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

Abstract

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.

Acetazolamide and topiramate lower intracranial pressure through differential mechanisms: The effect of acute and chronic administration

“…Topiramate reduced ICP to a similar degree as our previous study, where it reduced ICP when administered subcutaneously and in the food of sedated rats (Scotton et al, 2019). Our acetazolamide data are in contrast to some studies and corroborate others, where acetazolamide has been found to either reduce ICP or have no ICP modulatory effect (Barbuskaite et al, 2022;Scotton et al, 2019;Williamson et al, 2019). These previous studies differ from ours through differing administration routes, use of sedation and anaesthesia and the use of inappropriate vehicles: all of which can independently alter ICP (Eftekhari et al, 2020;Uldall et al, 2017).…”

“…With chronic administration of these drugs in female rats, there was minimal tachyphylaxis. The degree of ICP reduction we observed with chronic acetazolamide is mirrored by that in male rats (Barbuskaite et al, 2022). The equivalent effect of these drugs on ICP mirrors an open label trial where they conferred equivalent retinal outcomes in IIH patients (Çelebisoy et al, 2007).…”

“…The only study with comparable methods demonstrated a similar degree of acetazolamide mediated ICP reduction in male rats (Barbuskaite et al, 2022). We assessed the effects of acetazolamide and topiramate in freely moving female rats in normal physiological conditions with a clinically relevant administration route and patient drug formulations.…”

“…Acetazolamide lowers ICP through inhibiting CA activity and therefore CSF secretion (Barbuskaite et al, 2022). Systemic CA inhibition has clear physiological hallmarks: diuresis and acidosis.…”

“…A single study has assessed acetazolamide in freely moving male rats and demonstrated efficacy of acetazolamide to reduce ICP (Barbuskaite et al, 2022). In lieu of the limited clinical and preclinical data, it is imperative to establish whether acetazolamide and topiramate lower ICP, given their broad side effects profile.…”