Knockout of the P2Y Receptor Prevents Peri-Infarct Neuronal Loss After Transient, Focal Ischemia in Mouse Brain

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2022 Feb 26

PMID 35216419

Authors

Stefan Milde

Guy C Brown

Affiliations

Soon will be listed here.

Abstract

After stroke, there is a delayed neuronal loss in brain areas surrounding the infarct, which may in part be mediated by microglial phagocytosis of stressed neurons. Microglial phagocytosis of stressed or damaged neurons can be mediated by UDP released from stressed neurons activating the P2Y receptor on microglia, inducing microglial phagocytosis of such neurons. We show evidence here from a small trial that the knockout of the P2Y receptor, required for microglial phagocytosis of neurons, prevents the delayed neuronal loss after transient, focal brain ischemia induced by endothelin-1 injection in mice. Wild-type mice had neuronal loss and neuronal nuclear material within microglia in peri-infarct areas. P2Y receptor knockout mice had no significant neuronal loss in peri-infarct brain areas seven days after brain ischemia. Thus, delayed neuronal loss after stroke may in part be mediated by microglial phagocytosis of stressed neurons, and the P2Y receptor is a potential treatment target to prevent peri-infarct neuronal loss.

Citing Articles

Modification of Neural Circuit Functions by Microglial P2Y6 Receptors in Health and Neurodegeneration.

Zhang Y, Tang Y, Illes P Mol Neurobiol. 2024; 62(4):4139-4148.

PMID: 39400857 PMC: 11880064. DOI: 10.1007/s12035-024-04531-8.

The microglial P2Y receptor as a therapeutic target for neurodegenerative diseases.

Dundee J, Brown G Transl Neurodegener. 2024; 13(1):47.

PMID: 39243044 PMC: 11380353. DOI: 10.1186/s40035-024-00438-5.

Functionalized Congeners of 2-Chromene P2Y Receptor Antagonists.

Oliva P, Pramanik A, Jung Y, Lewicki S, Mwendwa J, Park J Cells. 2024; 13(16).

PMID: 39195256 PMC: 11352859. DOI: 10.3390/cells13161366.

The miR-210 Primed Endothelial Progenitor Cell Exosomes Alleviate Acute Ischemic Brain Injury.

Wang J, Chen S, Sawant H, Chen Y, Bihl J Curr Stem Cell Res Ther. 2023; 19(8):1164-1174.

PMID: 37957914 PMC: 11082070. DOI: 10.2174/011574888X266357230923113642.

Cell death by phagocytosis.

Brown G Nat Rev Immunol. 2023; 24(2):91-102.

PMID: 37604896 DOI: 10.1038/s41577-023-00921-6.

References

Tennant K, Jones T . Sensorimotor behavioral effects of endothelin-1 induced small cortical infarcts in C57BL/6 mice. J Neurosci Methods. 2009; 181(1):18-26. PMC: 6667280. DOI: 10.1016/j.jneumeth.2009.04.009. View

Kriz J, Lalancette-Hebert M . Inflammation, plasticity and real-time imaging after cerebral ischemia. Acta Neuropathol. 2009; 117(5):497-509. DOI: 10.1007/s00401-009-0496-1. View

Oliveira-Giacomelli A, M Albino C, de Souza H, Correa-Velloso J, de Jesus Santos A, Baranova J . P2Y6 and P2X7 Receptor Antagonism Exerts Neuroprotective/ Neuroregenerative Effects in an Animal Model of Parkinson's Disease. Front Cell Neurosci. 2019; 13:476. PMC: 6856016. DOI: 10.3389/fncel.2019.00476. View

Neher J, Neniskyte U, Hornik T, Brown G . Inhibition of UDP/P2Y6 purinergic signaling prevents phagocytosis of viable neurons by activated microglia in vitro and in vivo. Glia. 2014; 62(9):1463-75. PMC: 4336556. DOI: 10.1002/glia.22693. View

Lee Y, Lee S, Choi S, Yeo H, Chang K, Lee H . Therapeutically targeting neuroinflammation and microglia after acute ischemic stroke. Biomed Res Int. 2014; 2014:297241. PMC: 4095830. DOI: 10.1155/2014/297241. View

Butler C, Popescu A, Kitchener E, Allendorf D, Puigdellivol M, Brown G . Microglial phagocytosis of neurons in neurodegeneration, and its regulation. J Neurochem. 2021; 158(3):621-639. DOI: 10.1111/jnc.15327. View

Li Z, Gao Y, He C, Wei H, Zhang J, Zhang H . Purinergic Receptor P2Y Is a Negative Regulator of NK Cell Maturation and Function. J Immunol. 2021; 207(6):1555-1565. DOI: 10.4049/jimmunol.2000750. View

Katchanov J, Waeber C, Gertz K, Gietz A, Winter B, Bruck W . Selective neuronal vulnerability following mild focal brain ischemia in the mouse. Brain Pathol. 2003; 13(4):452-64. PMC: 8095859. DOI: 10.1111/j.1750-3639.2003.tb00476.x. View

Wang K, Li J, Zhang Y, Huang Y, Chen D, Shi Z . Central nervous system diseases related to pathological microglial phagocytosis. CNS Neurosci Ther. 2021; 27(5):528-539. PMC: 8025646. DOI: 10.1111/cns.13619. View

10.

Emmrich J, Ejaz S, Williamson D, Hong Y, Sitnikov S, Fryer T . Assessing the Effects of Cytoprotectants on Selective Neuronal Loss, Sensorimotor Deficit and Microglial Activation after Temporary Middle Cerebral Occlusion. Brain Sci. 2019; 9(10). PMC: 6827002. DOI: 10.3390/brainsci9100287. View

11.

Roth G, Mensah G, Johnson C, Addolorato G, Ammirati E, Baddour L . Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: Update From the GBD 2019 Study. J Am Coll Cardiol. 2020; 76(25):2982-3021. PMC: 7755038. DOI: 10.1016/j.jacc.2020.11.010. View

12.

Alawieh A, Langley E, Feng W, Spiotta A, Tomlinson S . Complement-Dependent Synaptic Uptake and Cognitive Decline after Stroke and Reperfusion Therapy. J Neurosci. 2020; 40(20):4042-4058. PMC: 7219298. DOI: 10.1523/JNEUROSCI.2462-19.2020. View

13.

Milde S, van Tartwijk F, Vilalta A, Hornik T, Dundee J, Puigdellivol M . Inflammatory neuronal loss in the substantia nigra induced by systemic lipopolysaccharide is prevented by knockout of the P2Y receptor in mice. J Neuroinflammation. 2021; 18(1):225. PMC: 8504061. DOI: 10.1186/s12974-021-02280-2. View

14.

Lyu J, Xie D, Bhatia T, Leak R, Hu X, Jiang X . Microglial/Macrophage polarization and function in brain injury and repair after stroke. CNS Neurosci Ther. 2021; 27(5):515-527. PMC: 8025652. DOI: 10.1111/cns.13620. View

15.

Fujioka M, Taoka T, Matsuo Y, Mishima K, Ogoshi K, Kondo Y . Magnetic resonance imaging shows delayed ischemic striatal neurodegeneration. Ann Neurol. 2003; 54(6):732-47. DOI: 10.1002/ana.10751. View

16.

Vilalta A, Brown G . Neurophagy, the phagocytosis of live neurons and synapses by glia, contributes to brain development and disease. FEBS J. 2017; 285(19):3566-3575. DOI: 10.1111/febs.14323. View

17.

Liu G, Ding J, Xiao Q, Chen S . P2Y6 receptor and immunoinflammation. Neurosci Bull. 2009; 25(3):161-4. PMC: 5552562. DOI: 10.1007/s12264-009-0120-3. View

18.

Alawieh A, Langley E, Tomlinson S . Targeted complement inhibition salvages stressed neurons and inhibits neuroinflammation after stroke in mice. Sci Transl Med. 2018; 10(441). PMC: 6689196. DOI: 10.1126/scitranslmed.aao6459. View

19.

Wegener S, Weber R, Ramos-Cabrer P, Uhlenkueken U, Sprenger C, Wiedermann D . Temporal profile of T2-weighted MRI distinguishes between pannecrosis and selective neuronal death after transient focal cerebral ischemia in the rat. J Cereb Blood Flow Metab. 2005; 26(1):38-47. DOI: 10.1038/sj.jcbfm.9600166. View

20.

Garcia J, Liu K, Ye Z, Gutierrez J . Incomplete infarct and delayed neuronal death after transient middle cerebral artery occlusion in rats. Stroke. 1997; 28(11):2303-9; discussion 2310. DOI: 10.1161/01.str.28.11.2303. View