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International Journal of Brain Sciences Review Article

Circadian Regulation of Lipid Peroxidation in the Brain: Linking Ferroptosis to Neurodegenerative Vulnerability

  1. Suraj Sen Dept. of Pharmacy, Harishchandra Pharmacy College
  2. Anit Jha Dept. of Pharmacy, Harishchandra Pharmacy College
  3. Rajeev Ratan Dept. of Pharmacy, Harishchandra Pharmacy College
  4. Neeraj Yadav Dept. of Pharmacy, Harishchandra Pharmacy College
  5. Ayush Bhardwaj Dept. of Pharmacy, Harishchandra Pharmacy College

Abstract

The human brain operates through highly coordinated physiological and biochemical processes that regulate cognition, behavior, and neural adaptability. Central to these processes are mechanisms governing brain function, neurophysiology, and neuroplasticity, which are increasingly recognized to be influenced by circadian rhythms. Recent advances in cognitive neuroscience, neuroimaging, and behavioral neuroscience have revealed that disruptions in circadian regulation can significantly impact oxidative balance within the brain, particularly through enhanced lipid peroxidation. Lipid peroxidation, a process involving oxidative degradation of membrane lipids, plays a crucial role in neuronal dysfunction and is closely associated with ferroptosis, an iron-dependent form of regulated cell death. The integration of neuropharmacology and drug development strategies has highlighted ferroptosis as a key therapeutic target in neurodegenerative conditions. Moreover, clinical neuropsychology studies indicate that oxidative damage and circadian misalignment contribute to cognitive decline and behavioral impairments. Neuroimaging and neurophysiological assessments further demonstrate that circadian disruption affects neuronal signaling, synaptic plasticity, and brain metabolism. Developmental neuroscience also suggests that early-life circadian disturbances may predispose individuals to long-term neurological vulnerabilities. The role of neuroplasticity in adapting to oxidative stress underscores the importance of maintaining circadian integrity for optimal brain health. This review explores the intersection of circadian rhythms, lipid peroxidation, and ferroptosis within the broader framework of neuroscience disciplines. It emphasizes how integrating concepts from cognitive, behavioral, and clinical neuroscience with pharmacological innovations can provide novel insights into neurodegenerative disease mechanisms. Additionally, it highlights emerging therapeutic approaches, including chronopharmacology and targeted antioxidant strategies, aimed at preserving neuronal function and improving clinical outcomes.

Keywords

References (48)

  1. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley
  2. AM, Yang WS, Morrison B. Ferroptosis: an iron-dependent form of nonapoptotic cell death. cell. 2012 May
  3. 25;149(5):1060-72.
  4. Stockwell BR, Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascón S, Hatzios SK, Kagan VE,
  5. Noel K. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. cell. 2017
  6. Oct 5;171(2):273-85.
  7. Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nature reviews
  8. Molecular cell biology. 2021 Apr;22(4):266-82.
  9. Yang WS, Stockwell BR. Ferroptosis: death by lipid peroxidation. Trends in cell biology. 2016 Mar
  10. 1;26(3):165-76.
  11. Ursini F, Maiorino M, Forman HJ. Redox homeostasis: The Golden Mean of healthy living. Redox biology.
  12. 2016 Aug 1;8:205-15.
  13. Brigelius-Flohé R, Maiorino M. Glutathione peroxidases. Biochimica et Biophysica Acta (BBA)-General
  14. Subjects. 2013 May 1;1830(5):3289-303.
  15. Hardeland R. Melatonin in aging and disease—multiple consequences of reduced secretion, options and
  16. limits of treatment. Aging and disease. 2011 Feb 10;3(2):194.
  17. Musiek ES, Holtzman DM. Mechanisms linking circadian clocks, sleep, and neurodegeneration. Science.
  18. 2016 Nov 25;354(6315):1004-8.
  19. Hood S, Amir S. The aging clock: circadian rhythms and later life. The Journal of clinical investigation. 2017
  20. Feb 1;127(2):437-46.
  21. Kondratova AA, Kondratov RV. The circadian clock and pathology of the ageing brain. Nature Reviews
  22. Neuroscience. 2012 May;13(5):325-35.
  23. Zhang Y, Chen X, Gueydan C, Han J. Plasma membrane changes during programmed cell deaths. Cell
  24. research. 2018 Jan;28(1):9-21.
  25. Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, Herbach N, Aichler M,
  26. Walch A, Eggenhofer E, Basavarajappa D. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal
  27. failure in mice. Nature cell biology. 2014 Dec;16(12):1180-91.
  28. Do Van B, Gouel F, Jonneaux A, Timmerman K, Gelé P, Pétrault M, Bastide M, Laloux C, Moreau C, Bordet
  29. R, Devos D. Ferroptosis, a newly characterized form of cell death in Parkinson's disease that is regulated by
  30. PKC. Neurobiology of disease. 2016 Oct 1;94:169-78.
  31. Hambright WS, Fonseca RS, Chen L, Na R, Ran Q. Ablation of ferroptosis regulator glutathione peroxidase 4
  32. in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox biology. 2017 Aug 1;12:8-
  33. Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: production, metabolism, and signaling mechanisms of
  34. malondialdehyde and 4‐hydroxy‐2‐nonenal. Oxidative medicine and cellular longevity. 2014;2014(1):360438.
  35. Butterfield DA, Halliwell B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nature
  36. Reviews Neuroscience. 2019 Mar;20(3):148-60.
  37. Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L. The role of iron in brain ageing and neurodegenerative
  38. disorders. The Lancet Neurology. 2014 Oct 1;13(10):1045-60.
  39. J. Reiter R, Tan DX, Rosales-Corral S, C. Manchester L. The universal nature, unequal distribution and
  40. antioxidant functions of melatonin and its derivatives. Mini reviews in medicinal chemistry. 2013 Mar
  41. 1;13(3):373-84.
  42. Terman M, Terman JS. Light therapy for seasonal and nonseasonal depression: efficacy, protocol, safety, and
  43. side effects. CNS spectrums. 2005 Aug;10(8):647-63.
  44. Cermakian N, Boivin DB. The regulation of central and peripheral circadian clocks in humans. Obesity
  45. Reviews. 2009 Nov;10:25-36.
  46. Li J, Cao F, Yin HL, Huang ZJ, Lin ZT, Mao N, Sun B, Wang G. Ferroptosis: past, present and future. Cell
  47. death & disease. 2020 Feb 3;11(2):88.
  48. Doll S, Conrad M. Iron and ferroptosis: a still ill‐defined liaison. IUBMB life. 2017 Jun;69(6):423-34.