Circadian rhythms of antioxidant enzymes activity, clock, and inflammation factors are disrupted in the prefrontal cortex of aged rats. Potential targets for therapeutic strategies for a healthy aging.

Year 2024, Volume: 16 Issue: 1, 1183 - 1194, 09.07.2024

Ivana Ponce Cinthia Coria-lucero María Gabriela Lacoste María Cecilia Della Vedova Cristina Devia Darío Ramírez Sandra Gómez-mejiba Silvia Marcela Delgado Ana Anzulovich

https://doi.org/10.37212/jcnos.1460272

Abstract

Age impairs cognitive functions and antioxidant defenses, for example, by increasing oxidative stress and inflammation in the brain. However, so far, there is no report on the consequences of aging on temporal patterns of proteins and lipids oxidation, antioxidant enzymes activity, endogenous clock and proinflammatory cytokine, in the prefrontal cortex (PFC). Therefore, our objectives here were: 1) to investigate the endogenous nature of 24h-rhythms of lipoperoxidation, protein carbonyls levels, CAT and GPx activity, RORa, and TNFα, in the rat PFC, and 2) to study the consequences of aging on the circadian organization of those factors in the same brain area. To do that, 3- and 22-mo-old male Holtzman rats were maintained under constant darkness conditions during 15 days before reaching the corresponding age. PFC samples were isolated every 4 h, under dim-red light, during a 24h period. Our results revealed circadian patterns of antioxidant enzymes activity, oxidative stress, RORa and TNFα proteins levels, in the PFC of young rats. The circadian distribution of the rhythms’ phases suggests the existence of a reciprocal communication among the antioxidant defenses, the endogenous clock, and the inflammation, in the PFC. Noteworthy, such circadian organization disappears in the PFC of aged rats. An increased oxidative stress would make the redox environment to change into an oxidative status, which alters the endogenous clock activity and disrupts the circadian organization of, at least part, of the antioxidant defenses and the TNFα, in the PFC. These results might highlight novel chronobiological targets for the design of therapeutic strategies addressed to a healthy aging.

Keywords

circadian rhythm, oxidative stress, RORa, TNFα, prefrontal cortex

Ethical Statement

The experiments were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80–23) and the National University of San Luis Committee's Guidelines for the Care and Use of Experimental Animals (Protocol approved by Res. RD-2-296/17 y 01/19.

Supporting Institution

National University of San Luis (UNSL), and National Council for Research on Science and Technology (CONICET)

Project Number

Projects: PICT 2020-01575-FONCYT; PIP 0986-CONICET; PROICO 02-0518-UNSL.

References

• Aebi H. (1984). Catalase in vitro. Methods Enzymol. 105:121-6. doi: 10.1016/s0076-6879(84)05016-3.
• Albrecht U. (2012). Circadian Rhythms and Sleep: The Metabolic Connection. Pflugers Arch. . 463(1):23-30. doi: 10.1007/s00424-011-0986-6.
• Altamirano F, Castro Pascual I, Ferramola M, Tula M, Delgado S, Anzulovich A, Lacoste MG. (2021). Aging disrupts the temporal organization of antioxidant defenses in the heart of male rats and phase shifts circadian rhythms of systolic blood pressure. Biogerontol. 22(6):603-621.doi: 10.1007/s10522-021-09938-7.
• Aschoff J. (1967). Human circadian rhythms in activity, body temperature and other functions. Life Sci Space Res. 5:159-73. PMID: 11973844.
• Binder S, Rawohl J, Born J, Marshall L. (2014). Transcranial slow oscillation stimulation during NREM sleep enhances acquisition of the radial maze task and modulates cortical network activity in rats. Front Behav Neurosci. 8;7:220. doi: 10.3389/fnbeh.2013.00220.
• Buhr ED, Takahashi JS. (2013). Molecular components of the Mammalian circadian clock. Handb Exp Pharmacol. (217):3-27. doi: 10.1007/978-3-642-25950-0_1.
• Buijink MR, Michel S. (2021). A multilevel assessment of the bidirectional relationship between aging and the circadian clock. J Neurochem. 157(1):73-94. doi: 10.1111/jnc.15286.
• Buijink MR, Olde Engberink AHO, Wit CB, Almog A, Meijer JH, Rohling JHT, Michel S. (2020). Aging affects the capacity of photoperiodic adaptation downstream from the central molecular clock. J Biol Rhythms. 35(2):167-179. doi: 10.1177/0748730419900867.
• Bollinger T, Schibler U. (2014). Circadian rhythms - from genes to physiology and disease. Swiss Med Wkly. 144:w13984. doi: 10.4414/smw.2014.13984.
• Chaudhury D, Colwell CS. (2002). Circadian modulation of learning and memory in fear-conditioned mice. Behav Brain Res. 133(1):95-108. doi: 10.1016/s0166-4328(01)00471-5.
• Cho H, Zhao X, Hatori M, Yu RT, Barish GD, Lam MT, Chong LW, DiTacchio L, Atkins AR, Glass CK, Liddle C, Auwerx J, Downes M, Panda S, Evans RM. (2012). Regulation of circadian behavior and metabolism by REV-ERB-α and REV-ERB-β. Nature. 485(7396):123-7. doi: 10.1038/nature11048.
• Coria-Lucero C, Castro A, Ledezma C, Leporatti J, Ramirez D, Ghersi M, Delgado SM, Anzulovich AC, Navigatore-Fonzo L. (2023). An intracerebroventricular injection of AΒ (1-42) modifies temporal profiles of spatial memory performance and oxidative status in the temporal cortex rat. Brain Res. 1804:148242. doi: 10.1016/j.brainres.2023.148242.
• Coria-Lucero CD, Golini RS, Ponce IT, Deyurka N, Anzulovich AC, Delgado SM, Navigatore-Fonzo LS. (2016). Rhythmic Bdnf and TrkB expression patterns in the prefrontal cortex are lost in aged rats. Brain Res. 1653:51-58. doi: 10.1016/j.brainres.2016.10.019.
• Dibner C, Schibler U, Albrecht U. (2010). The mammalian circadian timing system: organization and coordination of central and peripheral clocks. Annu Rev Physiol. 72:517-49. doi: 10.1146/annurev-physiol-021909-135821.
• Draper HH, Hadley M. (1990). Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol. 186:421-31. doi: 10.1016/0076-6879(90)86135-i.
• Farajnia S, Deboer T, Rohling JH, Meijer JH, Michel S. (2014). Aging of the suprachiasmatic clock. Neuroscientist. 20(1):44-55. doi: 10.1177/1073858413498936.
• Flohé L, Günzler WA. (1984). Assays of glutathione peroxidase. Methods Enzymol. 105:114-21. doi: 10.1016/s0076-6879(84)05015-1.
• Fonken LK, Kitt MM, Gaudet AD, Barrientos RM, Watkins LR, Maier SF. (2016). Diminished circadian rhythms in hippocampal microglia may contribute to age-related neuroinflammatory sensitization. Neurobiol Aging. 47:102-112. doi: 10.1016/j.neurobiolaging.2016.07.019.
• Fonzo LS, Golini RS, Delgado SM, Ponce IT, Bonomi MR, Rezza IG, Gimenez MS, Anzulovich AC. (2009). Temporal patterns of lipoperoxidation and antioxidant enzymes are modified in the hippocampus of vitamin A-deficient rats. Hippocampus. 19(9):869-80. doi: 10.1002/hypo.20571.
• Gillette MU, Wang TA. (2014). Brain circadian oscillators and redox regulation in mammals. Antioxid Redox Signal. 20(18):2955-65. doi: 10.1089/ars.2013.5598.
• Golombek DA, Rosenstein RE. (2010). Physiology of circadian entrainment. Physiol Rev. 90(3):1063-102. doi: 10.1152/physrev.00009.2009.
• Han YH, Kim HJ, Kim EJ, Kim KS, Hong S, Park HG, Lee MO. (2014). RORα decreases oxidative stress through the induction of SOD2 and GPx1 expression and thereby protects against nonalcoholic steatohepatitis in mice. Antioxid Redox Signal. 21(15):2083-94. doi: 10.1089/ars.2013.5.655.
• Harding HP, Lazar MA. (1995). The monomer-binding orphan receptor Rev-Erb represses transcription as a dimer on a novel direct repeat. Mol Cell Biol. 15(9):4791-802. doi: 10.1128/MCB.15.9.4791. Erratum in: Mol Cell Biol. 15(11):6479.
• He B, Chen Z. (2016). Molecular Targets for Small-Molecule Modulators of Circadian Clocks. Curr Drug Metab. 17(5):503-12. doi: 10.2174/1389200217666160111124439.
• Hood S, Amir S. The aging clock: circadian rhythms and later life. (2017) J Clin Invest. 127(2):437-446. doi: 10.1172/JCI90328.
• Ifeanyi OE. (2018). A Review on Free Radicals and Antioxidants. Int. J. Curr. Res. Med. Sci. 4(2): 123-133. doi: http://dx.doi.org/10.22192/ijcrms.2018.04.02.019.
• Kersanté F, Purple RJ, Jones MW. (2023). The GABAA receptor modulator zolpidem augments hippocampal-prefrontal coupling during non-REM sleep. Neuropsychopharmacology. 48(4):594-604. doi: 10.1038/s41386-022-01355-9.
• Koronowski KB, Sassone-Corsi P. (2021). Communicating clocks shape circadian homeostasis. Science. 371(6530):eabd0951. doi: 10.1126/science.abd0951.
• Lacoste MG, Ponce IT, Golini RL, Delgado SM, Anzulovich AC (2017). Aging modifies daily variation of antioxidant enzymes and oxidative status in the hippocampus. Exp Gerontol. 88:42-50. doi: 10.1016/j.exger.2016.12.002. 6.
• Manikonda PK, Jagota A. (2012) Melatonin administration differentially affects age-induced alterations in daily rhythms of lipid peroxidation and antioxidant enzymes in male rat liver. Biogerontol. 13(5):511-24. doi: 10.1007/s10522-012-9396-1.
• Meng J, Lv Z, Qiao X, Li X, Li Y, Zhang Y, Chen C. (2017). The decay of Redox-stress Response Capacity is a substantive characteristic of aging: Revising the redox theory of aging. Redox Biol. 11:365-374. doi: 10.1016/j.redox.2016.12.026.
• Miller MW, Lin AP, Wolf EJ, Miller DR (2018). Oxidative Stress, Inflammation, and Neuroprogression in Chronic PTSD. Harv Rev Psychiatry. 26(2):57-69. doi: 10.1097/HRP.0000000000000167.
• Molcan, L. (2019). Time distributed data analysis by Cosinor. Online application. bioRxiv, 805960. doi.org/10.1101/805960
• Navigatore-Fonzo LS, Delgado SM, Golini RS, Anzulovich AC (2014). Circadian rhythms of locomotor activity and hippocampal clock genes expression are dampened in vitamin A-deficient rats. Nutr Res. 34(4):326-35. doi: 10.1016/j.nutres.2014.02.002.
• Nejati Moharrami N, Bjørkøy Tande E, Ryan L, Espevik T, Boyartchuk V. (2018). RORα controls inflammatory state of human macrophages. PLoS One. 13(11):e0207374. doi: 10.1371/journal.pone.0207374.
• Paxinos, G. and Watson, C. 2006. The Rat Brain in Stereotaxic Coordinates. Academic Press, San Diego, 456 pp.
• Permpoonputtana K, Tangweerasing P, Mukda S, Boontem P, Nopparat C, Govitrapong P. (2018). Long-term administration of melatonin attenuates neuroinflammation in the aged mouse brain. EXCLI J. 7:634-646. doi: 10.17179/excli 2017-654.
• Ponce IT, Rezza IG, Delgado SM, Navigatore LS, Bonomi MR, Golini RL, Gimenez MS, Anzulovich AC. (2011). Daily oscillation of glutathione redox cycle is dampened in the nutritional vitamin A deficiency. Biol Rhythm Res. 43(4):351-372. doi: 10.1080/09291016.2011.593847.
• Qaid, EYA, Long I, Azman KF, Ahmad AH, et al. (2021). Quantitative description of publications (1986-2020) related to Alzheimer disease and oxidative stress: A bibliometric study. J Cell Neurosci Oxid Stress, 13(1), 971-984. https://doi.org/10.37212/jcnos.946898.
• Radak Z, Zhao Z, Goto S, Koltai E. (2011). Age-associated neurodegeneration and oxidative damage to lipids, proteins and DNA. Mol Aspects Med. 32(4-6):305-15. doi: 10.1016/j.mam.2011.10.010.
• Re R, Pellegrini N, Proteggente A, Pannala A, Yang M, Rice-Evans C. (1999). Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Radic Biol Med. 26(9-10):1231-7. doi: 10.1016/s0891-5849(98)00315-3.
• Sies H, Berndt C, Jones DP. (2017). Oxidative Stress. Annu Rev Biochem. 86:715-748. doi: 10.1146/annurev-biochem-061516-045037.
• Takeda Y, Jothi R, Birault V, Jetten AM. (2012). RORγ directly regulates the circadian expression of clock genes and downstream targets in vivo. Nuc Ac Res. 40(17):8519-35. doi: 10.1093/nar/gks630. Epub 2012 Jun 29.
• Thaela MJ, Jensen MS, Cornélissen G, Halberg F, Nöddegaard F, Jakobsen K, Pierzynowski SG. (1998). Circadian and ultradian variation in pancreatic secretion of meal-fed pigs after weaning. J Anim Sci. 76(4):1131-9. doi: 10.2527/1998.7641131x.
• Tononi G, Cirelli C. (2014). Sleep and the price of plasticity: from synaptic and cellular homeostasis to memory consolidation and integration. Neuron. 81(1):12-34. doi: 10.1016/j.neuron.2013.12.025.
• Wilking M, Ndiaye M, Mukhtar H, Ahmad N. (2013). Circadian rhythm connections to oxidative stress: implications for human health. Antiox Redox Signal. 10;19(2):192-208. doi: 10.1089/ars.2012.4889.
• Winterbourn CC, Buss IH. (1999). Protein carbonyl measurement by enzyme-linked immunosorbent assay. Meth Enzymol. 1999;300:106-11. doi: 10.1016/s0076-6879(99)00118-4.
• Wu A, Ying Z, Gomez-Pinilla F. (2004). The interplay between oxidative stress and brain-derived neurotrophic factor modulates the outcome of a saturated fat diet on synaptic plasticity and cognition. Eur J Neurosci. 19(7):1699-707. doi: 10.1111/j.1460-9568.2004.03246.x.
• Wyse CA, Coogan AN. (2010). Impact of aging on diurnal expression patterns of CLOCK and BMAL1 in the mouse brain. Brain Res. 1337:21-31. doi: 10.1016/j.brainres.2010.03.113.
• Yildizhan K & Naziroğlu M. (2019). Microglia and its role in neurodegenerative diseases. J Cell Neurosci Oxid Stress, 11(2), 861-873. https://doi.org/10.37212/jcnos.683407.
• Yoshida K, Nakai A, Kaneshiro K, Hashimoto N, Suzuki K, Uchida K, Hashimoto T, Kawasaki Y, Tateishi K, Nakagawa N, Shibanuma N, Sakai Y, Hashiramoto A. (2018). TNF-α induces expression of the circadian clock gene Bmal1 via dual calcium-dependent pathways in rheumatoid synovial cells. Biochem Biophys Res Commun. 495(2):1675-1680. doi: 10.1016/j.bbrc.2017.12.015.
• Zhao Y, Zhao B. (2013). Oxidative stress and the pathogenesis of Alzheimer's disease. Oxid Med Cell Longev.13:316523. doi: 10.1155/2013/316523.
• Zhang R, Lahens NF, Ballance HI, Hughes ME, Hogenesch JB. (2014). A circadian gene expression atlas in mammals: implications for biology and medicine. Proc Natl Acad Sci U S A. 111(45):16219-24. doi: 10.1073/pnas.1408886111.
• Zuther P, Gorbey S, Lemmer B. (2009). Chronos-Fit, revised Version 1.06. http://www.ma.uni-heidelberg.de/inst/phar/lehre/chrono.html.