cd. The treatments were administered orally for 30 consecutive days. Cd-induced marked disturbances in neurochemical parameters were indicated by the reduction in micro- and macro-elements (Zn, Fe, Cu, P, and Ca), with the highest reduction in Cd-exposed rabbits, followed by Cd + ALA group and then ALA group. In the brain tissues, Cd has significantly augmented the lipid hydroperoxides (LPO) and reduced the glutathione (GSH) and total antioxidant capacity (TAC), and glutathione peroxidase and glutathione S-transferase enzyme activities but had an insignificant effect on the antioxidant redox enzymes. Administration of ALA effectively restored LPO and sustained GSH and TAC contents. Moreover, Cd downregulated the transcriptional levels of Nrf2, MT3, and SOD1 genes, and upregulated that of Keap1 gene. ALA treatment, shortly following Cd exposure, downregulated Keap1, and upregulated Nrf2 and GPx1, while maintained MT3 and SOD1 mRNA gene expression in the rabbits’ brain. These data indicated the ALA effectiveness in protecting against Cd-induced oxidative stress and the depletion of cellular antioxidants in the brain of rabbits perhaps due to its antioxidant, free radical scavenging, and chelating properties.
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Abdel-Daim MM, Taha R, Ghazy EW, El-Sayed YS (2016) Synergistic ameliorative effects of sesame oil and alpha-lipoic acid against subacute diazinon toxicity in rats: hematological, biochemical, and antioxidant studies. Can J Physiol Pharmacol 94:81–88. https://doi.org/10.1139/cjpp-2015-0131
Abdel Moneim AE, Bauomy AA, Diab MM, Shata MT, 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. https://doi.org/10.1007/s12011-014-0066-9
Abib RT, Peres KC, Barbosa AM, Peres TV, Bernardes A, Zimmermann LM, Quincozes-Santos A, Fiedler HD, Leal RB, Farina M, Gottfried C (2011) Epigallocatechin-3-gallate protects rat brain mitochondria against cadmium-induced damage. Food Chem Toxicol 49:2618–2623. https://doi.org/10.1016/j.fct.2011.07.006
Adefegha SA, Omojokun OS, Oboh G, Fasakin O, Ogunsuyi O (2016) Modulatory effects of ferulic acid on cadmium-induced brain damage. J Evid Based Complement Alternat Med 21:NP56–NP61. https://doi.org/10.1177/2156587215621726
Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126. https://doi.org/10.1016/S0076-6879(84)05016-3
Agnihotri SK, Agrawal U, Ghosh I (2015) Brain most susceptible to cadmium induced oxidative stress in mice. J Trace Elem Med Biol 30:184–193. https://doi.org/10.1016/j.jtemb.2014.12.008
Almli LM, Hamrick SE, Koshy AA, Tauber MG, Ferriero DM (2001) Multiple pathways of neuroprotection against oxidative stress and excitotoxic injury in immature primary hippocampal neurons. Brain Res Dev Brain Res 132:121–129. https://doi.org/10.1016/s0165-3806(01)00302-9
Banni M, Messaoudi I, Said L, El Heni J, Kerkeni A, Said K (2010) Metallothionein gene expression in liver of rats exposed to cadmium and supplemented with zinc and selenium. Arch Environ Contam Toxicol 59:513–519. https://doi.org/10.1007/s00244-010-9494-5
Beutler E, Duron O, Kelly BM (1963) Improved method for the determination of blood glutathione. J Lab Clin Med 61:882–888
Bharath S, Cochran BC, Hsu M, Liu J, Ames BN, Andersen JK (2002) Pre-treatment with R-lipoic acid alleviates the effects of GSH depletion in PC12 cells: implications for Parkinson’s disease therapy. Neurotoxicology 23:479–486. https://doi.org/10.1016/S0161-813x(02)00035-9
Biewenga GP, Haenen GR, Bast A (1997) The pharmacology of the antioxidant lipoic acid. Gen Pharmacol 29:315–331. https://doi.org/10.1016/S0306-3623(96)00474-0
Bludovská M, Kotyzová D, Koutenský J, Eybl V (1999) The influence of alpha-lipoic acid on the toxicity of cadmium. Gen Physiol Biophys 18 Spec No:28–32
Cao Y, Chen A, Radcliffe J, Dietrich KN, Jones RL, Caldwell K, Rogan WJ (2009) Postnatal cadmium exposure, neurodevelopment, and blood pressure in children at 2, 5, and 7 years of age. Environ Health Perspect 117:1580–1586. https://doi.org/10.1289/ehp.0900765
Czarnecki LA, Moberly AH, Turkel DJ, Rubinstein T, Pottackal J, Rosenthal MC, McCandlish EF, Buckley B, McGann JP (2012) Functional rehabilitation of cadmium-induced neurotoxicity despite persistent peripheral pathophysiology in the olfactory system. Toxicol Sci 126:534–544. https://doi.org/10.1093/toxsci/kfs030
Dkhil MA, Al-Quraishy S, Diab MM, Othman MS, Aref AM, Abdel Moneim AE (2014) The potential protective role of Physalis peruviana L. fruit in cadmium-induced hepatotoxicity and nephrotoxicity. Food Chem Toxicol 74:98–106. https://doi.org/10.1016/j.fct.2014.09.013
Dong C (2015) Protective effect of proanthocyanidins in cadmium induced neurotoxicity in mice. Drug Res (Stuttg) 65:555–560. https://doi.org/10.1055/s-0034-1395544
Draper HH, Hadley M (1990) Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol 186:421–31. http://doi.org/10.1016/0076-6879(90)86135-I.
Dwivedi N, Flora G, Kushwaha P, Flora SJ (2014) Alpha-lipoic acid protects oxidative stress, changes in cholinergic system and tissue histopathology during co-exposure to arsenic-dichlorvos in rats. Environ Toxicol Pharmacol 37:7–23. https://doi.org/10.1016/j.etap.2013.10.010
El-Maraghy SA, Nassar NN (2011) Modulatory effects of lipoic acid and selenium against cadmium-induced biochemical alterations in testicular steroidogenesis. J Biochem Mol Toxicol 25:15–25. https://doi.org/10.1002/jbt.20354
El-Missiry MA, Shalaby F (2000) Role of beta-carotene in ameliorating the cadmium-induced oxidative stress in rat brain and testis. J Biochem Mol Toxicol 14:238–243. https://doi.org/10.1002/1099-0461(2000)14:5≤238::AID-JBT2>3.0.CO;2-X
El-Neweshy MS, El-Maddawy ZK, El-Sayed YS (2013) Therapeutic effects of date palm (Phoenix dactylifera L.) pollen extract on cadmium-induced testicular toxicity. Andrologia 45:369–378. https://doi.org/10.1111/and.12025
El-Sayed YS, Samak DH, Abou-Ghanema IY, Soliman MK (2015) Physiological and oxidative stress biomarkers in the freshwater monosex Nile tilapia, Oreochromis niloticus L., exposed to pendimethalin-based herbicide. Environ Toxicol 30:430–438. https://doi.org/10.1002/tox.21919
Ersahin M, Toklu HZ, Cetinel S, Yuksel M, Erzik C, Berkman MZ, Yegen BC, Sener G (2010) Alpha lipoic acid alleviates oxidative stress and preserves blood brain permeability in rats with subarachnoid hemorrhage. Neurochem Res 35:418–428. https://doi.org/10.1007/s11064-009-0072-z
Eybl V, Kotyzova D, Bludovska M (2004) The effect of curcumin on cadmium-induced oxidative damage and trace elements level in the liver of rats and mice. Toxicol Lett 151:79–85. https://doi.org/10.1016/j.toxlet.2004.02.019
Flora SJ (2009) Structural, chemical and biological aspects of antioxidants for strategies against metal and metalloid exposure. Oxidative Med Cell Longev 2:191–206. https://doi.org/10.4161/oxim.2.4.9112
Gilgun-Sherki Y, Melamed E, Offen D (2001) Oxidative stress induced-neurodegenerative diseases: the need for antioxidants that penetrate the blood brain barrier. Neuropharmacology 40:959–975. https://doi.org/10.1016/S0028-3908(01)00019-3
Goldberg DM, Spooner RJ (1983) Glutathione Reductase. In: Bergmeyer HU, Bergmeyer J, GraBI M (Eds) Methods of Enzymatic Analysis. Verlag Chemie, Weinheim, pp 258–265
Gong DK, Liu BH, Tan XH (2015) Genistein prevents cadmium-induced neurotoxic effects through its antioxidant mechanisms. Drug Res (Stuttg) 65:65–69. https://doi.org/10.1055/s-0034-1372595
Habig WH, Pabst MJ, Jakoby WB (1974) Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. J Biol Chem 249:7130–7139
Jones W, Li X, Qu ZC, Perriott L, Whitesell RR, May JM (2002) Uptake, recycling, and antioxidant actions of alpha-lipoic acid in endothelial cells. Free Radic Biol Med 33:83–93. https://doi.org/10.1016/S0891-5849(02)00862-6
Kanter M, Unsal C, Aktas C, Erboga M (2016) Neuroprotective effect of quercetin against oxidative damage and neuronal apoptosis caused by cadmium in hippocampus. Toxicol Ind Health 32:541–550. https://doi.org/10.1177/0748233713504810
Kim YO, Ahn YK, Kim JH (2000) Influence of melatonin on immunotoxicity of cadmium. Int J Immunopharmacol 22:275–284. https://doi.org/10.1016/S0192-0561(99)00082-X
Kleinkauf-Rocha J, Bobermin LD, Machado Pde M, Goncalves CA, Gottfried C, Quincozes-Santos A (2013) Lipoic acid increases glutamate uptake, glutamine synthetase activity and glutathione content in C6 astrocyte cell line. Int J Dev Neurosci 31:165–170. https://doi.org/10.1016/j.ijdevneu.2012.12.006
Koracevic D, Koracevic G, Djordjevic V, Andrejevic S, Cosic V (2001) Method for the measurement of antioxidant activity in human fluids. J Clin Pathol 54:356–361. https://doi.org/10.1136/jcp.54.5.356
Leret ML, Millan JA, Antonio MT (2003) Perinatal exposure to lead and cadmium affects anxiety-like behaviour. Toxicology 186:125–130. https://doi.org/10.1016/S0300-483X(02)00728-X
Li W, Simmons P, Shrader D, Herrman TJ, Dai SY (2013) Microwave plasma-atomic emission spectroscopy as a tool for the determination of copper, iron, manganese and zinc in animal feed and fertilizer. Talanta 112:43–48. https://doi.org/10.1016/j.talanta.2013.03.029
Loney KD, Uddin KR, Singh SM (2003) Strain-specific brain metallothionein II (MT-II) gene expression, its ethanol responsiveness, and association with ethanol preference in mice. Alcohol Clin Exp Res 27:388–395. https://doi.org/10.1097/01.ALC.0000056613.00588.7C
Mendez-Armenta M, Rios C (2007) Cadmium neurotoxicity. Environ Toxicol Pharmacol 23:350–358. https://doi.org/10.1016/j.etap.2006.11.009
Mohamed OI, El-Nahas AF, El-Sayed YS, Ashry KM (2016) Ginger extract modulates Pb-induced hepatic oxidative stress and expression of antioxidant gene transcripts in rat liver. Pharm Biol 54:1164–1172. https://doi.org/10.3109/13880209.2015.1057651
Moraes TB, Jacques CE, Rosa AP, Dalazen GR, Terra M, Coelho JG, Dutra-Filho CS (2013) Role of catalase and superoxide dismutase activities on oxidative stress in the brain of a phenylketonuria animal model and the effect of lipoic acid. Cell Mol Neurobiol 33:253–260. https://doi.org/10.1007/s10571-012-9892-5
Muhammad MT, Khan MN (2017) Kinetics, mechanistic and synergistic studies of alpha lipoic acid with hydrogen peroxide. J Saudi Chem Soc 21:123–131. https://doi.org/10.1016/j.jscs.2015.01.008
Mukherjee R, Banerjee S, Joshi N, Singh PK, Baxi D, Ramachandran AV (2011) A combination of melatonin and alpha lipoic acid has greater cardioprotective effect than either of them singly against cadmium-induced oxidative damage. Cardiovasc Toxicol 11:78–88. https://doi.org/10.1007/s12012-010-9092-9
Nemmiche S, Chabane-Sari D, Guiraud P (2007) Role of alpha-tocopherol in cadmium-induced oxidative stress in Wistar rat’s blood, liver and brain. Chem Biol Interact 170:221–230. https://doi.org/10.1016/j.cbi.2007.08.004
Nesbitt NM, Cicchillo RM, Lee K-H, Grove TL, Booker SJ (2008) Lipoic acid biosynthesis. In: Patel MS, Packer L (Eds) Lipoic acid: energy production, antioxidant activity and health effects. Oxidative stress and disease. CRC Press, Boca Raton, pp 11–57
Nishikimi M, Appaji N, Yagi K (1972) The occurrence of superoxide anion in the reaction of reduced phenazine methosulfate and molecular oxygen. Biochem Biophys Res Commun 46:849–854. https://doi.org/10.1016/S0006-291X(72)80218-3
Nordberg GF, Gerhardsson L, Mumtaz MM, Ruiz P, Fowler BA (2015a) Interactions and mixtures in metal toxicology. In: Nordberg GF, Fowler BA, Nordberg M (eds) Handbook on the toxicology of metals. Academic Press, San Diego, pp 213–238
Nordberg GF, Nogawa K, Nordberg M (2015b) Cadmium. In: Nordberg GF, Fowler BA, Nordberg M (eds) Handbook on the toxicology of metals. Academic Press, San Diego, pp 667–716
Paglia DE, Valentine WN (1967) Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 70:158–169
Pari L, Murugavel P (2007) Diallyl tetrasulfide improves cadmium induced alterations of acetylcholinesterase, ATPases and oxidative stress in brain of rats. Toxicology 234:44–50. https://doi.org/10.1016/j.tox.2007.01.021
Pedersen MO, Larsen A, Stoltenberg M, Penkowa M (2009) Cell death in the injured brain: roles of metallothioneins. Prog Histochem Cytochem 44:1–27. https://doi.org/10.1016/j.proghi.2008.10.002
Penkowa M, Caceres M, Borup R, Nielsen FC, Poulsen CB, Quintana A, Molinero A, Carrasco J, Florit S, Giralt M, Hidalgo J (2006) Novel roles for metallothionein-I + II (MT-I + II) in defense responses, neurogenesis, and tissue restoration after traumatic brain injury: insights from global gene expression profiling in wild-type and MT-I + II knockout mice. J Neurosci Res 84:1452–1474. https://doi.org/10.1002/jnr.21043
Perera J, Tan JH, Jeevathayaparan S, Chakravarthi S, Haleagrahara N (2011) Neuroprotective effects of alpha lipoic acid on haloperidol-induced oxidative stress in the rat brain. Cell Biosci 1:12. https://doi.org/10.1186/2045-3701-1-12
Rocamonde B, Paradells S, Barcia JM, Barcia C, Garcia Verdugo JM, Miranda M, Romero Gomez FJ, Soria JM (2012) Neuroprotection of lipoic acid treatment promotes angiogenesis and reduces the glial scar formation after brain injury. Neuroscience 224:102–115. https://doi.org/10.1016/j.neuroscience.2012.08.028
Shagirtha K, Muthumani M, Prabu SM (2011) Melatonin abrogates cadmium induced oxidative stress related neurotoxicity in rats. Eur Rev Med Pharmacol Sci 15:1039–1050
Shay KP, Moreau RF, Smith EJ, Smith AR, Hagen TM (2009) Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. Biochim Biophys Acta 1790:1149–1160. https://doi.org/10.1016/j.bbagen.2009.07.026
Shila S, Kokilavani V, Subathra M, Panneerselvam C (2005) Brain regional responses in antioxidant system to alpha-lipoic acid in arsenic intoxicated rat. Toxicology 210:25–36. https://doi.org/10.1016/j.tox.2005.01.003
Suh JH, Zhu BZ, deSzoeke E, Frei B, Hagen TM (2004) Dihydrolipoic acid lowers the redox activity of transition metal ions but does not remove them from the active site of enzymes. Redox Rep 9:57–61. https://doi.org/10.1179/135100004225003923
Sumathi R (1996) Effect of DL α-lipoic acid on tissue redox state in acute cadmium-challenged tissues. J Nutr Biochem 7:85–92. https://doi.org/10.1016/0955-2863(95)00182-4
Taguchi K, Motohashi H, Yamamoto M (2011) Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. Genes Cells 16:123–140. https://doi.org/10.1111/j.1365-2443.2010.01473.x
Tellez-Plaza M, Guallar E, Howard BV, Umans JG, Francesconi KA, Goessler W, Silbergeld EK, Devereux RB, Navas-Acien A (2013) Cadmium exposure and incident cardiovascular disease. Epidemiology 24:421–429. https://doi.org/10.1097/EDE.0b013e31828b0631
Veljkovic AR, Nikolic RS, Kocic GM, Pavlovic DD, Cvetkovic TP, Sokolovic DT, Jevtovic TM, Basic JT, Laketic DM, Marinkovic MR, Stojanovic SR, Djordjevic BS, Krsmanovic MM (2012) Protective effects of glutathione and lipoic acid against cadmium-induced oxidative stress in rat’s kidney. Ren Fail 34:1281–1287. https://doi.org/10.3109/0886022X.2012.723661
Waisberg M, Joseph P, Hale B, Beyersmann D (2003) Molecular and cellular mechanisms of cadmium carcinogenesis. Toxicology 192:95–117. https://doi.org/10.1016/S0300-483X(03)00305-6
Wang B, Du Y (2013) Cadmium and its neurotoxic effects. Oxidative Med Cell Longev 2013:898034. https://doi.org/10.1155/2013/898034
West AK, Hidalgo J, Eddins D, Levin ED, Aschner M (2008) Metallothionein in the central nervous system: roles in protection, regeneration and cognition. Neurotoxicology 29:489–503. https://doi.org/10.1016/j.neuro.2007.12.006
Yamada T, Hashida K, Takarada-Iemata M, Matsugo S, Hori O (2011) alpha-Lipoic acid (LA) enantiomers protect SH-SY5Y cells against glutathione depletion. Neurochem Int 59:1003–1009. https://doi.org/10.1016/j.neuint.2011.09.005
Zalejska-Fiolka J, Wielkoszynski T, Rokicki W Jr, Dabrowska N, Strzelczyk JK, Kasperczyk A, Owczarek A, Blaszczyk U, Kasperczyk S, Stawiarska-Pieta B, Birkner E, Gamian A (2015) The influence of alpha-lipoic acid and garlic administration on biomarkers of oxidative stress and inflammation in rabbits exposed to oxidized nutrition oils. Biomed Res Int 2015:827879. https://doi.org/10.1155/2015/827879
Zhang L, Xing GQ, Barker JL, Chang Y, Maric D, Ma W, Li BS, Rubinow DR (2001) Alpha-lipoic acid protects rat cortical neurons against cell death induced by amyloid and hydrogen peroxide through the Akt signalling pathway. Neurosci Lett 312:125–128. https://doi.org/10.1016/S0304-3940(01)02205-4
Zhang Y, Hou Y, Liu C, Li Y, Guo W, Wu JL, Xu D, You X, Pan Y, Chen Y (2016) Identification of an adaptor protein that facilitates Nrf2-Keap1 complex formation and modulates antioxidant response. Free Radic Biol Med 97:38–49. https://doi.org/10.1016/j.freeradbiomed.2016.05.017
Zou H, Liu X, Han T, Hu D, Yuan Y, Gu J, Bian J, Liu Z (2015) Alpha-lipoic acid protects against cadmium-induced hepatotoxicity via calcium signalling and gap junctional intercellular communication in rat hepatocytes. J Toxicol Sci 40:469–477. https://doi.org/10.2131/jts.40.469
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Saleh, H.M., El-Sayed, Y.S., Naser, S.M. et al. Efficacy of α-lipoic acid against cadmium toxicity on metal ion and oxidative imbalance, and expression of metallothionein and antioxidant genes in rabbit brain. Environ Sci Pollut Res 24, 24593–24601 (2017). https://doi.org/10.1007/s11356-017-0158-0
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DOI: https://doi.org/10.1007/s11356-017-0158-0