Table 3.
NOX2 inhibition promotes healthy microglial function and neuroprotection
| NOX2 inhibitor | Disease model | Effect | References |
|---|---|---|---|
| Alzheimer’s disease | |||
| Ibuprophin | B6-R1.40 mice | Enhanced Aβ clearance and reduced ROS | [222] |
| Apocynin | hAPP(751)(SL) mice | Reduced plaque size and microglial number | [240] |
| Nicotine | fAβ (1-42), in vitro | Reduced microglial NOX2 activation | [241] |
| Melatonin | fAβ (1-42), in vitro | Inhibits p47PHOX phosphorylation | [242] |
| Simvastatin and lovastatin | fAβ (1-42), in vitro | Inhibits NOX2 activation via Rac1 inhibition | [215] |
| Parkinson’s disease | |||
| Apocynin | MPTP, MPP+, in vitro | Anti-inflammatory and neuroprotective | [156] |
| Diphenyliodonium (DPI) | LPS, in vitro | Inhibited microglial activation; neuoroprtective | [194] |
| Interleukin-10 | LPS, in vitro | Anti-inflammatory and neuroprotective | [243] |
| Transforming growth factor β1 | LPS and MPP+, in vitro | Anti-inflammatory and neuroprotective | [228] |
| Morphine | LPS and MPP+, in vitro | Anti-inflammatory and neuroprotective | [195] |
| PACAP | LPS and MPP+, in vitro | Anti-inflammatory and neuroprotective | [200] |
| Leucine enkephalin | LPS, in vitro | Anti-inflammatory and neuroprotective | [199] |
| Dynorphin | LPS, in vitro | Anti-inflammatory and neuroprotective | [101, 244] |
| Dextromethorphin | LPS and MPP+, in vitro, and MPTP, in vitvo | Anti-inflammatory and neuroprotective | [198, 245] |
| Naloxone | LPS, in vitro | Binds NOX2; anti-inflammatory and neuroprotective | [244] |
| Sinomenine | LPS and MPP+, in vitro | Anti-inflammatory and neuroprotective | [196] |
| Glyceryl nonivamide | 6-hydroxydopamine, in vitro | Anti-inflammatory, neuoprotective | [246] |
| Resveratrol | LPS, in vitro | Reduced microglial NOX2 activation; attenuated microglia-mediated neurotoxicity | [224] |
| FLZ | LPS and MPP+, in vitro | Anti-inflammatory and neuroprotective | [28] |
| Minocycline | Nigral thrombin injection, mice | NOX2 inhibition, anti-inflammatory and neuroprotective | [247] |
| Fluoxetine (antidepressant) | MPTP, in vitro | Only protective in presence of microglia; anti-inflammatory and neuroprotective | [159] |
| Verapamil | LPS, in vitro | Binds to NOX2; anti-inflammatory and neuroprotective | [201] |
| Paroxetine | MPTP, mice | Reduced NOX2 activation, loss of nigrostriatal DA neurons, and glial activation | [248] |
| Nimodipine | LPS and MPTP, in vitro | Decreased pro-inflammatory cytokines and ROS production; neuroprotective | [249] |
| Ischemia | |||
| LY367385 (mGluR1 antagonist) | Transient focal ischemia, rat | Deceased NOX2 activation, decreased expression of the NOX2 complex subunits | [250] |
| Andrographolide | Hypoxia, mice | Reduced NOX2 activation, Anti-inflammatory and neuroprotective | [251] |
| Apocynin | Cerebral Ischemia, mice | Blocked IL-1β potentiation of pial venule permeability | [252] |
| Apocynin | Cerebral Ischemia, mice | 50 % less brain infarction and 70 % less cleaved spectrin | [253] |
| Atorvastatin (statin) | Transient focal ischemia, rat | Anti-inflammatory and neuroprotective | [254] |
| Other | |||
| Aripiprazole (atypical antipsychotic) | PMA, in vitro | Anti-inflammatory and neuroprotective | [255] |
| (RS)-2-chloro-5-hydroxyphenylglycine | LPS, in vitro | Reduced microglial NOX2 activation and expression | [256] |
| Cannabidiol (non-psychoactive cannabinoid) | LPS, retinal microglia cultures | Reduced NOX2-derived ROS and lowered production of pro-inflammatory factors | [257] |
At present, highly specific NOX2 inhibitors that regulate microglial activation of confer neuroprotection are unavailable. The compounds listed here are potential inhibitors that have not confirmed direct interaction with NOX2 enzyme components. These molecules have demonstrated the ability to impact NOX2 function, which was determined by loss of function in the presence of other NOX2 inhibitors, NOX2 genetic ablation, or demonstration of the ability to impair assembly of the NOX2 complex. Notably, microglia have the ability to produce ROS through other mechanisms, and all ROS-inhibiting compounds were not included. Further, the compounds listed may have many neuroprotective effects outside of what is noted in this table, which only focuses on NOX2-dependent effects
PACAP pituitary adenylate cyclase-activating polypeptide, LPS lipopolysaccharide, ROS reactive oxygen species, MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPP + 1-methyl-4-phenylpyridinium, Aβ beta amyloid, FLZ N-[2-(4-hydroxy-phenyl)-ethyl]-2-(2,5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide