Posthemorrhagic hydrocephalus associates with elevated inflammation and CSF hypersecretion via activation of choroidal transporters
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Posthemorrhagic hydrocephalus associates with elevated inflammation and CSF hypersecretion via activation of choroidal transporters. / Lolansen, Sara Diana; Rostgaard, Nina; Barbuskaite, Dagne; Capion, Tenna; Olsen, Markus Harboe; Norager, Nicolas H.; Vilhardt, Frederik; Andreassen, Søren Norge; Toft-Bertelsen, Trine L.; Ye, Fenghui; Juhler, Marianne; Keep, Richard F.; MacAulay, Nanna.
In: Fluids and Barriers of the CNS, Vol. 19, No. 1, 62, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Posthemorrhagic hydrocephalus associates with elevated inflammation and CSF hypersecretion via activation of choroidal transporters
AU - Lolansen, Sara Diana
AU - Rostgaard, Nina
AU - Barbuskaite, Dagne
AU - Capion, Tenna
AU - Olsen, Markus Harboe
AU - Norager, Nicolas H.
AU - Vilhardt, Frederik
AU - Andreassen, Søren Norge
AU - Toft-Bertelsen, Trine L.
AU - Ye, Fenghui
AU - Juhler, Marianne
AU - Keep, Richard F.
AU - MacAulay, Nanna
N1 - © 2022. The Author(s).
PY - 2022
Y1 - 2022
N2 - INTRODUCTION: Posthemorrhagic hydrocephalus (PHH) often develops following hemorrhagic events such as intraventricular hemorrhage (IVH) and subarachnoid hemorrhage (SAH). Treatment is limited to surgical diversion of the cerebrospinal fluid (CSF) since no efficient pharmacological therapies are available. This limitation follows from our incomplete knowledge of the molecular mechanisms underlying the ventriculomegaly characteristic of PHH. Here, we aimed to elucidate the molecular coupling between a hemorrhagic event and the subsequent PHH development, and reveal the inflammatory profile of the PHH pathogenesis.METHODS: CSF obtained from patients with SAH was analyzed for inflammatory markers using the proximity extension assay (PEA) technique. We employed an in vivo rat model of IVH to determine ventricular size, brain water content, intracranial pressure, and CSF secretion rate, as well as for transcriptomic analysis. Ex vivo radio-isotope assays of choroid plexus transport were employed to determine the direct effect of choroidal exposure to blood and inflammatory markers, both with acutely isolated choroid plexus and after prolonged exposure obtained with viable choroid plexus kept in tissue culture conditions.RESULTS: The rat model of IVH demonstrated PHH and associated CSF hypersecretion. The Na+/K+-ATPase activity was enhanced in choroid plexus isolated from IVH rats, but not directly stimulated by blood components. Inflammatory markers that were elevated in SAH patient CSF acted on immune receptors upregulated in IVH rat choroid plexus and caused Na+/K+/2Cl- cotransporter 1 (NKCC1) hyperactivity in ex vivo experimental conditions.CONCLUSIONS: CSF hypersecretion may contribute to PHH development, likely due to hyperactivity of choroid plexus transporters. The hemorrhage-induced inflammation detected in CSF and in the choroid plexus tissue may represent the underlying pathology. Therapeutic targeting of such pathways may be employed in future treatment strategies towards PHH patients.
AB - INTRODUCTION: Posthemorrhagic hydrocephalus (PHH) often develops following hemorrhagic events such as intraventricular hemorrhage (IVH) and subarachnoid hemorrhage (SAH). Treatment is limited to surgical diversion of the cerebrospinal fluid (CSF) since no efficient pharmacological therapies are available. This limitation follows from our incomplete knowledge of the molecular mechanisms underlying the ventriculomegaly characteristic of PHH. Here, we aimed to elucidate the molecular coupling between a hemorrhagic event and the subsequent PHH development, and reveal the inflammatory profile of the PHH pathogenesis.METHODS: CSF obtained from patients with SAH was analyzed for inflammatory markers using the proximity extension assay (PEA) technique. We employed an in vivo rat model of IVH to determine ventricular size, brain water content, intracranial pressure, and CSF secretion rate, as well as for transcriptomic analysis. Ex vivo radio-isotope assays of choroid plexus transport were employed to determine the direct effect of choroidal exposure to blood and inflammatory markers, both with acutely isolated choroid plexus and after prolonged exposure obtained with viable choroid plexus kept in tissue culture conditions.RESULTS: The rat model of IVH demonstrated PHH and associated CSF hypersecretion. The Na+/K+-ATPase activity was enhanced in choroid plexus isolated from IVH rats, but not directly stimulated by blood components. Inflammatory markers that were elevated in SAH patient CSF acted on immune receptors upregulated in IVH rat choroid plexus and caused Na+/K+/2Cl- cotransporter 1 (NKCC1) hyperactivity in ex vivo experimental conditions.CONCLUSIONS: CSF hypersecretion may contribute to PHH development, likely due to hyperactivity of choroid plexus transporters. The hemorrhage-induced inflammation detected in CSF and in the choroid plexus tissue may represent the underlying pathology. Therapeutic targeting of such pathways may be employed in future treatment strategies towards PHH patients.
KW - Intraventricular hemorrhage
KW - Subarachnoid hemorrhage
KW - Posthemorrhagic hydrocephalus
KW - Cerebrospinal fluid
KW - Immune response
KW - Biomarkers
KW - Choroid plexus
KW - CEREBROSPINAL-FLUID
KW - INTRAVENTRICULAR HEMORRHAGE
KW - ADENOSINE-TRIPHOSPHATASE
KW - PLEXUS
KW - INTERLEUKIN-6
KW - MANAGEMENT
KW - SECRETION
KW - ONTOLOGY
KW - SYSTEM
KW - ONLINE
U2 - 10.1186/s12987-022-00360-w
DO - 10.1186/s12987-022-00360-w
M3 - Journal article
C2 - 35948938
VL - 19
JO - Fluids and Barriers of the CNS
JF - Fluids and Barriers of the CNS
SN - 2045-8118
IS - 1
M1 - 62
ER -
ID: 316919358