Despite the availability of HAART, neurocognitive impairment remains a significant problem for HIV-infected individuals. We proposed the use of fluconazole as a potential neuroprotectant for HAND, since previous unpublished data found that fluconazole protects neuronal cultures against toxicity mediated by the HIV Tat protein and the mitochondrial toxin 3NP. We found that fluconazole decreases the amount of cleaved caspase 3 in neuronal cultures exposed to 3NP, suggesting an inhibitory effect on neuronal apoptosis. Next, we discovered that fluconazole leads to a decrease in EPSC and an increase in paired pulse ratio, suggesting a presynaptic effect on neurons. Since decreased cAMP levels can lead to decreased EPSC, we investigated whether fluconazole has a direct effect on cAMP levels in neurons and found that fluconazole decreased cAMP levels in a dose-dependent manner in mixed neuronal cultures. To further explore fluconazole's mechanism of action on neurons and whether a structure-function relationship is responsible for this mechanism, we also used a single-triazole fluconazole analog. Since cAMP is a downstream component in the Ala pathway, we next sought to determine if fluconazole's effect on cAMP levels is related to the Akt pathway. We found that the presence of both fluconazole and its single-triazole analog lead to increased levels of pAkt (T308), suggesting that both compounds can activate the Akt pathway. Moreover, a repetition of this experiment confirmed that fluconazole had no effect on the ubiquitous cytosolic protein HSP90, suggesting that the upregulation of pAkt (T308) by fluconazole and its analog may be a direct effect on the Akt pathway and not a nonspecific effect on cytosolic proteins. Next, we show that fluconazole effects on pAkt (T308) expression may be related to the IGF-1 receptor. We then investigated if an actual link exists between fluconazole and the IGF-1 receptor. Lastly, we found that fluconazole and the fluconazole analog increased expression of the IGF-1 receptor in a dose-dependent manner, which confirms that fluconazole and its analog have an effect on IGF-1 receptor expression and this may be the mechanism behind fluconazole's activation of the Akt pathway and subsequent inhibition of apoptosis.