Skip to main content
Log in

Upregulation of EHD2 after Intracerebral Hemorrhage in Adult Rats

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

EHD2, a member of the Eps15 homology domain (EH domain) family, is important for protein interactions during vesicular trafficking. Previous studies have proved that EHD2 can regulate trafficking from the plasma membrane in the process of endocytosis. However, its function in central nervous system diseases is still with limited understanding. In this frame, we found that EHD2 expression was upregulated in the perihematomal caudate in adult rats after intracerebral hemorrhage (ICH). Double immunofluorescence staining revealed that EHD2 was colocalized with neurons and activated microglias after ICH. Besides, we detected that neuronal apoptosis markers (TUNEL and caspase-3), and microglial activation marker (CD68), also known as a marker of macrophage, were colocated with EHD2. The vitro study also indicated that EHD2 was linked with neuronal apoptosis and microglial phagocytosis. All our findings suggested that EHD2 might be involved in the pathophysiology of ICH.

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

Access this article

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

Instant access to the full article PDF.

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

Similar content being viewed by others

References

  • Batchelor PE, Liberatore GT, Wong JY, Porritt MJ, Frerichs F, Donnan GA, Howells DW (1999) Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. J Neurosci 19:1708–1716

    CAS  PubMed  Google Scholar 

  • Benjamin S, Weidberg H, Rapaport D, Pekar O, Nudelman M, Segal D, Hirschberg K, Katzav S, Ehrlich M, Horowitz M (2011) EHD2 mediates trafficking from the plasma membrane by modulating Rac1 activity. Biochem J 439:433–442

    Article  CAS  PubMed  Google Scholar 

  • Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57–69

    Article  CAS  PubMed  Google Scholar 

  • Brown GC, Neher JJ (2012) Eaten alive! Cell death by primary phagocytosis: ‘phagoptosis’. Trends Biochem Sci 37:325–332

    Article  CAS  PubMed  Google Scholar 

  • David S, Kroner A (2011) Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci 12:388–399

    Article  CAS  PubMed  Google Scholar 

  • Gardai SJ, McPhillips KA, Frasch SC, Janssen WJ, Starefeldt A, Murphy-Ullrich JE, Bratton DL, Oldenborg PA, Michalak M, Henson PM (2005) Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123:321–334

    Article  CAS  PubMed  Google Scholar 

  • Gong C, Hoff JT, Keep RF (2000) Acute inflammatory reaction following experimental intracerebral hemorrhage in rat. Brain Res 871:57–65

    Article  CAS  PubMed  Google Scholar 

  • Gong C, Boulis N, Qian J, Turner DE, Hoff JT, Keep RF (2001) Intracerebral hemorrhage-induced neuronal death. Neurosurgery 48:875–882, discussion 882–3

    CAS  PubMed  Google Scholar 

  • Guilherme A, Soriano NA, Bose S, Holik J, Bose A, Pomerleau DP, Furcinitti P, Leszyk J, Corvera S, Czech MP (2004) EHD2 and the novel EH domain binding protein EHBP1 couple endocytosis to the actin cytoskeleton. J Biol Chem 279:10593–10605

    Article  CAS  PubMed  Google Scholar 

  • Hanisch UK (2002) Microglia as a source and target of cytokines. Glia 40:140–155

    Article  PubMed  Google Scholar 

  • Hua Y, Schallert T, Keep RF, Wu J, Hoff JT, Xi G (2002) Behavioral tests after intracerebral hemorrhage in the rat. Stroke 33:2478–2484

    Article  PubMed  Google Scholar 

  • Jiang Y, Wu J, Keep RF, Hua Y, Hoff JT, Xi G (2002) Hypoxia-inducible factor-1alpha accumulation in the brain after experimental intracerebral hemorrhage. J Cereb Blood Flow Metab 22:689–696

    Article  CAS  PubMed  Google Scholar 

  • Ke K, Li L, Rui Y, Zheng H, Tan X, Xu W, Cao J, Xu J, Cui G, Xu G, Cao M (2013) Increased expression of small heat shock protein alphaB-crystallin after intracerebral hemorrhage in adult rats. J Mol Neurosci 51:159–169

    Article  CAS  PubMed  Google Scholar 

  • Kong QY, Wu X, Li J, Peng WX, Ye R, Lindholm B, Wang T (2001) Loss of phospholipids asymmetry in red blood cells contributes to anemia in uremic patients. Adv Perit Dial 17:58–60

    CAS  PubMed  Google Scholar 

  • Lee ST, Chu K, Sinn DI, Jung KH, Kim EH, Kim SJ, Kim JM, Ko SY, Kim M, Roh JK (2006) Erythropoietin reduces perihematomal inflammation and cell death with eNOS and STAT3 activations in experimental intracerebral hemorrhage. J Neurochem 96:1728–1739

    Article  CAS  PubMed  Google Scholar 

  • Li L, Ke K, Tan X, Xu W, Shen J, Zhai T, Xu L, Rui Y, Zheng H, Zhai P, Zhao J, Cao M (2013) Up-regulation of NFATc4 involves in neuronal apoptosis following intracerebral hemorrhage. Cell Mol Neurobiol 33:893–905

    Article  PubMed  Google Scholar 

  • Liew HK, Pang CY, Hsu CW, Wang MJ, Li TY, Peng HF, Kuo JS, Wang JY (2012) Systemic administration of urocortin after intracerebral hemorrhage reduces neurological deficits and neuroinflammation in rats. J Neuroinflammation 9:13

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lu YZ, Lin CH, Cheng FC, Hsueh CM (2005) Molecular mechanisms responsible for microglia-derived protection of Sprague–Dawley rat brain cells during in vitro ischemia. Neurosci Lett 373:159–164

    Article  CAS  PubMed  Google Scholar 

  • Matsushita K, Meng W, Wang X, Asahi M, Asahi K, Moskowitz MA, Lo EH (2000) Evidence for apoptosis after intercerebral hemorrhage in rat striatum. J Cereb Blood Flow Metab 20:396–404

    Article  CAS  PubMed  Google Scholar 

  • Nakajima K, Yamamoto S, Kohsaka S, Kurihara T (2008) Neuronal stimulation leading to upregulation of glutamate transporter-1 (GLT-1) in rat microglia in vitro. Neurosci Lett 436:331–334

    Article  CAS  PubMed  Google Scholar 

  • Neher JJ, Neniskyte U, Zhao JW, Bal-Price A, Tolkovsky AM, Brown GC (2011) Inhibition of microglial phagocytosis is sufficient to prevent inflammatory neuronal death. J Immunol 186:4973–4983

    Article  CAS  PubMed  Google Scholar 

  • Ohnishi M, Katsuki H, Fukutomi C, Takahashi M, Motomura M, Fukunaga M, Matsuoka Y, Isohama Y, Izumi Y, Kume T, Inoue A, Akaike A (2011) HMGB1 inhibitor glycyrrhizin attenuates intracerebral hemorrhage-induced injury in rats. Neuropharmacology 61:975–980

    Article  CAS  PubMed  Google Scholar 

  • Okauchi M, Hua Y, Keep RF, Morgenstern LB, Schallert T, Xi G (2010) Deferoxamine treatment for intracerebral hemorrhage in aged rats: therapeutic time window and optimal duration. Stroke 41:375–382

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Perego C, Fumagalli S, De Simoni MG (2011) Temporal pattern of expression and colocalization of microglia/macrophage phenotype markers following brain ischemic injury in mice. J Neuroinflammation 8:174

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pohl U, Smith JS, Tachibana I, Ueki K, Lee HK, Ramaswamy S, Wu Q, Mohrenweiser HW, Jenkins RB, Louis DN (2000) EHD2, EHD3, and EHD4 encode novel members of a highly conserved family of EH domain-containing proteins. Genomics 63:255–262

    Article  CAS  PubMed  Google Scholar 

  • Qureshi AI, Suri MF, Ostrow PT, Kim SH, Ali Z, Shatla AA, Guterman LR, Hopkins LN (2003) Apoptosis as a form of cell death in intracerebral hemorrhage. Neurosurgery 52:1041–1047, discussion 1047–8

    Article  PubMed  Google Scholar 

  • Ravichandran KS (2011) Beginnings of a good apoptotic meal: the find-me and eat-me signaling pathways. Immunity 35:445–455

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Shen A, Liu Y, Zhao J, Qin J, Shi S, Chen M, Gao S, Xiao F, Lu Q, Cheng C (2008a) Temporal-spatial expressions of p27kip1 and its phosphorylation on Serine-10 after acute spinal cord injury in adult rat: Implications for post-traumatic glial proliferation. Neurochem Int 52:1266–1275

    Article  CAS  PubMed  Google Scholar 

  • Shen A, Yang J, Gu Y, Zhou D, Sun L, Qin Y, Chen J, Wang P, Xiao F, Zhang L, Cheng C (2008b) Lipopolysaccharide-evoked activation of p38 and JNK leads to an increase in ICAM-1 expression in Schwann cells of sciatic nerves. FEBS J 275:4343–4353

    Article  CAS  PubMed  Google Scholar 

  • Stoeber M, Stoeck IK, Hanni C, Bleck CK, Balistreri G, Helenius A (2012) Oligomers of the ATPase EHD2 confine caveolae to the plasma membrane through association with actin. EMBO J 31:2350–2364

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Stoll G, Jander S (1999) The role of microglia and macrophages in the pathophysiology of the CNS. Prog Neurobiol 58:233–247

    Article  CAS  PubMed  Google Scholar 

  • Thored P, Heldmann U, Gomes-Leal W, Gisler R, Darsalia V, Taneera J, Nygren JM, Jacobsen SE, Ekdahl CT, Kokaia Z, Lindvall O (2009) Long-term accumulation of microglia with proneurogenic phenotype concomitant with persistent neurogenesis in adult subventricular zone after stroke. Glia 57:835–849

    Article  PubMed  Google Scholar 

  • Wang J (2010) Preclinical and clinical research on inflammation after intracerebral hemorrhage. Prog Neurobiol 92:463–477

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wang J, Dore S (2007) Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab 27:894–908

    Article  CAS  PubMed  Google Scholar 

  • Xi G, Keep RF, Hoff JT (2006) Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol 5:53–63

    Article  PubMed  Google Scholar 

  • Xue M, Del Bigio MR (2000) Intracerebral injection of autologous whole blood in rats: time course of inflammation and cell death. Neurosci Lett 283:230–232

    Article  CAS  PubMed  Google Scholar 

  • Yang Y, Zhang XJ, Yin J, Li LT (2008) Brain damage related to hemorrhagic transformation following cerebral ischemia and the role of K ATP channels. Brain Res 1241:168–175

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Natural Science Foundation of China (No. 81371299).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Maohong Cao.

Additional information

Kaifu Ke and Ying Rui contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ke, K., Rui, Y., Li, L. et al. Upregulation of EHD2 after Intracerebral Hemorrhage in Adult Rats. J Mol Neurosci 54, 171–180 (2014). https://doi.org/10.1007/s12031-014-0271-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-014-0271-1

Keywords

Navigation