On the Role of DT-Diaphorase Inhibition in Aminochrome-Induced Neurotoxicity In Vivo

Abstract

Dopamine oxidation in the pathway leading to neuromelanin formation generates the ortho-quinone aminochrome, which is potentially neurotoxic but normally rapidly converted by DT-diaphorase to nontoxic leukoaminochrome. However, when administered exogenously into rat striatum, aminochrome is able to produce damage to dopaminergic neurons. Because of a recent report that substantia nigra pars compacta (SNpc) tyrosine hydroxylase (T-OH) levels were unaltered by aminochrome when there was cell shrinkage of dopaminergic neurons along with a reduction in striatal dopamine release, the following study was conducted to more accurately determine the role of DT-diaphorase in aminochrome neurotoxicity. In this study, a low dose of aminochrome (0.8 nmol) with or without the DT-diaphorase inhibitor dicoumarol (0.2 nmol) was injected into the left striatum of rats. Intrastriatal 6-hydroxydopamine (6-OHDA, 32 nmol) was used as a positive neurotoxin control in other rats. Two weeks later, there was significant loss in numbers of T-OH immunoreactive fibers in SNpc, also a loss in cell density in SNpc, and prominent apomorphine (0.5 mg/kg sc)-induced contralateral rotations in rats that had been treated with aminochrome, with aminochrome/dicoumarol, or with 6-OHDA. Findings demonstrate that neurotoxic aminochrome is able to exert neurotoxicity only when DT-diaphorase is suppressed-implying that DT-diaphorase is vital in normally suppressing toxicity of in vivo aminochrome, generated in the pathway towards neuromelanin formation.

NQO1: A target for the treatment of cancer and neurological diseases, and a model to understand loss of function disease mechanisms

“…Nevertheless, it appears that NQO1 plays a role in the neuroprotection of the dopaminergic system. Aminochrome only lead to neurotoxicity with the suppression of NQO1, manifesting itself with contralateral rotations and loss of dopaminergic neurons in rats [93]. Aminochrome toxicity was potentiated by NQO1 inhibition in a rat substantia nigra cell line.…”

Cancer-associated variants of human NQO1: impacts on inhibitor binding and cooperativity

“…NQO1 also has roles in cancer and some neurological diseases [4]. Inhibition of the proteasome is involved in the pathogenesis of Parkinson’s disease and NQO1 helps to protect against this inhibition by reducing the endogenous proteasome inhibitor, aminochrome, to a cyclized hydroquinone [21,22]. NQO1 has also been implicated in the regulation of oxidative stress associated with Alzheimer’s disease [23–27].…”

Addressing the Selectivity of Enzyme Biosensors: Solutions and Perspectives

“…Same potential inhibition should be taken into consideration also when using diaphorase for NA(D)PH electrochemistry purposes, this particular situation being even more complex since numerous enzymes are referred under the generic “diaphorase” name and thus the screening of the databases for potential inhibitors is even more complicated. Just to name a few examples, reported inhibitors for diaphorase include: anticoagulant dicoumarol [ 74 ], indolequinones derivatives [ 75 ] or stilbenes derivatives.…”