Advertisement

The potential roles of aquaporin 4 in amyotrophic lateral sclerosis

  • Shuang Zou
  • Yu-Long Lan
  • Hongjin Wang
  • Bo ZhangEmail author
  • Yan-Guo SunEmail author
Review Article

Abstract

Aquaporin 4 (AQP4) is a primary water channel found on astrocytes in the central nervous system (CNS). Besides its function in water and ion homeostasis, AQP4 has also been documented to be involved in a myriad of acute and chronic cerebral pathologies, including autoimmune neurodegenerative diseases. AQP4 has been postulated to be associated with the incidence of a progressive neurodegenerative disorder known as amyotrophic lateral sclerosis (ALS), a disease that targets the motor neurons, causing muscle weakness and eventually paralysis. Raised AQP4 levels were noted in association with vessels surrounded with swollen astrocytic processes as well as in the brainstem, cortex, and gray matter in patients with terminal ALS. AQP4 depolarization may lead to motor neuron degeneration in ALS via GLT-1. Besides, alterations in AQP4 expression in ALS may result in the loss of blood–brain barrier (BBB) integrity. Changes in AQP4 function may also disrupt K+ homeostasis and cause connexin dysregulation, the latter of which is associated to ALS disease progression. Furthermore, AQP4 suppression augments recovery in motor function in ALS, a phenomenon thought to be associated to NGF. No therapeutic drug targeting AQP4 has been developed to date. Nevertheless, the plethora of suggestive experimental results underscores the significance of further exploration into this area.

Keywords

AQP4 Amyotrophic lateral sclerosis Target Therapy 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical standards

This article does not contain any study with human subjects performed by any of the authors.

References

  1. 1.
    Papadopoulos MC, Verkman AS (2007) Aquaporin-4 and brain edema. Pediatr Nephrol 22:778–784CrossRefGoogle Scholar
  2. 2.
    Manley GT, Fujimura M, Ma T, Noshita N, Filiz F, Bollen AW, Chan P, Verkman AS (2000) Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med 6:159–163CrossRefGoogle Scholar
  3. 3.
    Xu M, Xiao M, Li S, Yang B (2017) Aquaporins in nervous system. Adv Exp Med Biol 969:81–103CrossRefGoogle Scholar
  4. 4.
    Binder DK, Yao X, Zador Z, Sick TJ, Verkman AS, Manley GT (2006) Increased seizure duration and slowed potassium kinetics in mice lacking aquaporin-4 water channels. Glia 53:631–636CrossRefGoogle Scholar
  5. 5.
    Binder DK, Oshio K, Ma T, Verkman AS, Manley GT (2004) Increased seizure threshold in mice lacking aquaporin-4 water channels. Neuroreport 15:259–262CrossRefGoogle Scholar
  6. 6.
    Rama Rao KV, Chen M, Simard JM, Norenberg MD (2003) Increased aquaporin-4 expression in ammonia-treated cultured astrocytes. Neuroreport 14:2379–2382CrossRefGoogle Scholar
  7. 7.
    Papadopoulos MC, Saadoun S, Binder DK, Manley GT, Krishna S, Verkman AS (2004) Molecular mechanisms of brain tumor edema. Neuroscience 129:1011–1020CrossRefGoogle Scholar
  8. 8.
    Hamby ME, Sofroniew MV (2010) Reactive astrocytes as therapeutic targets for CNS disorders. Neurotherapeutics 7:494–506CrossRefGoogle Scholar
  9. 9.
    Thrane AS, Rappold PM, Fujita T, Torres A, Bekar LK, Takano T, Peng W, Wang F, Rangroo Thrane V, Enger R, Haj-Yasein NN, Skare O, Holen T, Klungland A, Ottersen OP, Nedergaard M, Nagelhus EA (2011) Critical role of aquaporin-4 (AQP4) in astrocytic Ca2+ signaling events elicited by cerebral edema. Proc Natl Acad Sci U S A 108:846–851CrossRefGoogle Scholar
  10. 10.
    Kong H, Fan Y, Xie J, Ding J, Sha L, Shi X, Sun X, Hu G (2008) AQP4 knockout impairs proliferation, migration and neuronal differentiation of adult neural stem cells. J Cell Sci 121:4029–4036CrossRefGoogle Scholar
  11. 11.
    Li X, Gao J, Ding J, Hu G, Xiao M (2013) Aquaporin-4 expression contributes to decreases in brain water content during mouse postnatal development. Brain Res Bull 94:49–55CrossRefGoogle Scholar
  12. 12.
    MacAulay N, Zeuthen T (2010) Water transport between CNS compartments: contributions of aquaporins and cotransporters. Neuroscience 168:941–956CrossRefGoogle Scholar
  13. 13.
    Auguste KI, Jin S, Uchida K, Yan D, Manley GT, Papadopoulos MC, Verkman AS (2007) Greatly impaired migration of implanted aquaporin-4-deficient astroglial cells in mouse brain toward a site of injury. FASEB J 21:108–116CrossRefGoogle Scholar
  14. 14.
    Papadopoulos MC, Saadoun S, Verkman AS (2008) Aquaporins and cell migration. Pflugers Arch 456:693–700CrossRefGoogle Scholar
  15. 15.
    Fan Y, Zhang J, Sun XL, Gao L, Zeng XN, Ding JH, Cao C, Niu L, Hu G (2005) Sex- and region-specific alterations of basal amino acid and monoamine metabolism in the brain of aquaporin-4 knockout mice. J Neurosci Res 82:458–464CrossRefGoogle Scholar
  16. 16.
    Li L, Zhang H, Varrin-Doyer M, Zamvil SS, Verkman AS (2011) Proinflammatory role of aquaporin-4 in autoimmune neuroinflammation. FASEB J 25:1556–1566CrossRefGoogle Scholar
  17. 17.
    Benfenati V, Ferroni S (2010) Water transport between CNS compartments: functional and molecular interactions between aquaporins and ion channels. Neuroscience 168:926–940CrossRefGoogle Scholar
  18. 18.
    Hubbard JA, Szu JI, Binder DK (2017) The role of aquaporin-4 in synaptic plasticity, memory and disease. Brain Res Bull 136:118–129CrossRefGoogle Scholar
  19. 19.
    Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K (2007) Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci 10:608–614CrossRefGoogle Scholar
  20. 20.
    Amin Lari A, Ghavanini AA, Bokaee HR (2019) A review of electrophysiological studies of lower motor neuron involvement in amyotrophic lateral sclerosis. Neurol Sci.  https://doi.org/10.1007/s10072-019-03832-4
  21. 21.
    Benfenati V, Nicchia GP, Svelto M, Rapisarda C, Frigeri A, Ferroni S (2007) Functional down-regulation of volume-regulated anion channels in AQP4 knockdown cultured rat cortical astrocytes. J Neurochem 100:87–104CrossRefGoogle Scholar
  22. 22.
    Kaiser M, Maletzki I, Hulsmann S, Holtmann B, Schulz-Schaeffer W, Kirchhoff F, Bahr M, Neusch C (2006) Progressive loss of a glial potassium channel (KCNJ10) in the spinal cord of the SOD1 (G93A) transgenic mouse model of amyotrophic lateral sclerosis. J Neurochem 99:900–912CrossRefGoogle Scholar
  23. 23.
    Nicaise C, Soyfoo MS, Authelet M, De Decker R, Bataveljic D, Delporte C, Pochet R (2009) Aquaporin-4 overexpression in rat ALS model. Anat Rec (Hoboken) 292:207–213CrossRefGoogle Scholar
  24. 24.
    Hoshi A, Tsunoda A, Yamamoto T, Tada M, Kakita A, Ugawa Y (2018) Altered expression of glutamate transporter-1 and water channel protein aquaporin-4 in human temporal cortex with Alzheimer's disease. Neuropathol Appl Neurobiol 44:628–638CrossRefGoogle Scholar
  25. 25.
    Jimi T, Wakayama Y, Matsuzaki Y, Hara H, Inoue M, Shibuya S (2004) Reduced expression of aquaporin 4 in human muscles with amyotrophic lateral sclerosis and other neurogenic atrophies. Pathol Res Pract 200:203–209CrossRefGoogle Scholar
  26. 26.
    Dai J, Lin W, Zheng M, Liu Q, He B, Luo C, Lu X, Pei Z, Su H, Yao X (2017) Alterations in AQP4 expression and polarization in the course of motor neuron degeneration in SOD1G93A mice. Mol Med Rep 16:1739–1746CrossRefGoogle Scholar
  27. 27.
    Amiry-Moghaddam M, Williamson A, Palomba M, Eid T, de Lanerolle NC, Nagelhus EA, Adams ME, Froehner SC, Agre P, Ottersen OP (2003) Delayed K+ clearance associated with aquaporin-4 mislocalization: phenotypic defects in brains of alpha-syntrophiN-null mice. Proc Natl Acad Sci U S A 100:13615–13620CrossRefGoogle Scholar
  28. 28.
    Haj-Yasein NN, Jensen V, Østby I, Omholt SW, Voipio J, Kaila K, Ottersen OP, Hvalby Ø, Nagelhus EA (2012) Aquaporin-4 regulates extracellular space volume dynamics during high-frequency synaptic stimulation: a gene deletion study in mouse hippocampus. Glia 60:867–874CrossRefGoogle Scholar
  29. 29.
    Wei F, Zhang C, Xue R, Shan L, Gong S, Wang G, Tao J, Xu G, Zhang G, Wang L (2017) The pathway of subarachnoid CSF moving into the spinal parenchyma and the role of astrocytic aquaporin-4 in this process. Life Sci 182:29–40CrossRefGoogle Scholar
  30. 30.
    Li Y, Gu R, Zhu Q, Liu J (2018) Changes of spinal edema and expression of aquaporin 4 in methylprednisolone-treated rats with spinal cord injury. Ann Clin Lab Sci 48:453–459Google Scholar
  31. 31.
    Oklinski MK, Lim JS, Choi HJ, Oklinska P, Skowronski MT, Kwon TH (2014) Immunolocalization of water channel proteins AQP1 and AQP4 in rat spinal cord. J Histochem Cytochem 62:598–611CrossRefGoogle Scholar
  32. 32.
    Maragakis NJ, Rothstein JD (2006) Mechanisms of disease: astrocytes in neurodegenerative disease. Nat Clin Pract Neurol 2:679–689CrossRefGoogle Scholar
  33. 33.
    Maragakis NJ, Rothstein JD (2004) Glutamate transporters: animal models to neurologic disease. Neurobiol Dis 15:461–473CrossRefGoogle Scholar
  34. 34.
    Rothstein JD, Martin LJ, Kuncl RW (1992) Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med 326:1464–1468CrossRefGoogle Scholar
  35. 35.
    Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW (1995) Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 38:73–84CrossRefGoogle Scholar
  36. 36.
    Howland DS, Liu J, She Y, Goad B, Maragakis NJ, Kim B, Erickson J, Kulik J, DeVito L, Psaltis G, DeGennaro LJ, Cleveland DW, Rothstein JD (2002) Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci U S A 99:1604–1609CrossRefGoogle Scholar
  37. 37.
    Lan YL, Zhao J, Ma T, Li S (2016) The potential roles of aquaporin 4 in Alzheimer’s disease. Mol Neurobiol 53:5300–5309CrossRefGoogle Scholar
  38. 38.
    Lan YL, Zou S, Chen JJ, Zhao J, Li S (2016) The neuroprotective effect of the association of aquaporin-4/glutamate transporter-1 against Alzheimer’s disease. Neural Plast 2016:4626593CrossRefGoogle Scholar
  39. 39.
    Lan YL, Chen JJ, Hu G, Xu J, Xiao M, Li S (2017) Aquaporin 4 in astrocytes is a target for therapy in Alzheimer’s disease. Curr Pharm Des 23:4948–4957Google Scholar
  40. 40.
    Yang J, Li MX, Luo Y, Chen T, Liu J, Fang P, Jiang B, Hu ZL, Jin Y, Chen JG, Wang F (2013) Chronic ceftriaxone treatment rescues hippocampal memory deficit in AQP4 knockout mice via activation of GLT-1. Neuropharmacology 75:213–222CrossRefGoogle Scholar
  41. 41.
    Hinson SR, Roemer SF, Lucchinetti CF, Fryer JP, Kryzer TJ, Chamberlain JL, Howe CL, Pittock SJ, Lennon VA (2008) Aquaporin-4-binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down-regulating EAAT2. J Exp Med 205:2473–2481CrossRefGoogle Scholar
  42. 42.
    Mandrioli J, Rosi E, Fini N, Fasano A, Raggi S, Fantuzzi AL, Bedogni G (2017) Changes in routine laboratory tests and survival in amyotrophic lateral sclerosis. Neurol Sci 38:2177–2182CrossRefGoogle Scholar
  43. 43.
    Forte G, Bocca B, Oggiano R, Clemente S, Asara Y, Sotgiu MA, Farace C, Montella A, Fois AG, Malaguarnera M, Pirina P, Madeddu R (2017) Essential trace elements in amyotrophic lateral sclerosis (ALS): results in a population of a risk area of Italy. Neurol Sci 38:1609–1615CrossRefGoogle Scholar
  44. 44.
    Nakata M, Kuwabara S, Kanai K, Misawa S, Tamura N, Sawai S, Hattori T, Bostock H (2006) Distal excitability changes in motor axons in amyotrophic lateral sclerosis. Clin Neurophysiol 117:1444–1448CrossRefGoogle Scholar
  45. 45.
    Kanai K, Kuwabara S, Arai K, Sung JY, Ogawara K, Hattori T (2003) Muscle cramp in Machado-Joseph disease: altered motor axonal excitability properties and mexiletine treatment. Brain 126:965–973CrossRefGoogle Scholar
  46. 46.
    Newman EA, Frambach DA, Odette LL (1984) Control of extracellular potassium levels by retinal glial cell K+ siphoning. Science 225:1174–1175CrossRefGoogle Scholar
  47. 47.
    Bataveljić D, Nikolić L, Milosević M, Todorović N, Andjus PR (2012) Changes in the astrocytic aquaporin-4 and inwardly rectifying potassium channel expression in the brain of the amyotrophic lateral sclerosis SOD1(G93A) rat model. Glia 60:1991–2003CrossRefGoogle Scholar
  48. 48.
    Nagelhus EA, Mathiisen TM, Ottersen OP (2004) Aquaporin-4 in the central nervous system: cellular and subcellular distribution and coexpression with Kir4.1. Neuroscience 129:905–913CrossRefGoogle Scholar
  49. 49.
    Jo AO, Ryskamp DA, Phuong TT, Verkman AS, Yarishkin O, MacAulay N, Križaj D (2015) TRPV4 and AQP4 channels synergistically regulate cell volume and calcium homeostasis in retinal Müller glia. J Neurosci 35:13525–13537CrossRefGoogle Scholar
  50. 50.
    Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57:178–201CrossRefGoogle Scholar
  51. 51.
    Garbuzova-Davis S, Saporta S, Haller E, Kolomey I, Bennett SP, Potter H, Sanberg PR (2007) Evidence of compromised blood-spinal cord barrier in early and late symptomatic SOD1 mice modeling ALS. PLoS One 2:e1205CrossRefGoogle Scholar
  52. 52.
    Zhong Z, Deane R, Ali Z, Parisi M, Shapovalov Y, O’Banion MK, Stojanovic K, Sagare A, Boillee S, Cleveland DW, Zlokovic BV (2008) ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration. Nat Neurosci 11:420–422CrossRefGoogle Scholar
  53. 53.
    Garbuzova-Davis S, Haller E, Saporta S, Kolomey I, Nicosia SV, Sanberg PR (2007) Ultrastructure of blood-brain barrier and blood-spinal cord barrier in SOD1 mice modeling ALS. Brain Res 1157:126–137CrossRefGoogle Scholar
  54. 54.
    Steiner J, Bogerts B, Schroeter ML, Bernstein HG (2011) S100B protein in neurodegenerative disorders. Clin Chem Lab Med 49:409–424CrossRefGoogle Scholar
  55. 55.
    Wu YF, Sytwu HK, Lung FW (2018) Human aquaporin 4 gene polymorphisms and haplotypes are associated with serum S100B level and negative symptoms of schizophrenia in a southern Chinese Han population. Front Psychiatry 9:657CrossRefGoogle Scholar
  56. 56.
    Yu YJ, Watts RJ (2013) Developing therapeutic antibodies for neurodegenerative disease. Neurotherapeutics 10:459–472CrossRefGoogle Scholar
  57. 57.
    Hillebrand S, Schanda K, Nigritinou M, Tsymala I, Böhm D, Peschl P, Takai Y, Fujihara K, Nakashima I, Misu T, Reindl M, Lassmann H, Bradl M (2019) Circulating AQP4-specific auto-antibodies alone can induce neuromyelitis optica spectrum disorder in the rat. Acta Neuropathol 137:467–485CrossRefGoogle Scholar
  58. 58.
    Howe CL, Kaptzan T, Magana SM, Ayers-Ringler JR, LaFrance-Corey RG, Lucchinetti CF (2014) Neuromyelitis optica IgG stimulates an immunological response in rat astrocyte cultures. Glia 62:692–708CrossRefGoogle Scholar
  59. 59.
    Takeshita Y, Obermeier B, Cotleur AC, Spampinato SF, Shimizu F, Yamamoto E, Sano Y, Kryzer TJ, Lennon VA, Kanda T, Ransohoff RM (2017) Effects of neuromyelitis optica-IgG at the blood–brain barrier in vitro. Neurol Neuroimmunol Neuroinflammation 4:e311CrossRefGoogle Scholar
  60. 60.
    Zhou J, Kong H, Hua X, Xiao M, Ding J, Hu G (2008) Altered blood-brain barrier integrity in adult aquaporin-4 knockout mice. Neuroreport 19:1–5CrossRefGoogle Scholar
  61. 61.
    Saadoun S, Tait MJ, Reza A, Davies DC, Bell BA, Verkman AS, Papadopoulos MC (2009) AQP4 gene deletion in mice does not alter blood-brain barrier integrity or brain morphology. Neuroscience 161:764–772CrossRefGoogle Scholar
  62. 62.
    Eilert-Olsen M, Haj-Yasein NN, Vindedal GF, Enger R, Gundersen GA, Hoddevik EH, Petersen PH, Haug FMS, Skare Ø, Adams ME, Froehner SC, Burkhardt JM, Thoren AE, Nagelhus EA (2012) Deletion of aquaporin-4 changes the perivascular glial protein scaffold without disrupting the brain endothelial barrier. Glia 60:432–440CrossRefGoogle Scholar
  63. 63.
    Feng X, Papadopoulos MC, Liu J, Li L, Zhang D, Zhang H, Verkman AS, Ma T (2009) Sporadic obstructive hydrocephalus in Aqp4 null mice. J Neurosci Res 87:1150–1155CrossRefGoogle Scholar
  64. 64.
    Lin X, Xu Q, Veenstra RD (2014) Functional formation of heterotypic gap junction channels by connexins-40 and -43. Channels (Austin) 8:433–443CrossRefGoogle Scholar
  65. 65.
    Orthmann-Murphy JL, Abrams CK, Scherer SS (2008) Gap junctions couple astrocytes and oligodendrocytes. J Mol Neurosci 35:101–116CrossRefGoogle Scholar
  66. 66.
    Díaz-Amarilla P, Olivera-Bravo S, Trias E, Cragnolini A, Martínez-Palma L, Cassina P, Beckman J, Barbeito L (2011) Phenotypically aberrant astrocytes that promote motoneuron damage in a model of inherited amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 108:18126–18131CrossRefGoogle Scholar
  67. 67.
    Cui Y, Masaki K, Yamasaki R, Imamura S, Suzuki SO, Hayashi S, Sato S, Nagara Y, Kawamura MF, Kira J (2014) Extensive dysregulations of oligodendrocytic and astrocytic connexins are associated with disease progression in an amyotrophic lateral sclerosis mouse model. J Neuroinflammation 11:42CrossRefGoogle Scholar
  68. 68.
    Rash JE, Yasumura T, Dudek FE, Nagy JI (2001) Cell-specific expression of connexins and evidence of restricted gap junctional coupling between glial cells and between neurons. J Neurosci 21:1983–2000CrossRefGoogle Scholar
  69. 69.
    Griemsmann S, Höft SP, Bedner P et al (2015) Characterization of panglial gap junction networks in the thalamus, neocortex, and hippocampus reveals a unique population of glial cells. Cereb Cortex 25:3420–3433CrossRefGoogle Scholar
  70. 70.
    Katoozi S, Skauli N, Rahmani S, Camassa LMA, Boldt HB, Ottersen OP, Amiry-Moghaddam M (2017) Targeted deletion of Aqp4 promotes the formation of astrocytic gap junctions. Brain Struct Funct 222:3959–3972CrossRefGoogle Scholar
  71. 71.
    Strohschein S, Huttmann K, Gabriel S, Binder DK, Heinemann U, Steinhauser C (2011) Impact of aquaporin-4 channels on K+ buffering and gap junction coupling in the hippocampus. Glia 59:973–980CrossRefGoogle Scholar
  72. 72.
    Li G, Liu X, Liu Z, Su Z (2015) Interactions of connexin 43 and aquaporin-4 in the formation of glioma-induced brain edema. Mol Med Rep 11:1188–1194CrossRefGoogle Scholar
  73. 73.
    Hu AM, Li JJ, Sun W et al (2015) Myelotomy reduces spinal cord edema and inhibits aquaporin-4 and aquaporin-9 expression in rats with spinal cord injury. Spinal Cord 53:98–102CrossRefGoogle Scholar
  74. 74.
    Nesic O, Lee J, Ye Z, Unabia GC, Rafati D, Hulsebosch CE, Perez-Polo JR (2006) Acute and chronic changes in aquaporin 4 expression after spinal cord injury. Neuroscience 143:779–792CrossRefGoogle Scholar
  75. 75.
    Wu Q, Zhang YJ, Gao JY, Li XM, Kong H, Zhang YP, Xiao M, Shields CB, Hu G (2014) Aquaporin-4 mitigates retrograde degeneration of rubrospinal neurons by facilitating edema clearance and glial scar formation after spinal cord injury in mice. Mol Neurobiol 49:1327–1337CrossRefGoogle Scholar
  76. 76.
    Mao L, Wang HD, Pan H, Qiao L (2011) Sulphoraphane enhances aquaporin-4 expression and decreases spinal cord oedema following spinal cord injury. Brain Inj 25:300–306CrossRefGoogle Scholar
  77. 77.
    Saadoun S, Bell BA, Verkman AS, Papadopoulos MC (2008) Greatly improved neurological outcome after spinal cord compression injury in AQP4-deficient mice. Brain 131:1087–1098CrossRefGoogle Scholar
  78. 78.
    Kimura A, Hsu M, Seldin M, Verkman AS, Scharfman HE, Binder DK (2010) Protective role of aquaporin-4 water channels after contusion spinal cord injury. Ann Neurol 67:794–801Google Scholar
  79. 79.
    Nesic O, Guest JD, Zivadinovic D, Narayana PA, Herrera JJ, Grill RJ, Mokkapati VU, Gelman BB, Lee J (2010) Aquaporins in spinal cord injury: the janus face of aquaporin 4. Neuroscience 168:1019–1035CrossRefGoogle Scholar
  80. 80.
    Ferreira D, Westman E, Eyjolfsdottir H et al (2015) Brain changes in Alzheimer’s disease patients with implanted encapsulated cells releasing nerve growth factor. J Alzheimers Dis 43:1059–1072CrossRefGoogle Scholar
  81. 81.
    Appel SH (1981) A unifying hypothesis for the cause of amyotrophic lateral sclerosis, parkinsonism, and Alzheimer disease. Ann Neurol 10:499–505CrossRefGoogle Scholar
  82. 82.
    Anand P, Parrett A, Martin J, Zeman S, Foley P, Swash M, Leigh PN, Cedarbaum JM, Lindsay RM, Williams-Chestnut RE, Sinicropi DV (1995) Regional changes of ciliary neurotrophic factor and nerve growth factor levels in post mortem spinal cord and cerebral cortex from patients with motor disease. Nat Med 1:168–172CrossRefGoogle Scholar
  83. 83.
    Chen J, Zeng X, Li S, Zhong Z, Hu X, Xiang H, Rao Y, Zhang L, Zhou X, Xia Q, Wang T, Zhang X (2017) Lentivirus-mediated inhibition of AQP4 accelerates motor function recovery associated with NGF in spinal cord contusion rats. Brain Res 1669:106–113CrossRefGoogle Scholar
  84. 84.
    Verkman AS, Smith AJ, Phuan PW, Tradtrantip L, Anderson MO (2017) The aquaporin-4 water channel as a potential drug target in neurological disorders. Expert Opin Ther Targets 21:1161–1170CrossRefGoogle Scholar

Copyright information

© Fondazione Società Italiana di Neurologia 2019

Authors and Affiliations

  1. 1.Computer CenterThe Second Affiliated Hospital of Dalian Medical UniversityDalianChina
  2. 2.Department of NeurosurgeryThe Second Affiliated Hospital of Dalian Medical UniversityDalianChina
  3. 3.Department of NeurologyThe Second Affiliated Hospital of Dalian Medical UniversityDalianChina
  4. 4.Department of PhysiologyDalian Medical UniversityDalianChina
  5. 5.Department of NeurosurgeryShenzhen People’s HospitalShenzhenChina

Personalised recommendations