Neuroprotective effects of alpha-lipoic acid on radiation-induced brainstem injury in rats

Elham Motallebzadeh , Fatemeh Aghighi, Zarichehr Vakili, Sayyed Alireza Talaei , Mehran Mohseni

Abstract


Background and purpose: Alpha-lipoic acid (ALA) is an antioxidant with radioprotective properties. We designed the current work to assess the neuroprotective function of ALA in the presence of oxidative stress induced by radiation in the brainstem of rats.

Experimental approach: Whole-brain radiations (X-rays) was given at a single dose of 25 Gy with or without pretreatment with ALA (200 mg/kg BW). Eighty rats were categorized into four groups: vehicle control (VC), ALA, radiation-only (RAD), and radiation + ALA (RAL). The rats were given ALA intraperitoneally 1 h before radiation and killed following 6 h, thereafter superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and total antioxidant capacity (TAC) in the brainstem were measured. Furthermore, a pathological examination was carried out after 24 h, 72 h, and five days to determine tissue damage.

Findings/Results: The findings indicated that MDA levels in the brainstem were 46.29 ± 1.64 μM in the RAD group and decreased in the VC group (31.66 ± 1.72 μM). ALA pretreatment reduced MDA levels while simultaneously increasing SOD and CAT activity and TAC levels (60.26 ± 5.47 U/mL, 71.73 ± 2.88 U/mL, and 227.31 ± 9.40 mol/L, respectively). The greatest pathological changes in the rat’s brainstems were seen in RAD animals compared to the VC group after 24 h, 72 h, and 5 days. As a result, karyorrhexis, pyknosis, vacuolization, and Rosenthal fibers vanished in the RAL group in three periods.

Conclusion and implications: ALA exhibited substantial neuroprotectivity following radiation-induced brainstem damage.


Keywords


Alpha-lipoic acid; Brainstem; Histopathology; Ionizing radiation; Oxidative stress.

Full Text:

PDF

References


Caceres LG, Bertolino LA, Saraceno GE, Zubilete MAZ, Uran SL, Capani F, et al. Hippocampal-related memory deficits and histological damage induced by neonatal ionizing radiation exposure. Role of oxidative status. Brain Res. 2010;1312:67-78. DOI: 10.1016/j.brainres.2009.11.053.

Motallebzadeh E, Azami Tameh A, Zavareh SAT, Farhood B, Aliasgharzedeh A, Mohseni M. Neuroprotective effect of melatonin on radiation‐induced oxidative stress and apoptosis in the brainstem of rats. J Cell Physiol. 2020;235(11):8791-8798. DOI: 10.1002/jcp.29722.

Sezen O, Ertekin MV, Demircan B, Karslıoğlu İ, Erdoğan F, Koçer İ, et al. Vitamin E and L-carnitine, separately or in combination, in the prevention of radiation-induced brain and retinal damages. Neurosurg Rev. 2008;31(2):205-213. DOI: 10.1007/s10143-007-0118-0.

Nuszkiewicz J, Woźniak A, Szewczyk-Golec K. Ionizing radiation as a source of oxidative stress-the protective role of melatonin and vitamin D. Int J Mol Sci. 2020;21(16):5804,1-22. DOI: 10.3390/ijms21165804.

Sathyasaikumar K, Swapna I, Reddy P, Murthy CR, Gupta AD, Senthilkumaran B, et al. Fulminant hepatic failure in rats induces oxidative stress differentially in cerebral cortex, cerebellum and pons medulla. Neurochem Res. 2007;32(3):517-524. DOI: 10.1007/s11064-006-9265-x.

Sharma S, Haldar C. Melatonin prevents X-ray irradiation induced oxidative damage in peripheral blood and spleen of the seasonally breeding rodent, Funambulus pennanti during reproductively active phase. Int J Radiat Biol. 2006;82(6):411-419.DOI: 10.1080/09553000600774105.

Taysi S, Polat F, Gul M, Sari R, Bakan E. Lipid peroxidation, some extracellular antioxidants, and antioxidant enzymes in serum of patients with rheumatoid arthritis. Rheumatol Int. 2002;21(5):200-204. DOI: 10.1007/s00296-001-0163-x.

Mousavi SH, Bakhtiari E, Hosseini A, Jamialahmadi K. Protective effects of glucosamine and its acetylated derivative on serum/glucose deprivation-induced PC12 cells death: role of reactive oxygen species. Res Pharm Sci. 2018;13(2):121-129.DOI: 10.4103/1735-5362.223794.

Shaban NZ, Zahran AMA, El-Rashidy FH, Kodous ASA. Protective role of hesperidin against γ-radiation-induced oxidative stress and apoptosis in rat testis. J Biol Res (Thessalon). 2017;24(1):1-11. DOI: 10.1186/s40709-017-0059-x.

Erol FS, Topsakal C, Ozveren MF, Kaplan M, Ilhan N, Ozercan IH, et al. Protective effects of melatonin and vitamin E in brain damage due to gamma radiation: an experimental study. Neurosurg Rev. 2004;27(1):65-69. DOI: 10.1007/s10143-003-0291-8.

Fernandez-Gil MA, Palacios-Bote R, Leo-Barahona M, Mora-Encinas J, editors. Anatomy of the brainstem: a gaze into the stem of life. Semin Ultrasound CT and MR. 2010:31(3):196-219. DOI: 10.1053/j.sult.2010.03.006.

Schiller K, Specht HM, Haller B, Hallqvist D, Devecka M, von Rose AB, et al. Correlation between delivered radiation doses to the brainstem or vestibular organ and nausea & vomiting toxicity in patients with head and neck cancers-an observational clinical trial. Radiat Oncol. 2017;12(1):113.DOI: 10.1186/s13014-017-0846-4.

Karbownik M, Reiter RJ. Antioxidative effects of melatonin in protection against cellular damage caused by ionizing radiation. Proc Soc Exp Biol Med. 2000;225(1):9-22. DOI: 10.1046/j.1525-1373.2000.22502.x.

Reiter RJ, Tan DX, Herman TS, Thomas Jr CR. Melatonin as a radioprotective agent: a review. Int J Radiat Oncol Biol Phys. 2004;59(3):639-653. DOI: 10.1016/j.ijrobp.2004.02.006.

Jafarpour SM, Safaei M, Mohseni M, Salimian M, Aliasgharzadeh A, Fahood B. The radioprotective effects of curcumin and trehalose against genetic damage caused by I-131. Indian J Nucl Med. 2018;33(2):99-104. DOI: 10.4103/ijnm.IJNM_158_17.

Li J, Meng Z, Zhang G, Xing Y, Feng L, Fan S, et al. N-acetylcysteine relieves oxidative stress and protects hippocampus of rat from radiation-induced apoptosis by inhibiting caspase-3. Biom Pharmacother. 2015;70:1-6. DOI: 10.1016/j.biopha.2014.12.029.

Sudjarwo SA, Sudjarwo GW. Protective effect of curcumin on lead acetate-induced testicular toxicity in Wistar rats. Res Pharmaceut Sci. 2017;12(5):381-390. DOI: 10.4103/1735-5362.213983.

Bilska A, Wlodek L. Lipoic acid-the drug of the future? Pharmacol Rep. 2005;57(5):570-577.PMID: 16227639.

Manda K, Ueno M, Moritake T, Anzai K. α-Lipoic acid attenuates x-irradiation-induced oxidative stress in mice. Cell Biol Toxicol. 2007;23(2):129-137. DOI: 10.1007/s10565-006-0137-6.

Azmoonfar R, Amini P, Yahyapour R, Rezaeyan A, Tavassoli A, Motevaseli E, et al. Mitigation of radiation-induced pneumonitis and lung fibrosis using alpha-lipoic acid and resveratrol. Antiinflam Antiallergy Agents Med Chem. 2020;19(2):149-157. DOI: 10.2174/1871523018666190319144020.

Manda K, Ueno M, Moritake T, Anzai K. Radiation-induced cognitive dysfunction and cerebellar oxidative stress in mice: protective effect of α-lipoic acid. Behavi Brain Res. 2007;177(1):7-14.DOI: 10.1016/j.bbr.2006.11.013.

Li J, Zhang G, Meng Z, Wang L, Liu H, Liu Q, et al. Neuroprotective effect of acute melatonin treatment on hippocampal neurons against irradiation by inhibition of caspase‑3. Exp Ther Med. 2016;11(6):2385-2390. DOI: 10.3892/etm.2016.3215.

Yahyapour R, Amini P, Saffar H, Motevaseli E, Farhood B, Pooladvand V, et al. Protective effect of metformin, resveratrol and alpha-lipoic acid on radiation-induced pneumonitis and fibrosis: a histopathological study. Curr Drug Res Rev. 2019;11(2):111-117.DOI: 10.2174/2589977511666191018180758.

Naseri S, Moghahi SMHN, Mokhtari T, Roghani M, Shirazi AR, Malek F, et al. Radio-protective effects of melatonin on subventricular zone in irradiated rat: decrease in apoptosis and upregulation of nestin. J Mol Neurosci. 2017;63(2):198-205. DOI: 10.1007/s12031-017-0970-5.

Mohseni M, Mihandoost E, Shirazi A, Sepehrizadeh Z, Bazzaz JT, Ghazi-khansari M. Melatonin may play a role in modulation of bax and bcl-2 expression levels to protect rat peripheral blood lymphocytes from gamma irradiation-induced apoptosis. Mutat Res. 2012;738-739:19-27. DOI: 10.1016/j.mrfmmm.2012.08.006.

Panagiotakos G, Alshamy G, Chan B, Abrams R, Greenberg E, Saxena A, et al. Long-term impact of radiation on the stem cell and oligodendrocyte precursors in the brain. PloS One. 2007;2(7):e588.DOI: 10.1371/journal.pone.0000588.

Ferrer I, Serrano T, Rivera R, Olive M, Zujar M, Graus F. Radiosensitive populations and recovery in X-ray-induced apoptosis in the developing cerebellum. Acta Neuropathol. 1993;86(5):491-500.DOI: 10.1007/BF00228585.

Wang P, Han J, Wei M, Xu Y, Zhang G, Zhang H, et al. Remodeling of dermal collagen in photoaged skin using low‐dose 5‐aminolevulinic acid photodynamic therapy occurs via the transforming growth factor‐β pathway. J Biophotonics. 2018;11(6):e201700357.DOI: 10.1002/jbio.201700357.

Kopjar N, Miočić S, Ramić S, Milić M, Viculin T. Assessment of the radioprotective effects of amifostine and melatonin on human lymphocytes irradiated with gamma-rays in vitro. Arh Hig Rada Toksikol. 2006;57(2):155-163.PMID: 16832970.

El-Dein E, Anees LM, Aly SME. Effects of α-lipoic acid on γ-radiation and lindane-induced heart toxicity in rats. Pakistan J Zool. 2016;48(5):1523-1529.

Shay KP, Moreau RF, Smith EJ, Smith AR, Hagen TM. Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. Biochim Biophys Acta. 2009;1790(10):1149-1160. DOI: 10.1016/j.bbagen.2009.07.026

Jeong BK, Song JH, Jeong H, Choi HS, Jung JH, Hahm JR, et al. Effect of alpha-lipoic acid on radiation-induced small intestine injury in mice. Oncotarget. 2016;7(12):15105-15117. DOI: 10.18632/oncotarget.7874.

Jung JH, Jung J, Kim SK, Woo SH, Kang KM, Jeong BK, et al. Alpha lipoic acid attenuates radiation-induced thyroid injury in rats. PLoS One. 2014;9(11):e112253. DOI: 10.1371/journal.pone.0112253.

Seker U, Aktas A, Nergiz Y, Zincircioglu S, Ketani M. Investigation of the protective effects of melatonin, amifostine (WR-2721), and N-acetylcysteine on radiotherapy-induced uterine tissue injury in rats. Int J Radiat Res. 2020;18(4):791-798. DOI: 10.52547/ijrr.18.4.791.

Di Stefano A, Sozio P, Cocco A, Iannitelli A, Santucci E, Costa M, et al. L-Dopa and Dopamine-(R)-α-lipoic acid conjugates as multifunctional codrugs with antioxidant properties. J Med Chem. 2006;49(4):1486-1493. DOI: 10.1021/jm051145p.

Perricone N, Nagy K, Horváth F, Dajkó G, Uray I, Nagy IZ. Alpha lipoic acid (ALA) protects proteins against the hydroxyl free radical-induced alterations: rationale for its geriatric topical application. Arch Gerontol Geriatr. 1999;29(1):45-56. DOI: 10.1016/s0167-4943(99)00022-9.

Wollin SD, Jones PJ. α-Lipoic acid and cardiovascular disease. J Nutr. 2003;133(11):3327-3330. DOI: 10.1093/jn/133.11.3327.

Arivazhagan P, Thilakavathy T, Panneerselvam C. Antioxidant lipoate and tissue antioxidants in aged rats. J Nutr Biochem. 2000;11(3):122-127. DOI: 10.1016/S0955-2863(99)00079-0.

Şahin M, Sağdıç G, Elmas O, Akpınar D, Derin N, Aslan M, et al. Effect of chronic restraint stress and alpha-lipoic acid on lipid peroxidation and antioxidant enzyme activities in rat peripheral organs. Pharmacol Res. 2006;54(3):247-252. DOI: 10.1016/j.phrs.2006.05.007.

Mihandoost E, Shirazi A, Mahdavi SR, Aliasgharzadeh A. Consequences of lethal-whole-body gamma radiation and possible ameliorative role of melatonin. Sci World J. 2014;2014:621570. DOI: 10.1155/2014/621570.

Said RS, Mohamed HA, Kassem DH. Alpha-lipoic acid effectively attenuates ionizing radiation-mediated testicular dysfunction in rats: Crosstalk of NF-ĸB, TGF-β, and PPAR-ϒ pathways. Toxicology. 2020;442:152536.DOI: 10.1016/j.tox.2020.152536.

El-Maraghi EF, Abdel-Fattah KI, Soliman SM,El-Sayed WM. Taurine provides a time-dependent amelioration of the brain damage induced by γ-irradiation in rats. J Hazard Mater. 2018;359:40-46.DOI: 10.1016/j.jhazmat.2018.07.005.

Kale A, Pişkin Ö, Baş Y, Aydın BG, Can M, Elmas Ö, et al. Neuroprotective effects of quercetin on radiation-induced brain injury in rats. J Radiat Res. 2018;59(4):404-410. DOI: 10.1093/jrr/rry032.

Sheikholeslami S, Khodaverdian S, Dorri-Giv M, Hosseini SM, Souri S, Abedi-Firouzjah R, et al.The radioprotective effects of alpha-lipoic acid on radiotherapy-induced toxicities: a systematic review. Int Immunopharmacol. 2021;96:107741. DOI: 10.1016/j.intimp.2021.107741.


Refbacks

  • There are currently no refbacks.


Creative Commons LicenseThis work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.