TY - JOUR

T1 - Acetazolamide modulates intracranial pressure directly by its action on the cerebrospinal fluid secretion apparatus

AU - Barbuskaite, Dagne

AU - Ørnbo, Eva K.

AU - Wardman, Jonathan H.

AU - Toft-Bertelsen, Trine L.

AU - Conti, Eller

AU - Andreassen, Søren N.

AU - Gerkau, Niklas J.

AU - Rose, Christine R.

AU - MacAulay, Nanna

N1 - Publisher Copyright: © 2022. The Author(s).

PY - 2022

Y1 - 2022

N2 - BACKGROUND: Elevated intracranial pressure (ICP) is observed in many neurological pathologies, e.g. hydrocephalus and stroke. This condition is routinely relieved with neurosurgical approaches, since effective and targeted pharmacological tools are still lacking. The carbonic anhydrase inhibitor, acetazolamide (AZE), may be employed to treat elevated ICP. However, its effectiveness is questioned, its location of action unresolved, and its tolerability low. Here, we determined the efficacy and mode of action of AZE in the rat . METHODS: We employed in vivo approaches including ICP and cerebrospinal fluid secretion measurements in anaesthetized rats and telemetric monitoring of ICP and blood pressure in awake rats in combination with ex vivo choroidal radioisotope flux assays and transcriptomic analysis. RESULTS: AZE effectively reduced the ICP, irrespective of the mode of drug administration and level of anaesthesia. The effect appeared to occur via a direct action on the choroid plexus and an associated decrease in cerebrospinal fluid secretion, and not indirectly via the systemic action of AZE on renal and vascular processes. Upon a single administration, the reduced ICP endured for approximately 10 h post-AZE delivery with no long-term changes of brain water content or choroidal transporter expression. However, a persistent reduction of ICP was secured with repeated AZE administrations throughout the day. CONCLUSIONS: AZE lowers ICP directly via its ability to reduce the choroid plexus CSF secretion, irrespective of mode of drug administration.

AB - BACKGROUND: Elevated intracranial pressure (ICP) is observed in many neurological pathologies, e.g. hydrocephalus and stroke. This condition is routinely relieved with neurosurgical approaches, since effective and targeted pharmacological tools are still lacking. The carbonic anhydrase inhibitor, acetazolamide (AZE), may be employed to treat elevated ICP. However, its effectiveness is questioned, its location of action unresolved, and its tolerability low. Here, we determined the efficacy and mode of action of AZE in the rat . METHODS: We employed in vivo approaches including ICP and cerebrospinal fluid secretion measurements in anaesthetized rats and telemetric monitoring of ICP and blood pressure in awake rats in combination with ex vivo choroidal radioisotope flux assays and transcriptomic analysis. RESULTS: AZE effectively reduced the ICP, irrespective of the mode of drug administration and level of anaesthesia. The effect appeared to occur via a direct action on the choroid plexus and an associated decrease in cerebrospinal fluid secretion, and not indirectly via the systemic action of AZE on renal and vascular processes. Upon a single administration, the reduced ICP endured for approximately 10 h post-AZE delivery with no long-term changes of brain water content or choroidal transporter expression. However, a persistent reduction of ICP was secured with repeated AZE administrations throughout the day. CONCLUSIONS: AZE lowers ICP directly via its ability to reduce the choroid plexus CSF secretion, irrespective of mode of drug administration.

KW - Choroid plexus

KW - CSF secretion

KW - HCO3 − transporters

KW - Hydrocephalus

KW - ICP

KW - IIH

U2 - 10.1186/s12987-022-00348-6

DO - 10.1186/s12987-022-00348-6

M3 - Journal article

C2 - 35768824

AN - SCOPUS:85133144646

VL - 19

SP - 53

JO - Fluids and Barriers of the CNS

JF - Fluids and Barriers of the CNS

SN - 2045-8118

IS - 1

ER -