Membrane transporters control cerebrospinal fluid formation independently of conventional osmosis to modulate intracranial pressure.
Cerebrospinal fluid
Choroid plexus
Cotransport
Intracranial pressure
Osmosis
Journal
Fluids and barriers of the CNS
ISSN: 2045-8118
Titre abrégé: Fluids Barriers CNS
Pays: England
ID NLM: 101553157
Informations de publication
Date de publication:
29 Aug 2022
29 Aug 2022
Historique:
received:
02
03
2022
accepted:
13
07
2022
entrez:
29
8
2022
pubmed:
30
8
2022
medline:
1
9
2022
Statut:
epublish
Résumé
Disturbances in the brain fluid balance can lead to life-threatening elevation in the intracranial pressure (ICP), which represents a vast clinical challenge. Nevertheless, the details underlying the molecular mechanisms governing cerebrospinal fluid (CSF) secretion are largely unresolved, thus preventing targeted and efficient pharmaceutical therapy of cerebral pathologies involving elevated ICP. Experimental rats were employed for in vivo determinations of CSF secretion rates, ICP, blood pressure and ex vivo excised choroid plexus for morphological analysis and quantification of expression and activity of various transport proteins. CSF and blood extractions from rats, pigs, and humans were employed for osmolality determinations and a mathematical model employed to determine a contribution from potential local gradients at the surface of choroid plexus. We demonstrate that CSF secretion can occur independently of conventional osmosis and that local osmotic gradients do not suffice to support CSF secretion. Instead, the CSF secretion across the luminal membrane of choroid plexus relies approximately equally on the Na CSF secretion appears to not rely on conventional osmosis, but rather occur by a concerted effort of different choroidal transporters, possibly via a molecular mode of water transport inherent in the proteins themselves. Therapeutic modulation of the rate of CSF secretion may be employed as a strategy to modulate ICP. These insights identify new promising therapeutic targets against brain pathologies associated with elevated ICP.
Sections du résumé
BACKGROUND
BACKGROUND
Disturbances in the brain fluid balance can lead to life-threatening elevation in the intracranial pressure (ICP), which represents a vast clinical challenge. Nevertheless, the details underlying the molecular mechanisms governing cerebrospinal fluid (CSF) secretion are largely unresolved, thus preventing targeted and efficient pharmaceutical therapy of cerebral pathologies involving elevated ICP.
METHODS
METHODS
Experimental rats were employed for in vivo determinations of CSF secretion rates, ICP, blood pressure and ex vivo excised choroid plexus for morphological analysis and quantification of expression and activity of various transport proteins. CSF and blood extractions from rats, pigs, and humans were employed for osmolality determinations and a mathematical model employed to determine a contribution from potential local gradients at the surface of choroid plexus.
RESULTS
RESULTS
We demonstrate that CSF secretion can occur independently of conventional osmosis and that local osmotic gradients do not suffice to support CSF secretion. Instead, the CSF secretion across the luminal membrane of choroid plexus relies approximately equally on the Na
CONCLUSIONS
CONCLUSIONS
CSF secretion appears to not rely on conventional osmosis, but rather occur by a concerted effort of different choroidal transporters, possibly via a molecular mode of water transport inherent in the proteins themselves. Therapeutic modulation of the rate of CSF secretion may be employed as a strategy to modulate ICP. These insights identify new promising therapeutic targets against brain pathologies associated with elevated ICP.
Identifiants
pubmed: 36038945
doi: 10.1186/s12987-022-00358-4
pii: 10.1186/s12987-022-00358-4
pmc: PMC9422132
doi:
Substances chimiques
Membrane Transport Proteins
0
Sodium
9NEZ333N27
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
65Subventions
Organisme : Lundbeckfonden
ID : R303-2018-3005
Organisme : Lundbeckfonden
ID : R276-2018-403
Organisme : Deutsche Forschungsgemeinschaft
ID : FOR2795 - Ro2327/13-1
Organisme : Swiss National Science Foundation
ID : 182683
Pays : Switzerland
Organisme : Novo Nordisk Fonden
ID : NNF17OC0024718
Informations de copyright
© 2022. The Author(s).
Références
Exp Brain Res. 1976 May 28;25(2):157-67
pubmed: 945183
Alzheimers Dement. 2011 May;7(3):270-9
pubmed: 21514249
Br J Pharmacol. 2010 Aug;160(7):1577-9
pubmed: 20649561
Am J Physiol Cell Physiol. 2005 Dec;289(6):C1448-56
pubmed: 16093277
Glia. 2017 Nov;65(11):1777-1793
pubmed: 28787093
J Neurosci Methods. 2015 Feb 15;241:78-84
pubmed: 25554415
J Physiol. 1996 Mar 1;491 ( Pt 2):291-305
pubmed: 8866855
Br J Pharmacol. 2008 Mar;153(5):972-82
pubmed: 18204485
J Physiol. 2012 Mar 1;590(5):1139-54
pubmed: 22250214
Fluids Barriers CNS. 2019 Apr 10;16(1):9
pubmed: 30967147
Croat Med J. 2014 Aug 28;55(4):317-27
pubmed: 25165046
Fluids Barriers CNS. 2012 Jul 11;9(1):13
pubmed: 22784705
Br J Pharmacol. 2019 Dec;176 Suppl 1:S1-S20
pubmed: 31710719
Fluids Barriers CNS. 2022 Jun 29;19(1):53
pubmed: 35768824
Glia. 2017 Feb;65(2):388-400
pubmed: 27859594
Neurosci Lett. 2010 Oct 29;484(2):93-7
pubmed: 20674671
Pflugers Arch Gesamte Physiol Menschen Tiere. 1964 Jul 1;280:99-119
pubmed: 14257158
Eur J Neurosci. 2002 Dec;16(12):2358-70
pubmed: 12492431
Brain Res. 1972 Jan 14;36(1):37-45
pubmed: 5008383
J Neurophysiol. 1960 Sep;23:485-95
pubmed: 13743963
Fluids Barriers CNS. 2016 Oct 31;13(1):19
pubmed: 27799072
Nucleic Acids Res. 2013 Jan;41(Database issue):D561-5
pubmed: 23175613
JAMA. 2014 Apr 23-30;311(16):1641-51
pubmed: 24756514
Nat Rev Neurosci. 2021 Jun;22(6):326-344
pubmed: 33846637
Am J Physiol Cell Physiol. 2009 Jun;296(6):C1291-300
pubmed: 19369449
J Physiol. 1994 Jul 15;478 ( Pt 2):203-19
pubmed: 7965842
Am J Physiol Cell Physiol. 2019 Apr 1;316(4):C525-C544
pubmed: 30576237
J Appl Physiol (1985). 1987 Oct;63(4):1591-600
pubmed: 3693196
Bioinformatics. 2009 Jan 15;25(2):288-9
pubmed: 19033274
Neurochem Res. 2015 Dec;40(12):2583-99
pubmed: 25947369
Ann Neurol. 1981 Oct;10(4):333-40
pubmed: 7316486
Biochim Biophys Acta. 2003 Jan 10;1609(1):80-6
pubmed: 12507761
J Cell Sci. 1974 Mar;14(2):339-50
pubmed: 4822878
J Comp Neurol. 1966 Jul;127(3):413-34
pubmed: 5968004
J Physiol. 1984 Sep;354:3P-22P
pubmed: 6434728
Can J Physiol Pharmacol. 1982 Mar;60(3):405-9
pubmed: 7074425
Am J Physiol. 1966 Feb;210(2):232-6
pubmed: 5901459
FASEB J. 2005 Jan;19(1):76-8
pubmed: 15533949
J Cell Biol. 1969 Mar;40(3):648-77
pubmed: 5765759
Biophys J. 2010 Oct 6;99(7):L56-8
pubmed: 20923633
Am J Physiol Cell Physiol. 2006 Jul;291(1):C59-67
pubmed: 16481371
Front Physiol. 2016 Apr 22;7:141
pubmed: 27148079
J Physiol. 2010 Nov 1;588(Pt 21):4089-101
pubmed: 20819947
J Physiol. 1969 Sep;204(1):181-93
pubmed: 5352043
Anesthesiology. 1954 Nov;15(6):666-72
pubmed: 13207795
Neuroscience. 2010 Jul 28;168(4):941-56
pubmed: 19761815
Nat Med. 2017 Aug;23(8):997-1003
pubmed: 28692063
Fluids Barriers CNS. 2013 Mar 14;10(1):14
pubmed: 23497725
Pflugers Arch. 1985 Mar;403(3):301-7
pubmed: 3991334
Am J Physiol. 1989 Jun;256(6 Pt 2):F1059-66
pubmed: 2735420
Curr Pharm Des. 2012;18(10):1345-71
pubmed: 22360557
J Appl Physiol (1985). 2015 Sep 1;119(5):576-81
pubmed: 26159754
J Membr Biol. 1980 Oct 31;56(3):177-82
pubmed: 7005450
Exp Eye Res. 1977;25 Suppl:461-73
pubmed: 590401
J Physiol. 1991 Dec;444:133-51
pubmed: 1822548
Trends Cell Biol. 2020 Mar;30(3):213-225
pubmed: 31980346
Neuroscience. 2004;123(2):381-91
pubmed: 14698746
Cochrane Database Syst Rev. 2013 May 31;(5):CD009706
pubmed: 23728696
Brain Res Dev Brain Res. 1990 Oct 1;56(1):47-53
pubmed: 2279331
Pflugers Arch. 2007 Apr;454(1):1-18
pubmed: 17120021
Fluids Barriers CNS. 2022 Mar 22;19(1):26
pubmed: 35317823
Epilepsy Behav. 2016 Jun;59:42-9
pubmed: 27088517
Commun Biol. 2021 Feb 17;4(1):226
pubmed: 33597714
J Clin Invest. 2007 Jun;117(6):1708-17
pubmed: 17510708
Neuroscience. 2001;104(4):933-46
pubmed: 11457581
Am J Physiol. 1994 Dec;267(6 Pt 1):C1616-22
pubmed: 7810603
J Biol Chem. 2011 Sep 16;286(37):32563-74
pubmed: 21705333
Am J Physiol Cell Physiol. 2017 Jun 1;312(6):C673-C686
pubmed: 28330845
Cell Rep. 2020 Dec 22;33(12):108524
pubmed: 33357428
J Gen Physiol. 1967 Sep;50(8):2061-83
pubmed: 6066064
J Physiol. 2018 Oct;596(19):4709-4728
pubmed: 29956324
Pflugers Arch. 1975 Sep 9;359(3):253-64
pubmed: 1103083
J Physiol. 2020 Nov;598(21):4737-4739
pubmed: 32870507
BMJ Open. 2017 Jan 16;7(1):e013389
pubmed: 28093434
Biomark Med. 2012 Aug;6(4):419-30
pubmed: 22917144
BMC Cancer. 2017 Aug 14;17(1):542
pubmed: 28806945
J Clin Invest. 1993 Nov;92(5):2257-61
pubmed: 8227341
Physiol Rev. 2013 Oct;93(4):1847-92
pubmed: 24137023
Neuroscience. 2001;103(2):481-91
pubmed: 11246162
J Neurosurg. 1966 Oct;25(4):430-6
pubmed: 5925714
J Appl Physiol. 1972 May;32(5):612-7
pubmed: 5038848
Nat Commun. 2018 Jun 4;9(1):2167
pubmed: 29867199
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Fluids Barriers CNS. 2022 Jun 4;19(1):44
pubmed: 35659263
Brain Res. 1989 Oct 30;501(1):183-7
pubmed: 2804695
J Membr Biol. 1979 Dec 31;51(3-4):195-216
pubmed: 395308
Biochem J. 2014 Mar 15;458(3):559-73
pubmed: 24393035
Clin Chem. 1962 May-Jun;8:246-65
pubmed: 13906437
Nat Commun. 2021 Jan 19;12(1):447
pubmed: 33469018
Cochrane Database Syst Rev. 2015 Aug 07;(8):CD003434
pubmed: 26250102
Am J Physiol. 1972 Sep;223(3):503-6
pubmed: 5055305
Neurosurgery. 2005 Sep;57(3 Suppl):S4-16; discussion ii-v
pubmed: 16160425
Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7319-24
pubmed: 12777621
Nat Commun. 2017 Nov 10;8(1):1434
pubmed: 29127332
Am J Physiol. 1967 Oct;213(4):1031-8
pubmed: 6051171
Cerebrospinal Fluid Res. 2009 Dec 11;6:16
pubmed: 20003330
Genome Biol. 2016 May 06;17(1):91
pubmed: 27154141
J Comp Neurol. 2014 Jun 1;522(8):1897-914
pubmed: 24639001
J Membr Biol. 2010 Apr;234(2):57-73
pubmed: 20091162
Cell Mol Life Sci. 2021 Mar;78(6):2429-2457
pubmed: 33427948
BMC Bioinformatics. 2019 Dec 20;20(Suppl 24):679
pubmed: 31861985
J Membr Biol. 1983;76(2):113-22
pubmed: 6606049
Am J Physiol. 1951 Apr 1;165(1):87-92
pubmed: 14829576
Nucleic Acids Res. 2019 Jan 8;47(D1):D419-D426
pubmed: 30407594
Neurology. 2001 Jun 26;56(12):1746-8
pubmed: 11425944
Neurosurgery. 1985 Nov;17(5):768-72
pubmed: 2999636
Am J Physiol. 1963 Sep;205:617-24
pubmed: 14065919
J Physiol. 1965 Dec;181(3):516-24
pubmed: 5880375
Alzheimers Dement. 2011 May;7(3):263-9
pubmed: 21514250
Neurology. 2015 Jun 16;84(24):2449-56
pubmed: 25995055
Am J Physiol. 1964 May;206:1165-72
pubmed: 14208960
Int J Mol Sci. 2021 Feb 04;22(4):
pubmed: 33557294
Am J Physiol. 1962 Nov;203:775-81
pubmed: 13953498
Bioinformatics. 2007 Aug 15;23(16):2198-200
pubmed: 17545183
Life Sci. 1974 Oct 1;15(7):1309-16
pubmed: 4549978
Prog Neurobiol. 2011 Aug;94(3):238-58
pubmed: 21641963
Biophys J. 2008 May 15;94(10):3912-23
pubmed: 18234816
Cell Mol Life Sci. 2005 Aug;62(15):1692-706
pubmed: 15924268
J Physiol. 1970 Jul;209(1):131-53
pubmed: 5499038