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Protective effects of tetramethylpyrazine on dysfunction of the locus coeruleus in rats exposed to single prolonged stress by anti-ER stress mechanism

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Abstract

Post-traumatic stress disorder (PTSD) is a serious stress-related neuropsychiatric disorder caused by major traumatic events. Abnormal activity of the locus coeruleus (LC)-noradrenergic system is related to the development of PTSD-like symptoms. Our previous studies have indicated that endoplasmic reticulum (ER) stress induced neuronal apoptosis of LC in rats with PTSD. The purpose of this study was to further investigate the role of ER stress pathways in LC neuronal dysfunction and elucidate the effect of the bioactive component tetramethylpyrazine (TMP) against ER stress response. We used an acute exposure to single prolonged stress (SPS) to model PTSD in rats. There were higher norepinephrine (NE) levels in the brain, increased tyrosine hydroxylase expression in LC, and enhanced anxiety-like behaviors in rats exposed to SPS, which were observed by enzyme-linked immunosorbent assay, western blot analysis and elevated plus maze test, respectively. In addition, the three major pathways of ER stress were activated by SPS exposure, which may be involved in the dysregulation of the LC-noradrenergic system of rats with PTSD. Furthermore, we found that TMP administration significantly suppressed the increased responsiveness of LC-noradrenergic system, effectively reduced the anxiety response of SPS rats, and selectively attenuated the activation of pro-apoptotic ER stress pathways. The results suggest that TMP was efficient in improving the LC-NE dysfunction induced by excessive ER stress. TMP exhibited a significant neuroprotective effect and potential therapeutics on PTSD-like symptoms.

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Abbreviations

4-PBA:

4-Phenylbutyric acid

ASK1:

Apoptosis signal-regulating kinase 1

ATF4:

Activating transcription factor 4

ATF6:

Activating transcription factor 6

CHOP:

CCAAT/enhancer-binding protein-homologous protein

eIF2α:

Eukaryotic translation initiation factor 2α

EPM:

Elevated plus maze

ER:

Endoplasmic reticulum

GRP78:

78-KDa glucose-regulated protein

IRE1α:

Inositol-requiring enzyme 1α

JNK:

C-Jun N-terminal kinase

LC:

Locus coeruleus

NE:

Norepinephrine

PERK:

Protein kinase RNA-like ER kinase

PTSD:

Post-traumatic stress disorder

SPS:

Single prolonged stress

TH:

Tyrosine hydroxylase

TMP:

Tetramethylpyrazine

TRAF2:

Tumor necrosis factor receptor–associated factor 2

UPR:

Unfolded protein response

XBP1:

X-box-binding protein 1

References

  • American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders. Fifth Edition. DSM-5. American Psychiatric Association, Washington

    Google Scholar 

  • Bangasser DA, Wiersielis KR, Khantsis S (2016) Sex differences in the locus coeruleus-norepinephrine system and its regulation by stress. Brain Res 1641:177–188

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Brandizzi F (2013) IRE1: ER stress sensor and cell fate executor. Trends Cell Biol 23:547–555

    Article  CAS  PubMed  Google Scholar 

  • Clark EM, Nonarath HJT, Bostrom JR, Link BA (2020) Establishment and validation of an endoplasmic reticulum stress reporter to monitor zebrafish ATF6 activity in development and disease. Dis Model Mech 13(1):dmm041426. https://doi.org/10.1242/dmm.041426

  • Fu S, Wang J, Hao C, Dang H, Jiang S (2019) Tetramethylpyrazine ameliorates depression by inhibiting TLR4-NLRP3 inflammasome signal pathway in mice. Psychopharmacology (berl) 236:2173–2185

    Article  CAS  Google Scholar 

  • George SA, Knox D, Curtis AL, Aldridge JW, Valentino RJ, Liberzon I (2013) Altered locus coeruleus-norepinephrine function following single prolonged stress. Eur J Neurosci 37:901–909

    Article  PubMed  Google Scholar 

  • Geracioti TD Jr, Baker DG, Ekhator NN, West SA, Hill KK, Bruce AB, Schmidt D, Rounds-Kugler B, Yehuda R, Keck PE Jr, Kasckow JW (2001) CSF norepinephrine concentrations in posttraumatic stress disorder. Am J Psychiatry 158:1227–1230

    Article  PubMed  Google Scholar 

  • Glembotski CC, Rosarda JD, Wiseman RL (2019) Proteostasis and beyond: ATF6 in ischemic disease. Trends Mol Med 25:538–550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gong G, Yuan L, Cai L, Ran M, Zhang Y, Gong H, Dai X, Wu W, Dong H (2014) Tetramethylpyrazine suppresses transient oxygen-glucose deprivation-induced connexin32 expression and cell apoptosis via the ERK1/2 and p38 MAPK pathway in cultured hippocampal neurons. PLoS One 9:e105944

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Grillon C, Southwick SM, Charney DS (1996) The psychobiological basis of posttraumatic stress disorder. Mol Psychiatry 1:278–297

    CAS  PubMed  Google Scholar 

  • Hansen N (2017) The longevity of hippocampus-dependent memory is orchestrated by the locus coeruleus-noradrenergic system. Neural Plast 2017:2727602

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • He M, Huang XF, Gao G, Zhou T, Li W, Hu J, Chen J, Li J, Sun T (2019) Olanzapine-induced endoplasmic reticulum stress and inflammation in the hypothalamus were inhibited by an ER stress inhibitor 4-phenylbutyrate. Psychoneuroendocrinology 104:286–299

    Article  CAS  PubMed  Google Scholar 

  • Hetz C (2012) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 13:89–102

    Article  CAS  PubMed  Google Scholar 

  • Hetz C, Chevet E, Harding HP (2013) Targeting the unfolded protein response in disease. Nat Rev Drug Discov 12:703–719

    Article  CAS  PubMed  Google Scholar 

  • Huang S, **ng Y, Liu Y (2019) Emerging roles for the ER stress sensor IRE1α in metabolic regulation and disease. J Biol Chem 294:18726–18741

    Article  PubMed  PubMed Central  Google Scholar 

  • Kalin NH (2020) Novel insights into pathological anxiety and anxiety-related disorders. Am J Psychiatry 177:187–189

    Article  PubMed  Google Scholar 

  • Karam EG, Friedman MJ, Hill ED, Kessler RC, McLaughlin KA, Petukhova M, Sampson L, Shahly V, Angermeyer MC, Bromet EJ, de Girolamo G, de Graaf R, Demyttenaere K, Ferry F, Florescu SE, Haro JM, He Y, Karam AN, Kawakami N, Kovess-Masfety V, Medina-Mora ME, Browne MA, Posada-Villa JA, Shalev AY, Stein DJ, Viana MC, Zarkov Z, Koenen KC (2014) Cumulative traumas and risk thresholds: 12-month PTSD in the World Mental Health (WMH) surveys. Depress Anxiety 31:130–142

    Article  PubMed  Google Scholar 

  • Kimata Y, Kohno K (2011) Endoplasmic reticulum stress-sensing mechanisms in yeast and mammalian cells. Curr Opin Cell Biol 23:135–142

    Article  CAS  PubMed  Google Scholar 

  • Li L, Feng X, Zhou Z, Zhang H, Shi Q, Lei Z, Shen P, Yang Q, Zhao B, Chen S, Li L, Zhang Y, Wen P, Lu Z, Li X, Xu F, Wang L (2018) Stress accelerates defensive responses to looming in mice and involves a locus coeruleus-superior colliculus projection. Curr Biol 28:859–871

    Article  CAS  PubMed  Google Scholar 

  • Liberzon I, Lopez JF, Flagel SB, Vazquez DM, Young EA (1999) Differential regulation of hippocampal glucocorticoid receptors mRNA and fast feedback: relevance to post-traumatic stress disorder. J Neuroendocrinol 11:11–17

    Article  CAS  PubMed  Google Scholar 

  • Liu M, Xu F, Tao T, Song D, Li D, Li Y, Guo Y, Liu X (2016) Molecular mechanisms of stress-induced myocardial injury in a rat model simulating posttraumatic stress disorder. Psychosom Med 78:888–895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu W, Liu K, Zhang S, Shan L, Tang J (2018) Tetramethylpyrazine showed therapeutic effects on sepsis-induced acute lung injury in rats by inhibiting endoplasmic reticulum stress protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling- induced apoptosis of pulmonary microvascular endothelial cells. Med Sci Monit 24:1225–1231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lv L, Jiang SS, Xu J, Gong JB, Cheng Y (2012) Protective effect of ligustrazine against myocardial ischaemia reperfusion in rats: the role of endothelial nitric oxide synthase. Clin Exp Pharmacol Physiol 39:20–27

    Article  CAS  PubMed  Google Scholar 

  • Maeyashiki C, Melhem H, Hering L, Baebler K, Cosin-Roger J, Schefer F, Weder B, Hausmann M, Scharl M, Rogler G, de Vallière C, Ruiz PA (2020) Activation of pH-sensing receptor OGR1 (GPR68) induces ER stress via the IRE1α/JNK pathway in an intestinal epithelial cell model. Sci Rep 10:1438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mak SK, Yu CM, Sun WT, He GW, Liu XC, Yang Q (2017) Tetramethylpyrazine suppresses angiotensin II-induced soluble epoxide hydrolase expression in coronary endothelium via anti-ER stress mechanism. Toxicol Appl Pharmacol 336:84–93

    Article  CAS  PubMed  Google Scholar 

  • Mapanao R, Chang CC, Cheng W, Liu KF (2018) Silencing tyrosine hydroxylase retards depression of immunocompetence of Litopenaeus vannamei under hypothermal stress. Fish Shellfish Immunol 72:519–527

    Article  CAS  PubMed  Google Scholar 

  • Mercado G, Valdés P, Hetz C (2013) An ERcentric view of Parkinson’s disease. Trends Mol Med 19:165–175

    Article  CAS  PubMed  Google Scholar 

  • Naegeli C, Zeffiro T, Piccirelli M, Jaillard A, Weilenmann A, Hassanpour K, Schick M, Rufer M, Orr SP, Mueller-Pfeiffer C (2018) Locus coeruleus activity mediates hyperresponsiveness in posttraumatic stress disorder. Biol Psychiatry 83:254–262

    Article  PubMed  Google Scholar 

  • Paxinos G, Watson C (2004) The rat brain in stereotaxic coordinates, 5th edn. Academic Press, pp 112–119

  • Pitman RK, Rasmusson AM, Koenen KC, Shin LM, Orr SP, Gilbertson MW, Milad MR, Liberzon I (2012) Biological studies of post-traumatic stress disorder. Nat Rev Neurosci 13:769–787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rai U, Kosuru R, Prakash S, Tiwari V, Singh S (2019) Tetramethylpyrazine alleviates diabetic nephropathy through the activation of Akt signalling pathway in rats. Eur J Pharmacol 865:172763

    Article  CAS  PubMed  Google Scholar 

  • Rao RV, Ellerby HM, Bredesen DE (2004) Coupling endoplasmic reticulum stress to the cell death program. Cell Death Differ 11:372–380

    Article  CAS  PubMed  Google Scholar 

  • Rohde C, Becker S, Krähling V (2019) Marburg virus regulates the IRE1/XBP1- dependent unfolded protein response to ensure efficient viral replication. Emerg Microbes Infect 8:1300–1313

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Roy A, Kumar A (2019) ER stress and unfolded protein response in cancer cachexia. Cancers (Basel) 11(12):1929. https://doi.org/10.3390/cancers11121929

  • Sabban EL, Laukova M, Alaluf LG, Olsson E, Serova LI (2015) Locus coeruleus response to single-prolonged stress and early intervention with intranasal neuropeptide Y. J Neurochem 135:975–986

    Article  CAS  PubMed  Google Scholar 

  • Schwarz LA, Luo L (2015) Organization of the locus coeruleus- norepinephrine system. Curr Biol 25:R1051–R1056

    Article  CAS  PubMed  Google Scholar 

  • Seligowski AV, Merker JB, Swiercz AP, Park J, Marvar PJ, Ressler KJ, Jovanovic T (2020) Examining the cardiovascular response to fear extinction in a trauma-exposed sample. J Psychiatr Res 124:85–90

    Article  PubMed  PubMed Central  Google Scholar 

  • Senthilkumaran M, Johnson ME, Bobrovskaya L (2016) The effects of insulin-induced hypoglycaemia on tyrosine hydroxylase phosphorylation in rat brain and adrenal gland. Neurochem Res 41:1612–1624

    Article  CAS  PubMed  Google Scholar 

  • Serova LI, Tillinger A, Alaluf LG, Laukova M, Keegan K, Sabban EL (2013) Single intranasal neuropeptide Y infusion attenuates development of PTSD-like symptoms to traumatic stress in rats. Neuroscience 236:298–312

    Article  CAS  PubMed  Google Scholar 

  • Sharma M, Naura AS, Singla SK (2019) Modulatory effect of 4-phenyl butyric acid on hyperoxaluria-induced renal injury and inflammation. Mol Cell Biochem 451:185–196

    Article  CAS  PubMed  Google Scholar 

  • Shore GC, Papa FR, Oakes SA (2011) Signaling cell death from the endoplasmic reticulum stress response. Curr Opin Cell Biol 23:143–149

    Article  CAS  PubMed  Google Scholar 

  • Van Bockstaele EJ, Valentino RJ (2013) Neuropeptide regulation of the locus coeruleus and opiate-induced plasticity of stress responses. Adv Pharmacol 68:405–420

    Article  PubMed  PubMed Central  Google Scholar 

  • Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334:1081–1086

    Article  CAS  PubMed  Google Scholar 

  • Wang K, Zhu X, Zhang K, Zhou F, Zhu L (2017) Neuroprotective effect of tetramethylpyrazine against all-trans-retinal toxicity in the differentiated Y-79 cells via upregulation of IRBP expression. Exp Cell Res 359:120–128

    Article  CAS  PubMed  Google Scholar 

  • Wu X, **n Z, Zhang W, Zheng S, Wu J, Chen K, Wang H, Zhu X, Li Z, Duan Z, Li H, Liu Y (2014) A missense polymorphism in ATF6 gene is associated with susceptibility to hepatocellular carcinoma probably by altering ATF6 level. Int J Cancer 135:61–68

    Article  CAS  PubMed  Google Scholar 

  • Yin J, Gu L, Wang Y, Fan N, Ma Y, Peng Y (2015) Rapamycin improves palmitate-induced ER stress/NFκB pathways associated with stimulating autophagy in adipocytes. Mediators Inflamm 2015:272313. https://doi.org/10.1155/2015/272313

  • Zeng T, Peng L, Chao H, ** H, Fu B, Wang Y, Zhu Z, Wang G (2015) IRE1α-TRAF2-ASK1 complex-mediated endoplasmic reticulum stress and mitochondrial dysfunction contribute to CXC195-induced apoptosis in human bladder carcinoma T24 cells. Biochem Biophys Res Commun 460:530–536

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Liang Y, Lin Y, Liu Y, YouYou Y, W., (2016) IRE1α-TRAF2-ASK1 pathway is involved in CSTMP-induced apoptosis and ER stress in human non-small cell lung cancer A549 cells. Biomed Pharmacother 82:281–289

    Article  CAS  PubMed  Google Scholar 

  • Zhao W, Han F, Shi Y (2016) IRE1α pathway of endoplasmic reticulum stress induces neuronal apoptosis in the locus coeruleus of rats under single prolonged stress. Prog Neuropsychopharmacol Biol Psychiatry 69:11–18

    Article  CAS  PubMed  Google Scholar 

  • Zinszner H, Kuroda M, Wang X, Batchvarova N, Lightfoot RT, Remotti H, Stevens JL, Ron D (1998) CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev 12:982–995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank T. Liu, H. Li, and D. Wang for the technical assistance.

Funding

This work was supported by the financial grants from the Natural Science Foundation of Shaanxi Province, China (2020JM-328); the key Research and Development Program of Shandong Province, China (2018GSF118129); the Science and Technology Development Plan of Chinese Medicine of Shandong Province, China (2017–234); the National Natural Science Foundation of China (81701301); the Natural Science Foundation of Shandong Province, China (ZR2018PH017); the 2019 National Undergraduate Innovation and Entrepreneurship Training Program, China (201910440007), and the 2018 Binzhou Medical University Undergraduate Innovation and Entrepreneurship Training Program, China (201810440136).

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Authors and Affiliations

  1. Department of Histology and Embryology, Binzhou Medical University, No. 346 Guanhai Road, Yantai, 264003, Shandong, China

    Yun Hou, Feibo Xu & Wei Zhao

  2. Department of Intensive Care Unit, Yantai Yuhuangding Hospital Qingdao University, Yantai, 264000, Shandong, China

    Meifeng Li

  3. Department of Medical Psychology, Fourth Military Medical University, No. 169 West Changle Road, **’an, 710032, China

    Yinchuan **

  4. Department of Anatomy, Binzhou Medical University, No. 346 Guanhai Road, Yantai, 264003, Shandong, China

    Shaohua Liang

  5. Clinical Medicine College, Binzhou Medical University, No. 346 Guanhai Road, Yantai, 264003, Shandong, China

    Chen Xue & Kaili Wang

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  1. Yun Hou
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  3. Yinchuan **
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  4. Feibo Xu
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  8. Wei Zhao
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Contributions

WZ, YH, and YJ designed the study and provided technical guidance. CX and KW performed the study and acquired the data. FX and SL analyzed the data. WZ and ML wrote the manuscript. All authors reviewed and approved the final manuscript.

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Correspondence to Wei Zhao.

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Yun Hou, Meifeng Li and Yinchuan ** These authors contributed equally to this work

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Hou, Y., Li, M., **, Y. et al. Protective effects of tetramethylpyrazine on dysfunction of the locus coeruleus in rats exposed to single prolonged stress by anti-ER stress mechanism. Psychopharmacology 238, 2923–2936 (2021). https://doi.org/10.1007/s00213-021-05908-6

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