A MULTI-ARM, PARALLEL, PRECLINICAL STUDY INVESTIGATING THE POTENTIAL BENEFITS OF ACETAZOLAMIDE, CANDESARTAN, AND TRICIRIBINE IN THE TREATMENT OF CRYPTOCOCCAL MENINGITIS

Cryptococcus neoformans, an opportunistic fungus, is the causative agent of Cryptococcal meningoencephalitis (CM). Increased intracranial pressure (ICP) is a common complication responsible for increased morbidity and mortality in CM patients. Our knowledge of the molecular mechanisms regarding various steps leading to the infection and spreading of Cryptococcus spp. is limited. There is also a need for non-invasive pharmacological agents to treat CM patients. The objective of the study was to investigate the efficacies of pharmacological agents such as Acetazolamide (AZA), Candesartan (CAN), and Triciribine (TCBN) on cryptococcus-induced endothelial and brain/lung injury and edema in an experimental mouse model of CM. We demonstrated that C. neoformans enhanced the expression of brain endothelial (BEC) junctional proteins Claudin-5 (Cldn5) and VE-Cadherin and increased the inter-cellular gaps. Treatment with CAN and TCBN significantly reversed C. neoformans-induced Cldn5 expression, and all three agents inhibited C. neoformans-induced endothelial gap formation. C. neoformans activated Akt and P38 MAPK, both of which were reversed by treatment with TCBN. Differentconditions of C. neoformans numbers, fluconazole doses, and treatments with pharmacological agents did not affect brain and lung water content. However, C. neoformans induced lung and brain injury in the CM mouse model, which was significantly reversed by treatment with AZA, CAN, and TCBN. Our study provides novel insights into the direct effects of Cryptococcus on BECs in vitro, and the potential benefits of using AZA, CAN, and TCBN in the management of CM patients.

INDEX WORDS: Cryptococcus neoformans; Meningitis; Intracranial pressure; Blood-