Neuromelanin synthesis in rat and human substantia nigra

Abstract

A relation between neuromelanin synthesis and vulnerability of dopaminergic neurons is suggested by the fact that heavily pigmented cells are preferentially lost in aging and Parkinson's disease and that the dopaminergic neurotoxin MPP+ (1-methyl-4-phenyl-pyridine) binds to neuromelanin. To elucidate the mechanism of neuromelanin synthesis, we studied the formation of melanin in homogenates of human and rat substantia nigra tissue "in vitro". It was found that enzymatic processes accounted for 70% and 90% of the melanin formation in homogenates of human and rat tissue, respectively. The enzymatic synthesis was due to the activity of monoamine oxidase (MAO), since it was prevented by selective inhibitors of this enzyme. Both MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and MPP+ inhibited melanin formation, probably due to their ability to inhibit MAO. No evidence was found for involvement of cytochrome P-450 monooxigenases, which have been postulated to exist in central catecholaminergic neurons. Proadifen reduced melanin formation, not necessarily because it is an inhibitor of P-450 monooxigenases, but rather as it is also a potent inhibitor of MAO. Some antioxidants like ascorbic acid, but not agents destroying hydrogen peroxide, inhibited melanin formation. The findings suggest that the formation of neuromelanin in the substantia nigra involves MAO and non-enzymatic oxidative processes.

Enzymatic Oxidation of Dopamine: The Role of Prostaglandin H Synthase

“…Whether this is the predominant mechanism for neuromelanin formation in vivo is not known. However, in the absence of an identifiable enzyme in brain that catalyzes the oxidation of DA, it generally has been assumed that the process occurs spontaneously (Rodgers and Curzon, 1975;Graham, 1979 ;Rabey and Hefti, 1990) .…”

Identification of Catechol‐Protein Conjugates in Neostriatal Slices Incubated with [3H]Dopamine: Impact of Ascorbic Acid and Glutathione

“…Subsequently, it was found that DA also can form similar reactive compounds (Tse et al, 1976;Graham, 1978), and can exert neurotoxic effects both in vitro Moldéus et al, 1983 ;Michel and Hefti, 1990) and in vivo (Filloux and Townsend, 1993). The formation of these reactive metabolites can occur by one of the following three routes : (1) DA can undergo autoxidation by one or two electron transfers, a process accelerated by the presence of transition metal ions (Halliwell, 1992); (2) the brain can oxidize DA enzymatically (Grisham et al, 1987 ;Rabey and Hefti, 1990;Schipper et al, 1991), a process that can occur by several means, including via the peroxidase activity contained in prostaglandin synthase (Hastings and Zigmond, 1992); and (3) HZOZ is formed as a normal product of DA metabolism by monoamine oxidase and, without reduction by adequate GSH peroxidase, can be broken down through interaction with metal ions into free radical species such as OZ-or OH- (Maker et al, 1981 ;Halliwell, 1992). In short, conditions that increase concentration and/or turnover of DA should increase the potential for the formation of reactive metabolites through one or more of these routes .…”

Neurotoxicity due to o-Quinones: Neuromelanin formation and possible mechanisms for o-Quinone detoxification

“…In contrast to that mechanism, during the last years there are some further lines of evidence indicating the involvement of different enzymes in o-diphenol oxidation and neuromelanin formation inside the nervous system. These enzymatic species, are tyrosine hydroxylase (Haavik, 1997), tyrosinase (Steel et al, 1992;Tief et al, 1996), prostaglandin H synthase/synthetase (Hasting, 1995;Mattammal et al, 1995), peroxidase (Carstam et al, 1991;Okun et al, 1971) and monoamine oxidase (Rabey and Hefti, 1990).…”