Systematic review of neurological diseases and carbenoxolone: A double-edged sword?

In this systematic review, we aim to clarify common findings on carbenoxolone's effects on neurological conditions, including stroke, across studies and identify areas where knowledge remains incomplete. We searched several electronic databases, including PubMed, Web of Science, and the Cochrane Library, from their inception and finally included 60 studies in our review. This review reveals carbenoxolone's neuroprotective properties, such as gap junction inhibition, inhibiting the enzyme 11β-hydroxysteroid dehydrogenase (HSD) type I, inducing heat shock proteins, and inhibiting amyloid β42 aggregation. Conversely, it highlights carbenoxolone's neurotoxic potential, including inhibiting the enzyme 11β-HSD type II, mitochondrial dysfunction, and impaired astrocytic uptake of excitotoxic substances. Gap junctions also act as a pathway for neurotrophic factors and drugs that provide neuroprotection, and their inhibition by carbenoxolone may be detrimental to neuronal survival. In the systematic review, the comparison of carbenoxolone concentrations used in in vitro experiments that reported inhibition of 11β-HSD and gap junctions showed significant differences, with higher concentrations noted for gap junction inhibition. Induction of heat shock proteins and inhibition of amyloid-β were limited to long-term administration. Studies related to stroke demonstrated that all instances of hemorrhagic stroke exhibited neurotoxic effects. Additionally, studies administering carbenoxolone after cerebral ischemia reported poor outcomes in experiments with higher dosages and in chronic phases. In conclusion, carbenoxolone presents both neuroprotective and neurotoxic potential, necessitating cautious application in clinical settings. Future research should prioritize comprehensive, high-throughput studies to elucidate carbenoxolone's diverse mechanisms and long-term impacts, optimizing its therapeutic potential for neurological diseases.