Chronic stress-induced anxiety-like behavior, hippocampal oxidative, and endoplasmic reticulum stress are reversed by young plasma transfusion in aged adult rats

Document Type : Original Article

Authors

1 Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

2 Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

3 Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

4 Department of Biomedical Education, California Health Sciences University, College of Osteopathic Medicine, Clovis, CA, USA

Abstract

Objective(s): Aging and stress synergistically induce behavioral dysfunctions associated with oxidative and endoplasmic reticulum (ER) stress in brain regions. Considering the rejuvenating effects of young plasma on aging brain function, in the current study, we examined the effects of young plasma administration on anxiety-like behavior, NADH oxidase, NADPH oxidase, and ER stress markers in the hippocampus of old male rats.
Materials and Methods: Young (3 months old) and aged (22 months old) rats were randomly assigned into five groups: young control (Y), aged control (A), aged rats subjected to chronic stress for four weeks (A+S), aged rats subjected to chronic stress and treated with old plasma (A+S+OP), and aged rats subjected to chronic stress and treated with young plasma (A+S+YP). Systemic injection of (1 ml) young and old plasma was performed for four weeks (3 times/week). 
Results: Young plasma transfusion significantly improved anxiety-like behavior in aged rats and modulated oxidative stress in the hippocampus, evidenced by the increased NADH oxidase (NOX) activity and the reduced NADPH oxidase. In addition, the levels of C/EBP homologous protein (CHOP) and Glucose-Regulated Protein 78 (GRP-78), as ER stress markers, markedly reduced in the hippocampus following the administration of young plasma. 
Conclusion: These findings suggest that young plasma transfusion could reverse anxiety-like behavior in stress-exposed aged rats by modulating the hippocampal oxidative and ER stress markers.

Keywords

Main Subjects

References

1. Lee JE, Kwon HJ, Choi J, Seo JS, Han PL. Aging increases vulnerability to stress-induced depression via the upregulation of NADPH oxidase in mice. Commun Biol 2020; 3:292-306.
2. Chung HY, Cesari M, Anton S, Marzetti E, Giovannini S, Seo AY, et al. Molecular inflammation: Underpinnings of aging and age-related diseases. Ageing Res Rev 2009; 8:18–30. 
3. McEwen BS and Morrison JH. The brain on stress: Vulnerability and plasticity of the prefrontal cortex over the life course. Neuron 2013; 79:16–29. 
4. Javani G, Babri S, Farajdokht F, Ghaffari-Nasab A, Mohaddes G. Mitochondrial transplantation improves anxiety- and depression-like behaviors in aged stress-exposed rats. Mech Ageing Dev 2022; 202:111632. 
5. Zhu S, Shi R, Wang J, Wang JF, and Li XM. Unpredictable chronic mild stress not chronic restraint stress, induces depressive behaviours in mice. Neuroreport 2014; 25:1151–1155. 
6. Lindqvist D, Dhabhar FS, James SJ, Hough CM, Jain FA, Bersani FS, et al. Oxidative stress, inflammation and treatment response in major depression. Psychoneuroendocrinology 2017; 76:197–205. 
7. Stanger O, Renner W, Khoschsorur G, Rigler B, Wascher TC. NADH/NADPH oxidase p22 phox C242T polymorphism and lipid peroxidation in coronary artery disease. Clin Physiol 2001; 21:718–722. 
8. Avetisyan AV, Samokhin AN, Alexandrova IY, Zinovkin RA, Simonyan RA, Bobkova NV. Mitochondrial dysfunction in neocortex and hippocampus of olfactory bulbectomized mice, a model of Alzheimer’s disease. Biochem 2016; 81:615–623. 
9. Emelyanova L, Preston C, Gupta A, Viqar M, Negmadjanov U, Edwards S, et al. Effect of aging on mitochondrial energetics in the human atria. J Gerontol A Biol Sci Med Sci 2018; 73:608–616. 
10. Madrigal JLM, Olivenza R, Moro MA, Lizasoain I, Lorenzo P, Rodrigo J, et al. Glutathione depletion, lipid peroxidation and mitochondrial dysfunction are induced by chronic stress in rat brain. Neuropsychopharmacology 2001; 24:420–429. 
11. Murphy MP. How mitochondria produce reactive oxygen species. Biochem J 2009; 417:1–13. 
12. Popov D. Endoplasmic reticulum stress and the on site function of resident PTP1B. Biochem Biophys Res Commun 2012; 422:535–538. 
13. Mao J, Hu Y, Ruan L, Ji Y, and Lou Z. Role of endoplasmic reticulum stress in depression (Review). Mol Med Rep 2019; 20:4774–4780. 
14. Brown MK and Naidoo N. The endoplasmic reticulum stress response in aging and age-related diseases. Front Physiol 2012; 3: 263-Last page. 
15. Austin RC. The unfolded protein response in health and disease. Antioxidants Redox Signal 2009; 11:2279–2287. 
16. Jangra A, Sriram CS, Lahkar M. Lipopolysaccharide-induced behavioral alterations are alleviated by sodium phenylbutyrate via attenuation of oxidative stress and neuroinflammatory cascade. Inflammation 2016; 39:1441–1452. 
17. Ghaffari-Nasab A, Badalzadeh R, Mohaddes G, Alipour MR. Young plasma administration mitigates depression-like behaviours in chronic mild stress-exposed aged rats by attenuating apoptosis in prefrontal cortex. Exp Physiol 2021; 106:1621–1630. 
18. Ghosh AK, O’Brien M, Mau T, Qi N, Yung R. Adipose tissue senescence and inflammation in aging is reversed by the young milieu. J Gerontol A Biol Sci Med Sci 2019; 74:1709–1715. 
19. Pan M, Wang P, Zheng C, Zhang H, Lin S, Shao B, et al. Aging systemic milieu impairs outcome after ischemic stroke in rats. Aging Dis 2017; 8:519–530. 
20. Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med 2014; 20:659–663. 
21. Ghaffari-Nasab A, Badalzadeh R, Mohaddes G, Javani G, Ebrahimi-kalan A, Alipour MR. Young plasma induces antidepressant-like effects in aged rats subjected to chronic mild stress by suppressing indoleamine 2,3-dioxygenase enzyme and kynurenine pathway in the prefrontal cortex. Neurochem Res 2022; 47:358–371. 
22. Javani G, Babri S, Farajdokht F, Ghaffari-Nasab A, Mohaddes G. Mitotherapy restores hippocampal mitochondrial function and cognitive impairment in aged male rats subjected to chronic mild stress. Biogerontology 2023; 1–17. 
23. Shytikov D, Balva O, Debonneuil E, Glukhovskiy P, and Pishel I. Aged mice repeatedly injected with plasma from young mice: A survival study. Biores Open Access 2014; 3:226–232. 
24. Garrido P. Aging and stress: Past hypotheses, present approaches and perspectives. Aging Dis 2011; 2:80–99. 
25. Bachis A, Cruz MI, Nosheny RL, and Mocchetti I. Chronic unpredictable stress promotes neuronal apoptosis in the cerebral cortex. Neurosci Lett 2008; 442:104–108. 
26. Herrera-Pérez JJ, Martínez-Mota L, and Fernández-Guasti A. Aging increases the susceptibility to develop anhedonia in male rats. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:1798–1803. 
27. Buechel HM, Popovic J, Staggs K, Anderson KL, Thibault O, and Blalock EM. Aged rats are hypo-responsive to acute restraint: Implications for psychosocial stress in aging. Front Aging Neurosci 2014; 6. 
28. Wilson RS, Begeny CT, Boyle PA, Schneider JA, Bennett DA. Vulnerability to stress, anxiety, and development of dementia in old age. Am J Geriatr Psychiatry 2011; 19:327–334. 
29. Vida C, Gonzalez E, and Fuente M. Increase of oxidation and inflammation in nervous and immune systems with aging and anxiety. Curr Pharm Des 2014; 20:4656–4678. 
30. Luine VN, Beck KD, Bowman RE, Frankfurt M, Maclusky NJ. Chronic stress and neural function: Accounting for sex and age. J Neuroendocrinol 2007; 19:743–751. 
31. Li N, Zhang X, Gu Z, Su C, and Lian H. Young plasma attenuates cognitive impairment and the cortical hemorrhage area in cerebral amyloid angiopathy model mice. Ann Transl Med 2021; 9:147–147. 
32. Sun N, Youle RJ, and Finkel T. The mitochondrial basis of aging. Mol Cell 2016; 61:654–666. 
33. Hunter RG, Seligsohn M, Rubin TG, Griffiths BB, Ozdemir Y, Pfaff DW, et al. Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor. Proc Natl Acad Sci U S A 2016; 113:9099–9104. 
34. Kiss T, Tarantini S, Csipo T, Balasubramanian P, Nyúl-Tóth Á, Yabluchanskiy A, et al. Circulating anti-geronic factors from heterochonic parabionts promote vascular rejuvenation in aged mice: transcriptional footprint of mitochondrial protection, attenuation of oxidative stress, and rescue of endothelial function by young blood. GeroScience 2020; 42:727–748. 
35. Das A, Huang GX, Bonkowski MS, Longchamp A, Li C, Schultz MB, et al. Impairment of an endothelial NAD+-H2S signaling network is a reversible cause of vascular aging. Cell 2018; 173:74-89.e20. 
36. You JM, Yun SJ, Nam KN, Kang C, Won R, Lee EH. Mechanism of glucocorticoid-induced oxidative stress in rat hippocampal slice cultures. Can J Physiol Pharmacol 2009; 87:440–447. 
37. Seo JS, Park JY, Choi J, Kim TK, Shin JH, Lee JK, et al. NADPH oxidase mediates depressive behavior induced by chronic stress in mice. J Neurosci 2012; 32:9690–9699. 
38. Petrovic R, Puskas L, Jevtic Dozudic G, Stojkovic T, Velimirovic M, Nikolic T, et al. NADPH oxidase and redox status in amygdala, hippocampus and cortex of male Wistar rats in an animal model of post-traumatic stress disorder. Stress 2018; 21:494–502. 
39. Bedard K and Krause KH. The NOX family of ROS-generating NADPH oxidases: Physiology and pathophysiology. Physiol Rev 2007; 87:245–313. 
40. Ewald CY. Redox signaling of nadph oxidases regulates oxidative stress responses, immunity and aging. Antioxidants 2018; 7:130-145. 
41. Martínez G, Duran-Aniotz C, Cabral-Miranda F, Vivar JP, Hetz C. Endoplasmic reticulum proteostasis impairment in aging. Aging Cell 2017; 16:615–623. 
42. Chanmanee T, Wongpun J, Tocharus C, Govitrapong P, Tocharus J. The effects of agomelatine on endoplasmic reticulum stress related to mitochondrial dysfunction in hippocampus of aging rat model. Chem Biol Interact 2022; 351:109703. 
43. Chadwick SR and Lajoie P. Endoplasmic reticulum stress coping mechanisms and lifespan regulation in health and diseases. Front Cell Dev Biol 2019; 7:84-91. 
44. Timberlake MA and Dwivedi Y. Altered expression of endoplasmic reticulum stress associated genes in hippocampus of learned helpless rats: Relevance to depression pathophysiology. Front Pharmacol 2016; 6:319-327. 
45. Zhang Y, Liu W, Zhou Y, Ma C, Li S, and Cong B. Endoplasmic reticulum stress is involved in restraint stress-induced hippocampal apoptosis and cognitive impairments in rats. Physiol Behav 2014; 131:41–48. 
46. Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 2011; 477:90–96. 
47. Middeldorp J, Lehallier B, Villeda SA, Miedema SSM, Evans E, Czirr E, et al. Preclinical assessment of young blood plasma for Alzheimer disease. JAMA Neurol 2016; 73:1325–1333. 
48. Zhao Y, Qian R, Zhang J, Liu F, Iqbal K, Dai CL, et al. Young blood plasma reduces Alzheimer’s disease-like brain pathologies and ameliorates cognitive impairment in 3×Tg-AD mice. Alzheimer’s Res Ther 2020; 12:1–13. 
49. Liu A, Guo E, Yang J, Yang Y, Liu S, Jiang X, et al. Young plasma reverses age-dependent alterations in hepatic function through the restoration of autophagy. Aging Cell 2018; 17:e12708. 
50. Bouchard J and Villeda SA. Aging and brain rejuvenation as systemic events. J Neurochem 2015; 132:5–19. 
51. Popescu BO, Toescu EC, Popescu LM, Bajenaru O, Muresanu DF, Schultzberg M, et al. Blood-brain barrier alterations in ageing and dementia. J Neurol Sci 2009; 283:99–106. 
52. Rebo J, Mehdipour M, Gathwala R, Causey K, Liu Y, Conboy MJ, et al. A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood. Nat Commun 2016; 7:13363-13373. 
53. Mehdipour M, Mehdipour T, Skinner CM, Wong N, Liu C, Chen CC, et al. Plasma dilution improves cognition and attenuates neuroinflammation in old mice. GeroScience 2021; 43:1–18. 
54. Höving AL, Schmidt KE, Kaltschmidt B, Kaltschmidt C, Knabbe C. The Role of blood-derived factors in protection and regeneration of aged tissues. Int J Mol Sci 2022; 23:9626-9646. 
55. Kang JS and Yang YR. Circulating plasma factors involved in rejuvenation. Aging (Albany NY) 2020; 12:23394–23408. 
56. Gan KJ and Südhof TC. Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment. Proc Natl Acad Sci U S A 2019; 116:12524–12533. 
57. Wang W, Wang L, Ruan L, Oh J, Dong X, Zhuge Q, et al. Extracellular vesicles extracted from young donor serum attenuate inflammaging via partially rejuvenating aged T-cell immunotolerance. FASEB J 2018; 32:5899–5912. 
58. Lee M, Im W, and Kim M. Exosomes as a potential messenger unit during heterochronic parabiosis for amelioration of Huntington’s disease. Neurobiol Dis 2021; 155:105374. 
59. Sharon JS, Deutsch GK, Tian L, Richardson K, Coburn M, Gaudioso JL, et al. Safety, tolerability, and feasibility of young plasma infusion in the plasma for Alzheimer symptom amelioration study: A randomized clinical trial. JAMA Neurol 2019; 76:35–40. 
60. Kim D, Kiprov DD, Luellen C, Lieb M, Liu C, Watanabe E, et al. Old plasma dilution reduces human biological age: A clinical study. GeroScience 2022; 44:2701-2720. 
Iranian Journal of Basic Medical Sciences
Volume 27, Issue 1
January 2024
Pages 114-121

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