Alterations of Caspr2 and Nav1.6 on myelinated axon damage in a rat model of chronic cerebral hypoperfusion

Liang,Weihua; Zhang,Weiwei; Zhao,Shifu; Liang,Hua; Zhang,Jinli; Wang,Luyan

doi:10.3892/etm.2017.4228

Alterations of Caspr2 and Nav1.6 on myelinated axon damage in a rat model of chronic cerebral hypoperfusion

Authors:
- Weihua Liang
- Weiwei Zhang
- Shifu Zhao
- Hua Liang
- Jinli Zhang
- Luyan Wang
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Affiliations: No. 263 Clinic of PLA Army General Hospital, Beijing 101149, P.R. China, PLA Army General Hospital, Beijing 100700, P.R. China, Department of Neurology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400038, P.R. China, The 66083rd of PLA, Beijing 102488, P.R. China
Published online on: March 14, 2017 https://doi.org/10.3892/etm.2017.4228
Pages: 2468-2472
Copyright: © Liang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Myelinated axons require the correct localization of key proteins that are essential for nerve conduction and cognitive function. Little is known regarding the altered expression of contactin-associated protein 2 (Caspr2) at the juxtaparanodal regions and Nav1.6 at the node of Ranvier in response to chronic cerebral hypoperfusion (CCH). The aim of the present study was to examine the alterations in the key protein of myelinated axons and the potential mechanisms that may follow CCH. We established a rat model of CCH by controllable partial narrowing of bilateral common carotid arteries. Then, we detected cerebral blood flow (CBF) after surgery. We also evaluated motor-evoked potentials (MEPs), assessed the Morris water maze test, analyzed Caspr2 expression through immunohistochemistry and Nav1.6 protein expression through western blot analysis at 2, 4 and 12 weeks. The results revealed that the mean CBF value was significantly decreased to 33.90±5.48%. The MEP latencies and the escaping latencies were significantly prolonged. There was also an elongation of the first time passing of the hidden platform with a reduction of crossing platform times in spatial probing. Furthermore, the Caspr2 immunoreactivity demonstrated that the Caspr2 level was significantly downregulated with abnormal locations in the corpus callosum. The western blot analysis of Nav1.6 protein revealed that the level was reduced significantly over time. The results demonstrate that CCH leads to central conductive function loss, cognitive function damage and alterations in the key protein of myelinated axons, which may provide a molecular basis and key link for white matter damage.

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1	Akinyemi RO, Mukaetova-Ladinska EB, Attems J, Ihara M and Kalaria RN: Vascular risk factors and neurodegeneration in ageing related dementias: Alzheimer's disease and vascular dementia. Curr Alzheimer Res. 10:642–653. 2013. View Article : Google Scholar : PubMed/NCBI
2	Hainsworth AH, Brittain JF and Khatun H: Pre-clinical models of human cerebral small vessel disease: utility for clinical application. J Neurol Sci. 322:237–240. 2012. View Article : Google Scholar : PubMed/NCBI
3	Miki K, Ishibashi S, Sun L, Xu H, Ohashi W, Kuroiwa T and Mizusawa H: Intensity of chronic cerebral hypoperfusion determines white/gray matter injury and cognitive/motor dysfunction in mice. J Neurosci Res. 87:1270–1281. 2009. View Article : Google Scholar : PubMed/NCBI
4	Brown WR, Moody DM, Thore CR, Anstrom JA and Challa VR: Microvascular changes in the white mater in dementia. J Neurol Sci. 283:28–31. 2009. View Article : Google Scholar : PubMed/NCBI
5	Fernando MS, Simpson JE, Matthews F, Brayne C, Lewis CE, Barber R, Kalaria RN, Forster G, Esteves F, Wharton SB, et al: MRC Cognitive Function and Ageing Neuropathology Study Group: White matter lesions in an unselected cohort of the elderly: molecular pathology suggests origin from chronic hypoperfusion injury. Stroke. 37:1391–1398. 2006. View Article : Google Scholar : PubMed/NCBI
6	Nave K-A: Myelination and support of axonal integrity by glia. Nature. 468:244–252. 2010. View Article : Google Scholar : PubMed/NCBI
7	Salzer JL: Clustering sodium channels at the node of Ranvier: close encounters of the axon-glia kind. Neuron. 18:843–846. 1997. View Article : Google Scholar : PubMed/NCBI
8	Arroyo EJ and Scherer SS: On the molecular architecture of myelinated fibers. Histochem Cell Biol. 113:1–18. 2000. View Article : Google Scholar : PubMed/NCBI
9	Rios JC, Rubin M, St Martin M, Downey RT, Einheber S, Rosenbluth J, Levinson SR, Bhat M and Salzer JL: Paranodal interactions regulate expression of sodium channel subtypes and provide a diffusion barrier for the node of Ranvier. J Neurosci. 23:7001–7011. 2003.PubMed/NCBI
10	Susuki K and Rasband MN: Molecular mechanisms of node of Ranvier formation. Curr Opin Cell Biol. 20:616–623. 2008. View Article : Google Scholar : PubMed/NCBI
11	Peles E and Salzer JL: Molecular domains of myelinated axons. Curr Opin Neurobiol. 10:558–565. 2000. View Article : Google Scholar : PubMed/NCBI
12	Girault JA, Oguievetskaia K, Carnaud M, Denisenko-Nehrbass N and Goutebroze L: Transmembrane scaffolding proteins in the formation and stability of nodes of Ranvier. Biol Cell. 95:447–452. 2003. View Article : Google Scholar : PubMed/NCBI
13	Gasser A, Ho TS-Y, Cheng X, Chang K-J, Waxman SG, Rasband MN and Dib-Hajj SD: An ankyrinG-binding motif is necessary and sufficient for targeting Nav1.6 sodium channels to axon initial segments and nodes of Ranvier. J Neurosci. 32:7232–7243. 2012. View Article : Google Scholar : PubMed/NCBI
14	Leterrier C, Brachet A, Dargent B and Vacher H: Determinants of voltage-gated sodium channel clustering in neurons. Semin Cell Dev Biol. 22:171–177. 2011. View Article : Google Scholar : PubMed/NCBI
15	Coman I, Aigrot MS, Seilhean D, Reynolds R, Girault JA, Zalc B and Lubetzki C: Nodal, paranodal and juxtaparanodal axonal proteins during demyelination and remyelination in multiple sclerosis. Brain. 129:3186–3195. 2006. View Article : Google Scholar : PubMed/NCBI
16	Howell OW, Palser A, Polito A, Melrose S, Zonta B, Scheiermann C, Vora AJ, Brophy PJ and Reynolds R: Disruption of neurofascin localization reveals early changes preceding demyelination and remyelination in multiple sclerosis. Brain. 129:3173–3185. 2006. View Article : Google Scholar : PubMed/NCBI
17	Howell OW, Rundle JL, Garg A, Komada M, Brophy PJ and Reynolds R: Activated microglia mediate axoglial disruption that contributes to axonal injury in multiple sclerosis. J Neuropathol Exp Neurol. 69:1017–1033. 2010. View Article : Google Scholar : PubMed/NCBI
18	Wolswijk G and Balesar R: Changes in the expression and localization of the paranodal protein Caspr on axons in chronic multiple sclerosis. Brain. 126:1638–1649. 2003. View Article : Google Scholar : PubMed/NCBI
19	Zoupi L, Markoullis K, Kleopa KA and Karagogeos D: Alterations of juxtaparanodal domains in two rodent models of CNS demyelination. Glia. 61:1236–1249. 2013. View Article : Google Scholar : PubMed/NCBI
20	Mao Q, Jia F, Zhang XH, Qiu YM, Ge JW, Bao WJ, Luo QZ and Jiang JY: The up-regulation of voltage-gated sodium channel Nav1.6 expression following fluid percussion traumatic brain injury in rats. Neurosurgery. 66:1134–1139; discussion 1139. 2010. View Article : Google Scholar : PubMed/NCBI
21	Wang JALW, Lin W, Morris T, Banderali U, Juranka PF and Morris CE: Membrane trauma and Na⁺ leak from Nav1.6 channels. Am J Physiol Cell Physiol. 297:C823–C834. 2009. View Article : Google Scholar : PubMed/NCBI
22	Hunanyan AS, Alessi V, Patel S, Pearse DD, Matthews G and Arvanian VL: Alterations of action potentials and the localization of Nav1.6 sodium channels in spared axons after hemisection injury of the spinal cord in adult rats. J Neurophysiol. 105:1033–1044. 2011. View Article : Google Scholar : PubMed/NCBI
23	Wienecke J, Westerdahl A-C, Hultborn H, Kiehn O and Ryge J: Global gene expression analysis of rodent motor neurons following spinal cord injury associates molecular mechanisms with development of postinjury spasticity. J Neurophysiol. 103:761–778. 2010. View Article : Google Scholar : PubMed/NCBI
24	Hassen GWFJ, Feliberti J, Kesner L, Stracher A and Mokhtarian F: Prevention of axonal injury using calpain inhibitor in chronic progressive experimental autoimmune encephalomyelitis. Brain Res. 1236:206–215. 2008. View Article : Google Scholar : PubMed/NCBI
25	Black JA, Newcombe J, Trapp BD and Waxman SG: Sodium channel expression within chronic multiple sclerosis plaques. J Neuropathol Exp Neurol. 66:828–837. 2007. View Article : Google Scholar : PubMed/NCBI
26	Liao Y, Deprez L, Maljevic S, Pitsch J, Claes L, Hristova D, Jordanova A, Ala-Mello S, Bellan-Koch A, Blazevic D, et al: Molecular correlates of age-dependent seizures in an inherited neonatal-infantile epilepsy. Brain. 133:1403–1414. 2010. View Article : Google Scholar : PubMed/NCBI
27	Yao C, Williams AJ, Cui P, Berti R, Hunter JC, Tortella FC and Dave JR: Differential pattern of expression of voltage-gated sodium channel genes following ischemic brain injury in rats. Neurotox Res. 4:67–75. 2002. View Article : Google Scholar : PubMed/NCBI
28	Blumenfeld H, Lampert A, Klein JP, Mission J, Chen MC, Rivera M, Dib-Hajj S, Brennan AR, Hains BC and Waxman SG: Role of hippocampal sodium channel Nav1.6 in kindling epileptogenesis. Epilepsia. 50:44–55. 2009. View Article : Google Scholar : PubMed/NCBI
29	Yao C, Williams AJ, Hartings JA, Lu XC, Tortella FC and Dave JR: Down-regulation of the sodium channel Na(v)1.1 α-subunit following focal ischemic brain injury in rats: in situ hybridization and immunohistochemical analysis. Life Sci. 77:1116–1129. 2005. View Article : Google Scholar : PubMed/NCBI
30	Reimer MM, McQueen J, Searcy L, Scullion G, Zonta B, Desmazieres A, Holland PR, Smith J, Gliddon C, Wood ER, et al: Rapid disruption of axon-glial integrity in response to mild cerebral hypoperfusion. J Neurosci. 31:18185–18194. 2011. View Article : Google Scholar : PubMed/NCBI