Marine Mucor sp.-Derived Tyrosol Protects MPP+-Induced Dopaminergic Neuronal Cell Death in In Vitro Model of Parkinson's Disease

Abstract

Marine-derived fungi have gained growing attention as a rich source of biologically active secondary metabolites. The bioactivity guided purification of ethyl acetate extract of marine-derived Mucor sp., isolated from surface of a marine red algae, yielded tyrosol [4-(2-hydroxyethyl)phenol] and tryptophol [2-(1H-Indol-3-yl)ethanol] as major secondary metabolites. The structure of the compounds was established on the basis of nuclear magnetic resonance (NMR) and mass spectroscopic data. Tyrosol production of the isolated Mucor sp. was sensitive for culture conditions and optimum culture conditions for production of tyrosol were identified. The protective role of tyrosol on 1-methyl-4-phenylpyridinium (MPP+)-induced dopaminergic neuronal cell [CATH.a and pheochromocytoma (PC-12)] death and activation of BV-2 murine microglia cells were assessed. Tyrosol significantly protected MPP+-induced CATH.a cell death and apoptosis in dose and time-dependant manner. MPP+-induced morphological changes in differentiated PC-12 cells were considerably attenuated by tyrosol treatment. Further, the compound repressed MPP+-induced depletion of mitochondrial membrane potential (∆ψm), intracellular ATP production and apoptotic signalling cascade in CATH.a cells. The molecular signalling pathway studies revealed that tyrosol protected neuron cells via activation of PI3K/Akt signalling pathway along with upregulation of anti-oxidative enzymes (superoxide dismutases; SOD1, SOD2) and DJ-1/PARK7 activity of the cell. Moreover, tyrosol significantly inhibited the production of reactive oxygen species (ROS), nitric oxide (NO) and inflammatory cytokine TNF-α in lipopolysaccharide (LPS)-induced BV-2 cells by inhibiting the nuclear translocation of nuclear factor-κB p50 and p65 subunits. The anti-inflammatory activity of tyrosol reinforced the protective effect of tyrosol on neuronal apoptosis. Collectively, results demonstrated that tyrosol protected dopaminergic neuronal degradation via both neuroprotection and anti-inflammation.