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Table 2 Therapeutic targeting of NADPH oxidases in selected studies

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]