The blood–brain barrier-permeable catechol-O-methyltransferase inhibitor dinitrocatechol suppresses experimental autoimmune encephalomyelitis

Causes, consequences, and cures for neuroinflammation mediated via the locus coeruleus: noradrenergic signaling system

“…); or the blood–brain barrier permeable COMT inhibitor DNC (Polak et al . ), all described improved outcomes in mice with EAE. We also showed that treatment of EAE mice with vindeburnol, believed to increase LC TH+ neurons, significantly reduced clinical scores and neuroinflammation, as well as increasing NA levels and LC damage (Polak et al .…”

“…It was reported that COMT inhibitors can block amyloid fibril formation, however, those studies were done in vitro and likely due to the presence of the catechol ring (Di Giovanni et al 2010). Given the evidence for reduced NA levels in MS and its animal models, we characterized COMT expression during the course of mouse EAE, and tested if di-nitrocatechol (DNC) a blood-brain barrier permeable COMT inhibitor would provide benefit (Polak et al 2014). We found that treatment with DNC, initiated at day 15 after immunization (near the onset of clinical signs) significantly reduced the subsequent development of clinical scores.…”

“…As for mouse models of AD, experimentally increasing CNS NA levels can ameliorate disease and neuropathology in EAE. Studies using the MAO inhibitor phenelzine (Musgrave et al 2011;Benson et al 2013); the antidepressant venlafaxine (Vollmar et al 2009), the NA precursor DOPS (Simonini et al 2010); or the blood-brain barrier permeable COMT inhibitor DNC (Polak et al 2014), all described improved outcomes in mice with EAE. We also showed that treatment of EAE mice with vindeburnol, believed to increase LC TH+ neurons, significantly reduced clinical scores and neuroinflammation, as well as increasing NA levels and LC damage .…”

Preventing neurodegeneration by adrenergic astroglial excitation

“…Moreover, one such agent is antagonist for a 2 -ARs, which blocks these receptors, also known as a 2 -autoreceptors, since they are located at the presynaptic membrane and mediate the inhibition of release of NA from LC neurons via the activation of a G i -protein second messenger pathway. Inhibitors of COMT have been used for many years to reduce levodopa breakdown during treatment of PD [126]; and recently it was shown that dinitrocatechol, a BBBpermeable COMT antagonist, was beneficial in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis (MS) [127]. The NA levels could be also elevated by using NA reuptake inhibitors such as atomoxetine and reboxetine, to exert anti-inflammatory action in vivo [116][117][118].…”

“…Levels of MAO mRNA were increased in AD patients versus controls [124], while variants in the MAO genes are risk factor to develop AD [125]. Inhibitors of COMT have been used for many years to reduce levodopa breakdown during treatment of PD [126]; and recently it was shown that dinitrocatechol, a BBBpermeable COMT antagonist, was beneficial in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis (MS) [127].…”