Link 15- Neuromelanin
www.tightrope.it/nicolaus/index.htm
In Memory of Giuseppe Prota
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Melanins and Melanogenesis
Giuseppe Prota
Universitΰ
degli studi di Napoli Federico II
Dipartimento di Chimica Organica e Biologica
Napoli, Italy
Academic Press Inc.
San Diego 1992
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At present little is definitely known about the structure of neuromelanin : Even the elemental composition is uncertain. This is largely due to the relative inaccessibility of the substantia nigra, the exceedingly low amounts of neuromelanin present , and the difficulties connected with liberating the pigment granules from the surrounding lipid matrix in which they are deeply embedded ( G.Prota Melanins and melanogenesis AP, San Diego 1992. )
In early studies a complex purification procedure was used involving prolonged proteolytic digestion with trypsin or pronase, treatment with lysing solutions, extensive extracions with organic solvents, and in some cases drastic acid hydrolysis with 6 M HCI. Spectroscopic studies of the pigment preparations thus obtained did not provide evidence for any distinguishing structural feature except a vague similarity of the absorption spectrum to that of dopamine melanin Recently, an improved procedure for isolating human substantia nigra neuromelanin has been developed This involves extraction of lipids and proteins with 2% sodium cholate in 30% ethanol followed by 2% SDS in 10% glycerol. Reductive hydrolysis of the pigment thus obtained with idroiodic acid and real phosphorous yilded 4-amino-3-hydroxyphenylethylamine in large quantities along with trace amounts of 4-amino-3-hydroxyphenylalanine indicating that 5-cysdopamine and 5-cysdopa,to a lesser extent,both concur to form the polymer.Dopamine and small quantities of dopa were also obtained by hydrolysis,whereas permanganate oxidation afforded some PTCA.These data would convey an image of neuromelanin as a mixed type melanin derived from dopamine in which pheomelanic and eumelanic type components coexist, probably as a result of an exhaustion of the GSH- cysteine defense system of the substantia nigra neurons. On going work in other laboratories, however, does not seem to provide confirming evidence for this structural view. and failed to detect cysdopamine- derived units in human substantia nigra melanin. On the other hand, it is reported analytical and spectroscopic data suggesting that 5 cysdopa or 5-cysdopamine linked to a palmityl residue are the most abundant constituents of human neuromelanin It is therefore clear that the current picture of neuromelanin structure is still very uncertain and susceptible to profound modifications .
Although the role of neuromelanin is not known
studies of the physicochemical properties of the pigment have given rise to
several hypotheses that may or not mutually related
(
M.E.Lacy Neuromelanin : A
hypothetical component of bioelectronic mechanism in brain function
Physiol.Chem. Phys.
15, 319-324, 1981 ;
M.B.H. Youdim, D.Ben-Shachar, P.Riederer
Is Parkinson disease
a progressive siderosis of substantia nigra
in iron and melanin-induced neurodegeneration
?
Acta Neurol.Scand., 126, 47-54,
1989 ; J.M.Rabey, F.
Hefti Neuromelanin synthesis
in rat and human substantia
nigra
J.Neural. Transm . 2, 1-14, 1990 ) .
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One view is that neuromelanin could function as
a device for the inactivation of harmfully excited molecules into innocuous
vibrational energy
(
J., McGinness,
P. Proctor, The
importance of the fact that melanin is black
J. Theor. Biol. 39, 677-578, 1973 ;
J.McGinness, P.Corry, P.Proctor
Amorphous semiconductors switching in melanins Science 183,
853-854, 1974 ) . www.organicsemiconductors.com
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Other authors have postulated that neuromelanin
could exert a protective role by acting as a sink for free radicals
( B.Commoner
, J.Townsend, J.E.Pake Free radicals in biological material Nature,
174, 689-691, 1954 ) or as a
redox buffer against reducing or oxidizing toxic conditions ( E.V.Gan,
K.M. Lam, H.F.Haberman, I. A. Menon,
Electron transfer properties of melanin
Br.J.Dermatol, 96, 25-28, 1977
; Arch.Biochem.Biophys.,
173, 666-672, 1976 ) .
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Another property of neuromelanin which is
typical of eumelanins is the ability to bind a number of foreign substances and
to retain them for a very long time
(
R.M.J.Ings The
melanin binding of drugs and its implications
Drug
Metabol. Rev. 15, 1185-1212, 1984)
).
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(
N.G.Lindquist, B.S.Larsson, A.Lyden-Sokolowski
Neuromelanin and its possible
protective and destructive properties
Pigment Cell Res. 1, 133-136, 1987
)
This has led to suggest that neuromelanin may
protect the surrounding cells by keeping potentially harmful substances bound
and thereafter slowly releasing them in low, non-toxic concentrations.
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(
F.M. Forrest Evolutionary origin extrapyramidal disorders in drug treated
mental patients ,its significance, and the role of neuromelanin
Adv.Biochem.Psychopharmacol., 9, 255-268, 1974 )
An
interesting theory envisages neuromelanin as serving a
biocybernetic function whereby its lack or depletion causes the substantia nigra
to revert from its neuroendocrine role to its original motoric role. Moreover it
would inhibit the bioelectric activity of the neuron producing a decrease in the
cell s discharge frequency by controlling the electron flow from the cell
cytoplasm into the original axon cylinder.
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Polyindoles obtained from anodic coupling of
indoles are electroconductive materials and display a noticeable interest since
they have been considered in applications such as sensors and because they may
be model polymers for biopolymers such as melanins.
(
A.Berlin, A.Canavesi, G.Schiavon, S.Zecchin, G.Zotti
Electrooxidation
products of methylindoles :
Mechanisms and structures
Tetrahedron 52, 7947-7960, 1996 )
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The pigmented neurons of substantia nigra
are typically lost in Parkinsons diseases : however the possible relationship
between neuronal
vulnerability and the presence of neuromelanin has not been elucidated.
(
L.Zecca, F.A.Zucca, P.Costi,D.Tampellini,
A.Gatti, M.Gerlach, P.Riederer, R.G.Fariello, S.Ito, M.Gallorini, D.Sulzer. The neuromelanin
of human substantia nigra :
structure, synthesis, and molecular
behaviour J.Neural.Transm. Suppl, (65), 145-155, 2003 )
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The hydrate form and possible neuromelanin
precursors :
Units or precursors
SALSOLINOL black (brown)
PHEOMELANIN (brown)
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R = H ;R1
= H ; R2 = CH2
CH (NH2) ( COOH)
Tryptophane- black
R = H ; R1
= COOH ; R2 = H
DHICA-black
(brown)
R = H ; R1
= 2H ; R2 = 2H
Dopamine -black
R = H ; R1 = H ; R2
= CH2 CH2N
( CH3 )2
Bufotenin -black
For adrenalin-black a tetrameric units is showed. Pyrrolidine ring may be
present (J. Harley-Mason, The
Chemistry of Adrenochrome and its derivatives Soc.
1276, 1950 )
Nero di Adrenalina
Found C% 54.7 H% 4.9 N% 7.0
Calculated for C9 H9 O4 N
: C% 55.4 H% 4.6 N%
7.2
For its conductivity neuromelanin may be considered a communication
material in the brain.The Proctor McGinness effect
( www.organicsemiconductors.com ) has not been taken
into consideration.
Thanks
are due to B. Nicolaus for preparation of melanin samples.
Appendice
The majority of our
knowledge came from the Institute of Organic Chemistry of the University of
Naples. The Neapolitain School (Bakunin
1924), ( Panizzi 1949 ),
(Nicolaus,Piattelli ( 1956 ), ( Prota 1980 ) of melanin is well
known.Financial supports were obtained from the CNR (Rome ) and NCI,Bethesda,USA.
Revised, Naples August 2003.