Skip to main content

Advertisement

SpringerLink
Log in

The Protective Effects of Up-Regulating Prostacyclin Biosynthesis on Neuron Survival in Hippocampus

  • ORIGINAL ARTICLE
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

Cellular arachidonic acid (AA), an unsaturated fatty acid found ubiquitously in plasma membranes, is metabolized to different prostanoids, such as prostacyclin (PGI2) and prostaglandin E2 (PGE2), by the three-step reactions coupling the upstream cyclooxygenase (COX) isoforms (COX-1 and COX-2) with the corresponding individual downstream synthases. While the vascular actions of these prostanoids are well-characterized, their specific roles in the hippocampus, a major brain area for memory, are poorly understood. The major obstacle for its understanding in the brain was to mimic the biosynthesis of each prostanoid. To solve the problem, we utilized Single-Chain Hybrid Enzyme Complexes (SCHECs), which could successfully control cellular AA metabolites to the desired PGI2 or PGE2. Our in vitro studies suggested that neurons with higher PGI2 content and lower PGE2 content exhibited survival protection and resistance to Amyloid-β-induced neurotoxicity. Further extending to an in vivo model, the hybrid of PGI2-producing transgenic mice and Alzheimer’s disease (AD) mice showed restored long-term memory. These findings suggested that the vascular prostanoids, PGI2 and PGE2, exerted significant regulatory influences on neuronal protection (by PGI2), or damage (by PGE2) in the hippocampus, and raised a concern that the wide uses of aspirin in cardiovascular diseases may exert negative impacts on neurodegenerative protection.

Our study intended to understand the crosstalk of prostanoids in the hippocampus, a major brain area impacted in AD, by using hybrid enzymes to redirect the synthesis of prostanoids to PGE2 and PGI2, respectively. Our data indicated that during inflammation, the vascular mediators, PGI2 and PGE2, exerted significant regulatory influences on neuronal protection (by PGI2), or damage (by PGE2) in the hippocampus. These findings also raised a concern that the widely uses of non-steroidal anti-inflammatory drugs in cardiovascular diseases may exert negative impacts on neurodegenerative protection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Akasaka H, Ruan K-H (2016) Identification of the two-phase mechanism of arachidonic acid regulating inflammatory prostaglandin E2 biosynthesis by targeting COX-2 and mPGES-1. Arch Biochem Biophys 603:29–37

    CAS  PubMed  Google Scholar 

  • Akitake Y, Nakatani Y, Kamei D, Hosokawa M, Akatsu H, Uematsu S, Akira S, Kudo I, Hara S, Takahashi M (2013) Microsomal prostaglandin E synthase-1 is induced in alzheimer's disease and its deletion mitigates alzheimer's disease-like pathology in a mouse model. J Neurosci Res 91(7):909–919

    CAS  PubMed  Google Scholar 

  • An Y, Belevych N, Wang Y, Zhang H, Nasse JS, Herschman H, Chen Q, Tarr A, Liu X, Quan N (2014) Prostacyclin mediates endothelial COX-2-dependent neuroprotective effects during excitotoxic brain injury. J Inflamm Res 7:57–67

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bley KR, Hunter JC, Eglen RM, Smith JAM (1998) The role of IP prostanoid receptors in inflammatory pain. Trends Pharmacol Sci 19(4):141–147

    CAS  PubMed  Google Scholar 

  • Bley KR, Bhattacharya A, Daniels DV, Gever J, Jahangir A, O'Yang C, Smith S, Srinivasan D, Ford AP, Jett MF (2006) RO1138452 and RO3244794: characterization of structurally distinct, potent and selective IP (prostacyclin) receptor antagonists. Br J Pharmacol 147(3):335–345

    CAS  PubMed  Google Scholar 

  • Caceres A, Banker G, Steward O, Binder L, Payne M (1984) MAP2 is localized to the dendrites of hippocampal neurons which develop in culture. Brain Res 315(2):314–318

    CAS  PubMed  Google Scholar 

  • Cazevieille C, Muller A, Bonne C (1993) Prostacyclin (PGI2) protects rat cortical neurons in culture against hypoxia/reoxygenation and glutamate-induced injury. Neurosci Lett 160(1):106–108

    CAS  PubMed  Google Scholar 

  • Deng Y, Yang Z, Terry T, Pan S, Woodside DG, Wang J et al (2016) Prostacyclin-producing human mesenchymal cells target H19 lncRNA to augment endogenous progenitor function in hindlimb ischaemia. Nat Commun 7:11276

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dotti CG, Sullivan CA, Banker GA (1988) The establishment of polarity by hippocampal neurons in culture. J Neurosci 8(4):1454–1468

    CAS  PubMed  PubMed Central  Google Scholar 

  • Egan KM, Lawson JA, Fries S, Koller B, Rader DJ, Smyth EM, Fitzgerald GA (2004) COX-2-derived prostacyclin confers atheroprotection on female mice. Science. 306(5703):1954–1957

    CAS  PubMed  Google Scholar 

  • Ganesh T (2013) Prostanoid receptor EP2 as a therapeutic target: Miniperspective. J Med Chem 57(11):4454–4465

    PubMed  PubMed Central  Google Scholar 

  • Griñán-Ferré C, Sarroca S, Ivanova A, Puigoriol-Illamola D, Aguado F, Camins A, Sanfeliu C, Pallàs M (2016) Epigenetic mechanisms underlying cognitive impairment and Alzheimer disease hallmarks in 5XFAD mice. Aging (Albany NY) 8(4):664–684

    Google Scholar 

  • He T, Santhanam AR, Lu T, d'Uscio LV, Katusic ZS (2017) Role of prostacyclin signaling in endothelial production of soluble amyloid precursor protein-α in cerebral microvessels. J Cereb Blood Flow Metab 37(1):106–122

    CAS  PubMed  Google Scholar 

  • Hein AM, O'Banion MK (2009) Neuroinflammation and memory: the role of prostaglandins. Mol Neurobiol 40(1):15–32

    CAS  PubMed  PubMed Central  Google Scholar 

  • Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT (2013) NLRP3 is activated in Alzheimer/'s disease and contributes to pathology in APP/PS1 mice. Nature. 493(7434):674–678

    CAS  PubMed  Google Scholar 

  • Iii GMJ, Lee S-H, Singh D, Yuan Y, Ng Y-G, Reichardt LF et al (2012) Culturing pyramidal neurons from the early postnatal mouse hippocampus and cortex. Nat Protoc 7(9):1741–1754

    Google Scholar 

  • Jaturapatporn D, Isaac MGEKN, McCleery J, Tabet N (2012) Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer's disease. Cochrane Database Syst Rev 2

  • Jiang J, Dingledine R (2013) Prostaglandin receptor EP2 in the crosshairs of anti-inflammation, anti-cancer, and neuroprotection. Trends Pharmacol Sci 34(7):413–423

    CAS  PubMed  Google Scholar 

  • Kaur G, Dufour JM (2014) Cell lines. Spermatogenesis. 2(1):1–5

    CAS  Google Scholar 

  • Lin Y-Z, Deng H, Ruan K-H (2000) Topology of catalytic portion of prostaglandin I2 synthase: identification by molecular modeling-guided site-specific antibodies. Arch Biochem Biophys 379(2):188–197

    CAS  PubMed  Google Scholar 

  • Ling Q-l, Murdoch E, Ruan K-H (2016) How can we address the controversies surrounding the use of NSAIDS in neurodegeneration? Future Med Chem 8(11):1153–1155

    CAS  PubMed  Google Scholar 

  • Ling Q-L, Mohite AJ, Murdoch E, Akasaka H, Li Q-Y, So S-P, Ruan KH (2018) Creating a mouse model resistant to induced ischemic stroke and cardiovascular damage. Sci Rep 8(1):1653

    PubMed  PubMed Central  Google Scholar 

  • Lundblad C, Grände PO, Bentzer P (2008) Increased cortical cell loss and prolonged hemodynamic depression after traumatic brain injury in mice lacking the IP receptor for prostacyclin. J Cereb Blood Flow Metab 28(2):367–376

    CAS  PubMed  Google Scholar 

  • Muramatsu R, Takahashi C, Miyake S, Fujimura H, Mochizuki H, Yamashita T (2012) Angiogenesis induced by CNS inflammation promotes neuronal remodeling through vessel-derived prostacyclin. Nat Med 18(11):1658–1664

    CAS  PubMed  Google Scholar 

  • Ransohoff RM (2016) How neuroinflammation contributes to neurodegeneration. Science. 353(6301):777–783

    CAS  PubMed  Google Scholar 

  • Ray J, Peterson DA, Schinstine M, Gage FH (1993) Proliferation, differentiation, and long-term culture of primary hippocampal neurons. Proc Natl Acad Sci 90(8):3602–3606

    CAS  PubMed  Google Scholar 

  • Ruan K-H, Deng H, So S-P (2006) Engineering of a protein with cyclooxygenase and prostacyclin synthase activities that converts Arachidonic acid to prostacyclin†. Biochemistry. 45(47):14003–14011

    CAS  PubMed  Google Scholar 

  • Ruan KH, So SP, Cervantes V, Wu H, Wijaya C, Jentzen RR (2008) An active triple-catalytic hybrid enzyme engineered by linking cyclo-oxygenase isoform-1 to prostacyclin synthase that can constantly biosynthesize prostacyclin, the vascular protector. FEBS J 275(23):5820–5829

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ruan KH, Cervantes V, So SP (2009) Engineering of a novel hybrid enzyme: an anti-inflammatory drug target with triple catalytic activities directly converting arachidonic acid into the inflammatory prostaglandin E2. Protein Eng Des Sel 22(12):733–740

    CAS  PubMed  PubMed Central  Google Scholar 

  • Samaroo HD, Opsahl AC, Schreiber J, O'Neill SM, Marconi M, Qian J, Carvajal-Gonzalez S, Tate B, Milici AJ, Bales KR, Stephenson DT (2012) High throughput object-based image analysis of β-amyloid plaques in human and transgenic mouse brain. J Neurosci Methods 204(1):179–188

    PubMed  Google Scholar 

  • Satoh T, Ishikawa Y, Kataoka Y, Cui Y, Yanase H, Kato K et al (1999) CNS-specific prostacyclin ligands as neuronal survival-promoting factors in the brain. Eur J Neurosci 11(9):3115–3124

    CAS  PubMed  Google Scholar 

  • Siegle I, Klein T, Zou M-H, Fritz P, Kömhoff M (2000) Distribution and cellular localization of prostacyclin synthase in human brain. J Histochem Cytochem 48(5):631–641

    CAS  PubMed  Google Scholar 

  • Smyth EM, Grosser T, Wang M, Yu Y, FitzGerald GA (2009) Prostanoids in health and disease. J Lipid Res 50(Supplement):S423–S428

  • Stitham J, Midgett C, Martin KA, Hwa J (2011) Prostacyclin: An inflammatory paradox. Front Pharmacol 2:24

    CAS  PubMed  PubMed Central  Google Scholar 

  • Takechi H, Matsumura K, Watanabe Y, Kato K, Noyori R, Suzuki M et al (1996) A novel subtype of the prostacyclin receptor expressed in the central nervous system. J Biol Chem 271(10):5901–5906

    CAS  PubMed  Google Scholar 

  • Tsai MAY, Shyue S, Weng C, Chung Y, Liou D, Huang CHI et al (2005) Effect of enhanced prostacyclin synthesis by adenovirus mediated transfer on lipopolysaccharide stimulation in neuron glia cultures. Ann N Y Acad Sci 1042(1):338–348

    CAS  PubMed  Google Scholar 

  • Ventimiglia R, Jones B, Møller A (1995) A quantitative method for morphometric analysis in neuronal cell culture: unbiased estimation of neuron area and number of branch points. J Neurosci Methods 57(1):63–66

    CAS  PubMed  Google Scholar 

  • Wang M, Zukas AM, Hui Y, Ricciotti E, Puré E, FitzGerald GA (2006) Deletion of microsomal prostaglandin E synthase-1 augments prostacyclin and retards atherogenesis. Proc Natl Acad Sci 103(39):14507–14512

    CAS  PubMed  Google Scholar 

  • Wang J, Tan L, Wang H-FF, Tan C-CC, Meng X-FF, Wang C et al (2015) Anti-inflammatory drugs and risk of Alzheimer's disease: an updated systematic review and meta-analysis. J Alzheimer's Dis: JAD 44(2):385–396

    Google Scholar 

  • Wei G, Kibler KK, Koehler RC, Maruyama T, Narumiya S, Doré S (2008) Prostacyclin receptor deletion aggravates hippocampal neuronal loss after bilateral common carotid artery occlusion in mouse. Neuroscience 156(4):1111–1117

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wise H (2002) Jones RL. IP-receptors in the central nervous system, Prostacyclin and Its Receptors

    Google Scholar 

  • Wong PY, Sun FF, McGiff JC (1978) Metabolism of prostacyclin in blood vessels. J Biol Chem 253(16):5555–5557

    CAS  PubMed  Google Scholar 

  • Zenaro E, Pietronigro E, Bianca V, Piacentino G, Marongiu L, Budui S et al (2015) Neutrophils promote Alzheimer's disease-like pathology and cognitive decline via LFA-1 integrin. Nat Med 21(8):880–886

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr. Samina Salim for giving us HT22 cells. We would also like to thank Dr. Min Hu and Dr. Wei-qun Wang for helping us on generating LC/MS/MS data.

Funding

This work was supported by NIH Grants (RO1 HL56712 and HL79389 for KHR) and American Heart Association grants (10GRNT4470042 and 14GRNT20380687 for KHR).

Author information

Authors and Affiliations

  1. The Center for Experimental Therapeutics and Pharmacoinformatics, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Health and Biomedical Sciences Building 2, 4849 Calhoun Road, Room 3044, Houston, TX, 77204-5037, USA

    Qing-Lan Ling, Hironari Akasaka, Chang Chen & Ke-He Ruan

  2. Department of Anesthesia, Zhongnan Hospital of Wuhan University, Wuhan, 430071, People’s Republic of China

    Chang Chen

  3. University of Houston Animal Behavior Core Facility, Texas Institute for Measurement, Evaluation and Statistics (TIMES), Department of Psychology, University of Houston, Houston, TX, 77204, USA

    Colin N Haile & Kevin Winoske

Authors
  1. Qing-Lan Ling
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hironari Akasaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Colin N Haile
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kevin Winoske
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ke-He Ruan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Q-L.L. performed the experiments, analyzed the data, and prepared the Figures. H.A. helped generating the mice. C.C. helped on performing the experiments and revising the manuscript. C.H. and K.W. provided behavioral facility, and helped design, set up, and extract data of the behavioral experiments. Q-L.L. and K-H.R. designed the experiments. Q-L.L. and K-H.R. wrote the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Ke-He Ruan.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(PDF 133 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ling, QL., Akasaka, H., Chen, C. et al. The Protective Effects of Up-Regulating Prostacyclin Biosynthesis on Neuron Survival in Hippocampus. J Neuroimmune Pharmacol 15, 292–308 (2020). https://doi.org/10.1007/s11481-019-09896-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-019-09896-5

Keywords

Search

Navigation