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

Abstract

Background and purposeDiseases of raised intracranial pressure (ICP) cause severe morbidity and mortality. Multiple drugs are utilised to lower ICP including acetazolamide and topiramate. However, the evidence for their use is unclear. We aimed to assess the ICP modulatory effects and molecular effects at choroid plexus (CP) of acetazolamide and topiramate.Experimental approachFemale rats were implanted with telemetric ICP probes for physiological, freely moving 24/7 ICP recordings. Randomised cross‐over studies were performed, where rats received acute (24 hour) high doses of acetazolamide and topiramate, and chronic (10 days) clinically equivalent doses of acetazolamide and topiramate, all via oral gavage. CSF secretion assays, and RT‐qPCR and western blots on in vitro and in vivo CP, were used to assign function of the drugs.Key resultsWe demonstrate that acetazolamide and topiramate achieved maximal ICP reduction within 120 minutes of administration, where a combination of these doubled the ICP reduction over a 24‐hour period. Chronic administration of acetazolamide and topiramate lowered ICP by a quarter. Topiramate decreased CSF secretion by 40%. Chronic topiramate increased the gene expression of Slc12a2 and Slc4a10 and protein expression of NCBE, whereas chronic acetazolamide did not affect the expression of assessed genes.Conclusions and implicationsAcetazolamide and topiramate are effective at lowering ICP at therapeutic levels. We provide the first evidence that topiramate lowers CSF secretion and that acetazolamide and topiramate may lower ICP via distinct molecular mechanisms. Thus, the combination of acetazolamide and topiramate may have utility for treating raised ICP.