Chloroquine (CQ) and hydroxychloroquine (HCQ) have long been used worldwide to treat and prevent human malarias. However, these 4-aminoquinolines have also shown promising potential in treating chronic illnesses with an inflammatory component, including neurological diseases. Given the current demand for serum avoidance during pharmacological testing and modeling of some pathologies, we compared cytotoxicities of CQ and HCQ in both serum-deprived and -fed murine BV-2 microglia. Furthermore, we assessed the anti-neuroinflammatory potential of both compounds in serum-deprived cells. Under both conditions, CQ showed higher cytotoxicity than HCQ. However, the comparable MTT-assay-derived data measured under different serum conditions were associated with disparate cytotoxic mechanisms of CQ and HCQ. In particular, under serum starvation, CQ mildly enhanced secondary ROS, mitochondrial hyperpolarization, and decreased phagocytosis. However, CQ promoted G1 phase cell cycle arrest and mitochondrial depolarization in serum-fed cells. Under both conditions, CQ fostered early apoptosis. Additionally, we confirmed that both compounds could exert anti-inflammatory effects in microglia through interference with MAPK signaling under nutrient-deprivation-related stress. Nevertheless, unlike HCQ, CQ is more likely to exaggerate intracellular prooxidant processes in activated starved microglia, which are inefficiently buffered by Nrf2/HO-1 signaling pathway activation. These outcomes also show HCQ as a promising anti-neuroinflammatory drug devoid of CQ-mediated cytotoxicity.
Keywords: Autophagy; Chloroquine; Hydroxychloroquine; Neuroinflammation; Nrf2; Serum Starvation.
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