From: NADPH oxidases in Parkinson’s disease: a systematic review
NADPH oxidase signaling step | Mode of action | Inhibitors | Experimental model | Effects of the inhibitor on the experimental model | Current therapeutic roadblocks | Reference |
---|---|---|---|---|---|---|
Subunit expression | Decrease specific subunit mRNA and protein levels | Adeno-associated virus serotype 2 (AAV2) expression cassettes with Nox1shRNA | Striatal injection of 6-OHDA in the rat | Nox1 knockdown reduced 6-OHDA-induced oxidative DNA damage and dopaminergic neuronal degeneration. | Drug delivery | [89] |
Knockdown of Nox4 achieved by adenoviral-encoded small interfering RNA | Mouse catecholaminergic neuronal cell model (CATH.a) exposed to angiotensine II | Nox4 knockdown attenuated of angiotensine II-induced mitochondrial O2∙-production. | Drug delivery | [88] | ||
Ligand-receptor binding | Block the interaction between alpha-synuclein and P2X7R | Brilliant Blue G, a P2X7R antagonist | BV2 microglial cells treated with wild type or A53T alpha-synuclein | Pretreatment with Brilliant Blue G reduced the translocation of p47phox from the cytoplasm to the membrane after treatment with each form of alpha-synuclein. | Targets one of many NADPH oxidase activators | [135] |
Complex assembly and activation | AAV2 expression cassettes with a T17N dominant negative Rac1 variant | Striatal injection of 6-OHDA in the rat | Rac1 inhibition reduced 6-OHDA-induced oxidative DNA damage and dopaminergic neuronal degeneration. | Drug delivery | [89] | |
Prevent p47phox association with NADPH oxidase complex | Apocynin | Lipopolysaccharide induced PD model: single injection of lipopolysaccharide at a dose of 5ug/5ul PBS into the SN of rats. | Apocynin prevents α-synuclein aggregation, microglial activation, dopaminergic neurodegeneration and relieves motor system abnormality following lipopolysaccharide injection. | Unspecific, dosing: | [189] | |
gp91-ds,a peptide inhibitor for NADPH oxidase assembly | SH-SY5Y dopaminergic cells exposed to rotenone | Preincubation with Nox2-ds partially attenuated LC3 and p62 protein levels and protected against rotenone-dependent upregulation in apoptotic signaling (Pal et al., 2016). | Drug delivery, pharmacokinetic and CNS biodisponibility | [177] | ||
Block PI3K signaling needed for NADPH oxidase activation | LY294002, a potent and specific cell-permeable inhibitor of PI3K | [135] | ||||
Electron transfer | Extracts electrons | Diphenyleneiodonium | Neuron-glia cultures pretreated with lipopolysaccharide, 1-methyl-4-phenylpyridinium or rotenone | Diphenyleneiodonium protected the dopaminergic neurons at subpicomolar concentrations. | 2non-specificity for other flavoenzymes and high cytotoxicity at standard doses (μM) | [190] |