Viridicatin from the Antarctic Fungus Penicillium sp. Protects Human Microglia and Patient-Derived Peripheral Immune...

Neurodegenerative diseases remain a major therapeutic challenge, with oxidative stress playing a central role in central and peripheral immune system dysfunction that leads to neuronal loss. Natural products from extreme environments represent an underexplored source of neuroprotective agents. In this study, viridicatin, a quinoline-derived alkaloid, was isolated from the Antarctic fungus Penicillium sp. collected from sediments taken from Deception Island, and its structure was unambiguously confirmed by 1D/2D-NMR spectroscopy and single-crystal X-ray diffraction. Viridicatin (100 µM) significantly attenuated H₂O₂-induced cytotoxicity in HMC-3 human microglial cells, preserving cell viability and mitochondrial membrane potential. Viridicatin modulated the Nrf2 antioxidant signaling pathway, accompanied by increased expression of the downstream antioxidant enzymes HO-1 and NQO1. Moreover, molecular docking revealed preferential binding to the KEAP1 Kelch domain (-8.0 kcal/mol), suggesting indirect Nrf2 pathway modulation. A 100 ns molecular dynamics simulation with MM-GBSA analysis supported the stability of the viridicatin-KEAP1 complex. Notably, viridicatin rescued peripheral immune cells, i.e., peripheral blood mononuclear cells (PBMCs) obtained from older adults with mild cognitive impairment from H₂O₂-induced cell death, bridging the gap between in vitro mechanistic evidence and clinically relevant human cellular models. This is the first report of neuroprotective activity for viridicatin, positioning this Antarctic-derived alkaloid as a compelling candidate for further preclinical development against age-related neurodegeneration.