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 Parkinson’s 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=CH3 ; R1=H ; R2 = OH                              Adrenalin -black     

R = H ; R1 = H ; R2  =  CH2-CH2-NH2               Serotonin- black

                                                                      

R = H ;R1 = H ; R2 = CH2 CH (NH2) ( COOH)                 Tryptophane- black

                                                                   

R = H ; R1 = H ; R2 = H                                       DHI-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.

 

bnicolaus@icmib.na.cnr.it

bologne@unina.it

rnicolaus@tightrope.it

bruno.nicolaus@virgilio.it

 

 

Revised, Naples August 2003.