Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Inhibition of LPA5 Activity Provides Long-Term Neuroprotection in Mice with Brain Ischemic Stroke

  • Received : 2020.09.13
  • Accepted : 2020.09.22
  • Published : 2020.11.01
Download PDF
⟨ Previous Next ⟩

Abstract

Stroke is a leading cause of long-term disability in ischemic survivors who are suffering from motor, cognitive, and memory impairment. Previously, we have reported suppressing LPA5 activity with its specific antagonist can attenuate acute brain injuries after ischemic stroke. However, it is unclear whether suppressing LPA5 activity can also attenuate chronic brain injuries after ischemic stroke. Here, we explored whether effects of LPA5 antagonist, TCLPA5, could persist a longer time after brain ischemic stroke using a mouse model challenged with tMCAO. TCLPA5 was administered to mice every day for 3 days, starting from the time immediately after reperfusion. TCLPA5 administration improved neurological function up to 21 days after tMCAO challenge. It also reduced brain tissue loss and cell apoptosis in mice at 21 days after tMCAO challenge. Such long-term neuroprotection of TCLPA5 was associated with enhanced neurogenesis and angiogenesis in post-ischemic brain, along with upregulated expression levels of vascular endothelial growth factor. Collectively, results of the current study indicates that suppressing LPA5 activity can provide long-term neuroprotection to mice with brain ischemic stroke.

Keywords

References

  1. Arvidsson, A., Collin, T., Kirik, D., Kokaia, Z. and Lindvall, O. (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat. Med. 8, 963-970. https://doi.org/10.1038/nm747
  2. Caron, C., Spring, K., Laramee, M., Chabot, C., Cloutier, M., Gu, H. and Royal, I. (2009) Non-redundant roles of the Gab1 and Gab2 scaffolding adapters in VEGF-mediated signalling, migration, and survival of endothelial cells. Cell. Signal. 21, 943-953. https://doi.org/10.1016/j.cellsig.2009.02.004
  3. Chen, J., Sanberg, P. R., Li, Y., Wang, L., Lu, M., Willing, A. E., Sanchez-Ramos, J. and Chopp, M. (2001) Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke 32, 2682-2688. https://doi.org/10.1161/hs1101.098367
  4. Choi, J. W. and Chun, J. (2013) Lysophospholipids and their receptors in the central nervous system. Biochim. Biophys. Acta 1831, 20-32. https://doi.org/10.1016/j.bbalip.2012.07.015
  5. Claesson-Welsh, L. and Welsh, M. (2013) VEGFA and tumour angiogenesis. J. Intern. Med. 273, 114-127. https://doi.org/10.1111/joim.12019
  6. Ergul, A., Alhusban, A. and Fagan, S. C. (2012) Angiogenesis: a harmonized target for recovery after stroke. Stroke 43, 2270-2274. https://doi.org/10.1161/STROKEAHA.111.642710
  7. Flamme, I., Breier, G. and Risau, W. (1995) Vascular endothelial growth factor (VEGF) and VEGF receptor 2 (flk-1) are expressed during vasculogenesis and vascular differentiation in the quail embryo. Dev. Biol. 169, 699-712. https://doi.org/10.1006/dbio.1995.1180
  8. Frechou, M., Margaill, I., Marchand-Leroux, C. and Beray-Berthat, V. (2019) Behavioral tests that reveal long-term deficits after permanent focal cerebral ischemia in mouse. Behav. Brain Res. 360, 69-80. https://doi.org/10.1016/j.bbr.2018.11.040
  9. Freret, T., Chazalviel, L., Roussel, S., Bernaudin, M., Schumann-Bard, P. and Boulouard, M. (2006) Long-term functional outcome following transient middle cerebral artery occlusion in the rat: correlation between brain damage and behavioral impairment. Behav. Neurosci. 120, 1285-1298. https://doi.org/10.1037/0735-7044.120.6.1285
  10. Gaire, B. P., Sapkota, A., Song, M. R. and Choi, J. W. (2019) Lysophosphatidic acid receptor 1 (LPA1) plays critical roles in microglial activation and brain damage after transient focal cerebral ischemia. J. Neuroinflammation 16, 170. https://doi.org/10.1186/s12974-019-1555-8
  11. Girard, S., Murray, K. N., Rothwell, N. J., Metz, G. A. and Allan, S. M. (2014) Long-term functional recovery and compensation after cerebral ischemia in rats. Behav. Brain Res. 270, 18-28. https://doi.org/10.1016/j.bbr.2014.05.008
  12. Gladstone, D. J., Black, S. E. and Hakim, A. M.; Heart and Stroke Foundation of Ontario Centre of Excellence in Stroke Recovery (2002) Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke 33, 2123-2136. https://doi.org/10.1161/01.STR.0000025518.34157.51
  13. Greenberg, D. A. and Jin, K. (2013) Vascular endothelial growth factors (VEGFs) and stroke. Cell. Mol. Life Sci. 70, 1753-1761. https://doi.org/10.1007/s00018-013-1282-8
  14. Huang, L., Cao, W., Deng, Y., Zhu, G., Han, Y. and Zeng, H. (2016) Hypertonic saline alleviates experimentally induced cerebral oedema through suppression of vascular endothelial growth factor and its receptor VEGFR2 expression in astrocytes. BMC Neurosci. 17, 64. https://doi.org/10.1186/s12868-016-0299-y
  15. Jin, K., Mao, X. O. and Greenberg, D. A. (2006) Vascular endothelial growth factor stimulates neurite outgrowth from cerebral cortical neurons via Rho kinase signaling. J. Neurobiol. 66, 236-242. https://doi.org/10.1002/neu.20215
  16. Jin, K., Zhu, Y., Sun, Y., Mao, X. O., Xie, L. and Greenberg, D. A. (2002) Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc. Natl. Acad. Sci. U.S.A. 99, 11946-11950. https://doi.org/10.1073/pnas.182296499
  17. Kinugasa, M., Amano, H., Satomi-Kobayashi, S., Nakayama, K., Miyata, M., Kubo, Y., Nagamatsu, Y., Kurogane, Y., Kureha, F., Yamana, S., Hirata, K., Miyoshi, J., Takai, Y. and Rikitake, Y. (2012) Necl-5/poliovirus receptor interacts with VEGFR2 and regulates VEGF-induced angiogenesis. Circ. Res. 110, 716-726. https://doi.org/10.1161/CIRCRESAHA.111.256834
  18. Koh, S. H. and Park, H. H. (2017) Neurogenesis in stroke recovery. Transl. Stroke Res. 8, 3-13. https://doi.org/10.1007/s12975-016-0460-z
  19. Lee, H. T., Chang, Y. C., Tu, Y. F. and Huang, C. C. (2009) VEGF-A/VEGFR-2 signaling leading to cAMP response element-binding protein phosphorylation is a shared pathway underlying the protective effect of preconditioning on neurons and endothelial cells. J. Neurosci. 29, 4356-4368. https://doi.org/10.1523/JNEUROSCI.5497-08.2009
  20. Li, W. L., Fraser, J. L., Yu, S. P., Zhu, J., Jiang, Y. J. and Wei, L. (2011) The role of VEGF/VEGFR2 signaling in peripheral stimulation-induced cerebral neurovascular regeneration after ischemic stroke in mice. Exp. Brain Res. 214, 503-513. https://doi.org/10.1007/s00221-011-2849-y
  21. Luo, C. X., Jiang, J., Zhou, Q. G., Zhu, X. J., Wang, W., Zhang, Z. J., Han, X. and Zhu, D. Y. (2007) Voluntary exercise-induced neurogenesis in the postischemic dentate gyrus is associated with spatial memory recovery from stroke. J. Neurosci. Res. 85, 1637-1646. https://doi.org/10.1002/jnr.21317
  22. Palma-Tortosa, S., Garcia-Culebras, A., Moraga, A., Hurtado, O., Perez-Ruiz, A., Duran-Laforet, V., Parra, J., Cuartero, M. I., Pradillo, J. M., Moro, M. A. and Lizasoain, I. (2017) Specific features of SVZ neurogenesis after cortical ischemia: a longitudinal study. Sci. Rep. 7, 16343. https://doi.org/10.1038/s41598-017-16109-7
  23. Plate, K. H., Beck, H., Danner, S., Allegrini, P. R. and Wiessner, C. (1999) Cell type specific upregulation of vascular endothelial growth factor in an MCA-occlusion model of cerebral infarct. J. Neuropathol. Exp. Neurol. 58, 654-666. https://doi.org/10.1097/00005072-199906000-00010
  24. Sapkota, A., Lee, C. H., Park, S. J. and Choi, J. W. (2020) Lysophosphatidic acid receptor 5 plays a pathogenic role in brain damage after focal cerebral ischemia by modulating neuroinflammatory responses. Cells 9,1446. https://doi.org/10.3390/cells9061446
  25. Schabitz, W. R., Steigleder, T., Cooper-Kuhn, C. M., Schwab, S., Sommer, C., Schneider, A. and Kuhn, H. G. (2007) Intravenous brainderived neurotrophic factor enhances poststroke sensorimotor recovery and stimulates neurogenesis. Stroke 38, 2165-2172. https://doi.org/10.1161/STROKEAHA.106.477331
  26. Schmidt-Pogoda, A., Bonberg, N., Koecke, M. H. M., Strecker, J. K., Wellmann, J., Bruckmann, N. M., Beuker, C., Schabitz, W. R., Meuth, S. G., Wiendl, H., Minnerup, H. and Minnerup, J. (2020) Why most acute stroke studies are positive in animals but not in patients: a systematic comparison of preclinical, early phase, and phase 3 clinical trials of neuroprotective agents. Ann. Neurol. 87, 40-51. https://doi.org/10.1002/ana.25643
  27. Shen, S. W., Duan, C. L., Chen, X. H., Wang, Y. Q., Sun, X., Zhang, Q. W., Cui, H. R. and Sun, F. Y. (2016) Neurogenic effect of VEGF is related to increase of astrocytes transdifferentiation into new mature neurons in rat brains after stroke. Neuropharmacology 108, 451-461. https://doi.org/10.1016/j.neuropharm.2015.11.012
  28. Shimotake, J., Derugin, N., Wendland, M., Vexler, Z. S. and Ferriero, D. M. (2010) Vascular endothelial growth factor receptor-2 inhibition promotes cell death and limits endothelial cell proliferation in a neonatal rodent model of stroke. Stroke 41, 343-349. https://doi.org/10.1161/STROKEAHA.109.564229
  29. Sun, Y., Jin, K., Xie, L., Childs, J., Mao, X. O., Logvinova, A. and Greenberg, D. A. (2003) VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J. Clin. Invest. 111, 1843-1851. https://doi.org/10.1172/JCI200317977
  30. Wang, R., Li, J., Duan, Y., Tao, Z., Zhao, H. and Luo, Y. (2017) Effects of erythropoietin on gliogenesis during cerebral ischemic/reperfusion recovery in adult mice. Aging Dis. 8, 410-419. https://doi.org/10.14336/AD.2016.1209
  31. Yang, J., Wu, S., Hou, L., Zhu, D., Yin, S., Yang, G. and Wang, Y. (2020) Therapeutic effects of simultaneous delivery of nerve growth factor mrna and protein via exosomes on cerebral ischemia. Mol. Ther. Nucleic Acids 21, 512-522. https://doi.org/10.1016/j.omtn.2020.06.013
  32. Zhang, Z. G., Zhang, L., Jiang, Q., Zhang, R., Davies, K., Powers, C., Bruggen, N. and Chopp, M. (2000) VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J. Clin. Invest. 106, 829-838. https://doi.org/10.1172/JCI9369
  33. Zhu, W., Fan, Y., Hao, Q., Shen, F., Hashimoto, T., Yang, G. Y., Gasmi, M., Bartus, R. T., Young, W. L. and Chen, Y. (2009) Postischemic IGF-1 gene transfer promotes neurovascular regeneration after experimental stroke. J. Cereb. Blood Flow Metab. 29, 1528-1537. https://doi.org/10.1038/jcbfm.2009.75

Cited by

  1. Receptor for Advanced Glycation End Products Is Involved in LPA5-Mediated Brain Damage after a Transient Ischemic Stroke vol.11, pp.2, 2020, https://doi.org/10.3390/life11020080
  2. Critical Roles of Lysophospholipid Receptors in Activation of Neuroglia and Their Neuroinflammatory Responses vol.22, pp.15, 2021, https://doi.org/10.3390/ijms22157864