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A ROUND TABLE ON SCIENCE , LETTER AND ART NIC'S CORNER FROM THE STARS TO THE MIND |
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NEUROMELANIN AND BIOLOGICAL FUNCTION >
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SULLE NEUROMELANINE E LORO RUOLO BIOLOGICO >
Nota
del socio ord. non res. Bruno
J.R. Nicolaus [1,2]
Accademia
Pontaniana, Napoli, June. 24.2004
KEYWORDS melanin, eumelanin, pheomelanin, allomelanin, neuromelanin,
sepiomelanin, eye, iris, eye fundus, ear, brainstem, substantia nigra,
locus coeruleus, retinal epithelial cells, RPE, melanocyte, melanosome,
albinism, Parkinson, Alzheimer, deafness, tyrosinase, monoaminoxidase,
tyrosine, dopamine, serotonine, epinephrine, norepinephrine,
catecholamines, polyacetylene, polypirrole, polyindole, polyphenylene,
acetyleneblack, pyrroleblack, indoleblack, benzeneblack, epinephrineblack,
serotonineblack, dopamineblack, tyrosineblack, black particles,
semiconductors, conducting polymers.
PREFACE
< Natura enim simplex est >
Isaac Newton, 1687
Modern
biochemistry and molecular biology confirm
Newton’s axiom, according to which, all life’s systems are run
on the same lines of simplicity, as physical phenomena. Melanin’s do
comply with this law, being
sometime difficult to prove it, due to their
peculiar physical and chemical behaviour.
All
over the planet, there are manifold variegated pigments playing major
biological roles.
The black particles of the living world are synthesized under genetic and
hormonal control in specific cell systems (melanocytes and neuro
epithelial cells) and are called Melanin’s (from
Greek, melanos = black). The melanins were currently grouped in
four classes [3], updated as follows:
1)
Eumelanins
( eu, good ): Black or brown amorphous
particles formed in the chemical or enzymatic oxidation of the amino acid DOPA; found in hair, feather, skin, eyes, melanoma, etc.;
mainly consisting of 5,6-dihydroxyindole units (DHI); derived
biogenetically from tyrosine.
2)
Pheomelanins
(faios, dusky): Sulphur or protein containing amorphous particles,
obtained by oxidation of CYSDOPA ( chiefly cystein-5-S-yl-dopa ); found in
hair, fur, feather, etc.; often accompanied by crystalline feochromes (
tricosiderin, tricochromes ); they contain the dibenzothyazinone
chromophore, firstly synthesized by Kaul
[4].
3)
Allomelanins:
Black or brown amorphous, often nitrogen-free, particles, obtained by
oxidation of typical polyphenols ( catechols, 1,8-dihydroxynaphtalene
).They are widely spread in fungi’s and
in soil (humic acids).
4)
Neuromelanins:
Black or brown, amorphous particles found in the CNS of humans and
vertebrates. They are formed by enzymatic or chemical oxidation of
catecholamines in various substrates (tyrosine, dopamine, epinephrine, nor
epinephrine, serotonine, dihydroxy-quinolines, etc.).
Hybrids
of these classes are formed by inclusion
of foreign materials.
***
The
melanin’s are derivatives of pyrrole,
indole, or benzene and belong to three macro systems: polypyrrole,
polyindole and polyphenylene.
Black,
red biline and porphyrins are namely pyrrole derivatives; epinephrine
black and serotonine black, two components of neuromelanin, are indole
derivatives; graphite, fullerenes, aspergillin from Aspergillum niger,
humic acids, DOPA-black, again a component of neuromelanin, are
benzene derivatives.
Under
proper conditions, these black pigment particles are able, to absorb and
dissipate light and sound, to bind organic compounds and ions, to store
liquid and gases, to conduct electricity and to transform light in
electric energy. This wide range of heterogeneous
physical and chemical properties has been currently correlated to
biological functions, which still deserve extensive physiological
confirmation, as free radical scavenging, detoxification from drugs and
other harmful substances, iron binding/ release, radiation shield, sound
protection, etc. The true biological role of
substrate specific melanin’s is, accordingly, difficult to
understand, suggesting they may just represent biological garbage.
The
term particle in melanin chemistry was introduced for the first time by
Chedekel, recent studies
showing that they are organized in units
and subunits, responsible for the physical and biological behaviour [5].
Carbonaceous
black materials were identified on meteorites, as well as in the clouds of
interstellar space by means of radio-spectroscopy [6].
The
neuromelanins
build a family of black particles, typical of the Central Nervous System
(CNS) and some other inner organs of humans and
vertebrates. Their biological function is not always evident or
well documented and their mode of action remains in many cases obscure.
In
this paper, we shall focus on neuromelanin’s, with the aim of
interpreting their physical, chemical and biological properties by an
integrated approach.
INTRODUCTION
In
humans, melanin is found in the skin, retina, iris, and certain areas of
the CNS. Melanin may increase or decrease with age and greying of the hair
occurs in all individuals irrespective of gender and race. This
age-related pigment reduction of the hair bulb is
observed in the epidermis, in the retinal pigment epithelial cells
(RPE) and in other areas of the CNS, namely the substantia nigra
and locus coeruleus. An aged related increase in melanin can be
found in the senile lentigo, which occurs
on exposed surfaces of the skin of past middle age individuals.
The
granular dark brown pigment of the nigrostriatal neurons of the brain stem
is chemically similar but not identical to skin melanin, which is
synthesized in the epidermal
melanocytes, under the influence of light, whereas neuromelanin is formed
in the absence of visible light, in the catecholaminergic neurons of the
CNS, which are furthermore deprived of true melanocytes.
Different
chemical structure, different
biogenetic site, different biochemical pathway must
necessarily lead to different biological properties and functions [10].
Skin
melanin (an indole derivative) acts as sun screen, while the biological
activities of neuromelanin ( a benzene derivative) can vary, according to
the site of deposition and chemical composition. Based upon the present
state of the art, the substantia nigra melanin is involved in
movement coordination and protection of neurons against oxidative stress
being moreover supposed to be instrumental to neuronal death and
Parkinson’s disease; in the eye, ocular melanin is devoted to absorption
of excessive light; in the ear, in deadening acoustic waves. Several
attempts were made, to correlate the biological activities of melanin’s
with their property to conduct electricity and to transform light into
current. Convincing physiological evidence is, however, still missing.
***
The
neuromelanins show biological functions, which are strictly related to
chemical and particle structure. There is not one single neuromelanin, but
a family of chemically different black pigments, exercising specific roles
on different substrates, at different sites.
Surprisingly enough, amount and location of neuromelanin varies
among animal species, being greatest in humans and progressively lower in
the lower species. In humans and primates, neuromelanin
predominates in the catecholaminergic neurons of the substantia
nigra and locus coeruleus,
were dopamine,
epinephrine and nor epinephrine are present in high concentration, raising
the question, whether this melanin is composed by one pigment only, or by
a mixture of two or more.
Fig.1,2
Dopamine
brain concentration is age related, with a marked decline in senescence (onset
of senescence: cattle 15-20 years; dog 10-15 years; humans 60-80
years; mouse 2-3 years; rhesus monkey 20-30 years; rat 2-3 years; rabbit
4-6 years).
During
aging, a dark brown pigment called lipofuscin (age pigment) accumulates throughout the body in the
lysosomes .These intracellular deposits, which in the past were
often confused with melanin, are the end product of the natural cell
turnover, representing biological garbage [11,12].
Depigmentation
of the substantia nigra is a constant feature of Parkinson’s
disease and is caused by greatly
reduced dopamine concentrations ( to about one-tenth of normal ), as
consequence of the concomitant death of dopaminergic neurons, either as a
result of virus infection, exposure to exogenous toxins or other unknown
causes.
CONJUGATED ORGANIC
POLYMERS
Chemically,
natural and synthetic melanin’s
are
substituted derivatives of polyacetylene, containing in their backbone the
polyacetylene spine. They are stable free radicals (radical polarones),
holding positive charges balanced by counter anions, exhibit typical broad
IR and EPR spectra and behave like electrical conductors, in the doped state. The
unpaired electrons and the positive charges distributed along the
conjugated polyacetylene chain are responsible for their conductivity and
colour.
.Fig.3
The
most synthetic electrically conducting polymers are black in the doped
state. In the un-doped, semi conducting state, their colour can vary from
clear to red, depending on the forbidden electron energy band gap. The
colours change according to the length
and the identity of the polymer chain, whereby the longer the
chain, the darker the polymer.
Here
below, we shall review some properties of synthetic conjugated organic
polymers, a class of intriguing compounds, to which melanin’s are
chemically related.
***
Polymeric
materials in the form of wood, bone, skin and fibres have been used since
very ancient times. During history, man found out how to modify in a
proper way all these materials, as well as to manufacture new ones. The
main target of the synthetic polymers has been focused so far, on
mechanical strength, processing, barrier properties, electrical
insulation, etc. Electrical conductivity represent the new frontier of
conjugated polymers, materials able of being doped to states of high
electrical conductivity.
In
1964, W.A.Little proposed a chemical structure for a consistent ideal
organic superconductor, composed by a polyunsaturated chain, called <spine>,
substituted in some points by heterocyclic structures (often resonance
hybrids) having cation centres and counteranion. Even if the target of
finding a room temperature superconductor has not been realized,
Little’s hypothesis has been very fruitful, allowing the synthesis of
numerous organic compounds, which proved to be semiconductors in the doped
state [13].
In
1977, Heeger, MacDarmid and Shirakawa succeeded in doping polyacetylene to a relatively high electrical conductivity,
of approx. 10+3 Scm-1,
although various kinds of conducting
polymers had been described
for almost one century. The chemistry of conjugated polymers, produced
thereafter interesting practical
developments in the areas of electronics (LED and transistors), integrated
circuit technology ( electro-resistant materials for high spatial
resolution ) and high technology materials ( aircraft construction
materials and high-strength fibres ).
This
new class of synthetic materials combines the electronic and optical
properties of semiconductors and metals with the outstanding mechanical
properties and processing advantages of synthetic polymers [14].
The
best known synthetic conducting polymers are listed in Fig. 4.
***
Polyacetylene
is
the simplest organic polymer. Its repeating unit consists of two carbon
and two hydrogen atoms with a carbon-carbon double bond -
(CH=CH)n-,
simply denoted as (CH)n.
In
1958, Natta et al. for the first time converted acetylene into a
polymer, using Ziegler-Natta catalysts, to open the triple bond of
acetylene. The discovery, that polyacetylene films can be doped with a
variety of agents, increasing
conductivity up to 105 Scm-1,
started the era of conducing polymers (Chiang et al.).
Polyacetylene
itself is an inhomogeneous mixture of non-perfect planar polymeric chains,
with varying conjugation lengths,
linked through structural kinks (sp3 carbon atoms ), not allowing to
establish a linear relationship between chemical, structural and
electronic properties. Undoped polyacetylene is silver grey, with a
forbidden energy gap of about 1.7 eV. In the doped state, it looks
black, becoming electrically conducting.
Polyacetylene
occurs in the two possible cis and trans configurations, whereby the
cis/trans isomers content can be varied, according to the polymerisation
conditions. The conductivity of polyacetylene films is decreasing with
film thickness and is increasing with in-plane alignment of the conjugated
chains. Once made, polyacetylene is insoluble, infusible and unstable to
air: properties which make it less attractive, indeed.
***
Industrial
conductive polymers are usually a physical mixture of a non- conductive
polymer with a conductive material, such as a metal or carbon powder,
distributed throughout the material. An organic polymer that has the
electrical, electronic, magnetic and optical properties of a metal, while
retaining the mechanical properties, processibility, etc., commonly
associated with a conventional polymer, is called an
intrinsically conducting polymer (ICP),
more commonly known as a synthetic metal. Its properties are intrinsic to a doped form of the polymer. During the
doping process, an organic polymer, having a low conductivity (10 -10/10 -5 S cm -1
) is converted to a conducting polymer ( 1-10 +4 S cm-1 ). The
addition of small non stoichiometric quantities of chemical species
results in dramatic reversible changes in the electronic, magnetic,
electrical, optical and structural properties.
THE
NEUROMELANINS
In
men and other vertebrates, neuromelanin
is found in
the brain stem, the eye and the ear. In the brain, two mesencephalic
areas, the substantia nigra and the locus coeruleus, are
reach in melanin in form of granules
located in the catecholaminergic neurons, surrounded by a double membrane.
The same neurons, account for 80% of the dopamine in the brain and also
contain remarkable concentrations of
nor epinephrine. The black dark brown neuromelanin makes the
pigmented brain regions appear black. Oxidative degradation studies of
neuromelanin, from human substantia nigra (SNM) in
comparison to model melanin, showed that the pigment is a mixed-type
indole polymer, consisting of benzothiazine
and dopamine units in equal amounts. It is chemically different from that
of skin melanin formed in the melanocytes, when stimulated by sunlight [3,15].
Electron
paramagnetic resonance spectroscopy (EPR) was showing, that SNM is an
atypical melanin, structurally different from synthetic dopamine melanin.
Both pigments include, however, an
aromatic multilayer graphite-like three dimensional
backbone, substituted by aliphatic chains [16].
The
graphite-like conformation is common to all synthetic and natural
melanin’s, building the base to their bioelectric behaviour.
Structurally and functionally, neuromelanin appears to be a
more complex pigment, than synthetic
dopamine melanin, simply formed via dopamine self oxidation
[17].
Recent
comparative degradation studies on SNM
of normal individuals post mortem and synthetic melanin’s confirm that
it derives from dopamine with a 25% incorporation of cysteine in the form
of benzothiazine structures. Preventing dopamine and cysdopa to accumulate
in the brain, was interpreted in terms of an hypothetical cellular
detoxification mechanism [18].
***
During
the course of life, SNM
accumulates in the dopaminergic neurons, decreasing during senescence,
accompanied by a decline in the number of neurons and in synthesised
dopamine. The neurons with the highest amounts of black pigment and the
smallest quantities of reduced glutathione (GSH) are the first to
degenerate, leading to the axiom neuromelanin
accumulation = neuronal death.
Fig 5.
According
to this view, SNM would behave
like a waste product, whose pathologic accumulation takes precious
dopamine away from the life cycle, thus becoming a neuron killer. Whilst
the epidermis’ melanocytes and melanosomes are conceived for the
production and distribution of melanin from tyrosine, the brain lacks such
a system, as well as tyrosinase, and is not exposed to solar radiation [19,20].
These facts enforced the hypothesis, according to which extracellular
neuromelanin, both in normal and pathological conditions ( e.g.
Parkinson’s disease), would originate at random from dopamine by
radicalic accidents, catalyzed by iron (Fe/ H2O2)
and monoamine oxidase (MAO),
both largely present in the substrata.
Certain
drugs and chemicals are bound to melanin and retained in pigment cells for
long periods of time. This specific retention can cause adverse effects in
the skin, eye, inner ear and pigmented
nerve
cells of the cerebral substantia nigra [21].
The
‘neuromelanin =
biological garbage
hypothesis neglects aspects, worth of closer consideration:
-
Both skin and eye melanin are definitely instrumental to light
absorption and protection, confirming that, melanogenesis plays a
fundamental non casual, genetically controlled biological role;
-
The structural similarity and Newton’s simplicity axiom suggest that, SNM carries
out some related biological function;
-
SNM is formed in the brainstem at a very early age, being
continuously regenerated during life, whereby the basal nuclei are
knowingly involved in modulating and transmitting nervous impulses. SNM
presence at this strategic site is unlikely to be fortuitous, suggesting
some more fundamental biological role;
-
SNM is absent or significantly scarce in two life conditions, in
which movement coordination is either not efficient (newborn babies) or
strongly compromised ( Parkinson’s patients );
-
The traditional neuronal theory provides a convincing model for the
transmission of nervous impulses. It is still unclear, however, if in the
strongly pigmented basal nuclei, the information is transmitted by
dopamine only, or if SNM also plays a role;
-
Assuming that SNM is not biological trash, let us suggest, the
bioelectric properties of SNM to be somehow involved in this process.
As a
conclusive remark, we can say, that the biological functions of
neuromelanins are specific to site of action and substrate, while
the mechanisms of action remain rather obscure.
The bioelectric
properties of melanin’s in general and SNM in particular, deserve
accordingly further attention in future studies.
Doctors
still display different views on the disease’s historical origins: some
claim it is not a modern-age illness but rather a plague that has always
caused distress to mankind, as reported in old Ayurvedic texts [39].
The disease,
as a matter of fact, is ubiquitously widespread amongst the elderly
populations of all countries and amongst the different ethnic groups and
socio-economic classes. Furthermore, its distribution does not seem to
depend on demographical, climatic, dietary, socio-cultural elements or any
factor related to industrialisation.
Its prevalence does not vary from country to country, with the
exception of China, Japan and Africa, where it is slightly lower [40].
Other
researchers, on the other hand, believe what is written in the old Chinese
and Indian texts not to refer to Parkinson’s disease proper, but rather
to mere tremors that are common to several pathologies.
The disease’s explosion-like diffusion, thus, can be linked to
industrialisation, and especially to the presence of an exogenous
neurotoxin in the environment and/or to a substantial change in dietary
habits. This hypothesis is
corroborated by the consequences of the substitution of whole meal with
refined white flour in Great Britain in the early 1800s, which led to the
loss of the antioxidant vitamin pool [41].
The
damage caused by different kinds of herbicidal pesticides and other
chemicals, which can cause diseases similar to PD, gives us further
evidence that the neurotoxic hypothesis is valuable .
The
aetiopathogenesis of Parkinson’s disease is still controversial. This
disorder is largely widespread and develops in a most insidious way in
elderly age, causing progressive movement
impairment. This process follows four clearly-defined stages:
tremors, bradykinesia, rigidity and postural instability [42].
Parkinson’s
disease, after Alzheimer’s disease, is the chronic degenerative
neurological disease affecting the largest number of people worldwide.
It is estimated that 1.5 million people are affected in the USA,
80,000 in France, 100,000 in England and 120,000 in Italy. In the USA
50,000 new cases are reported every year.
It
is exceptional for patients to develop the disease before they reach the
age of 30. In rare occasions the illness may occur before 40, but 80% of
cases concern people between 40 and 70 years of age. After the age of 80
the disease no longer occurs. This data must be taken carefully, as often
PD is not diagnosed at all or is mistakenly diagnosed in patients affected
by other neurological pathologies.
Our
current knowledge does not allow us to prove any link between PD and other
pathologies, and the role of risk factors, such as brain traumas,
low-vegetable-income diets and hypertension, should be investigated
further. It is interesting to note that the number of smokers affected by
PD is extremely low. Such phenomenon has been interpreted as the
consequence of nicotine’s alleged protective effect on the dopaminergic
system, namely on the substantia nigra and striata.
The symptomatology consists in the derangement of basal ganglions’ functions, with a reduced activity of dopaminergic components and deficiency of the neurotransmitter dopamine, as well as of the black pigment neuromelanin.
It
has been hypothesised that the disease is triggered by a slow and
progressive lack of dopamine, but there is still controversy on what leads
the brains’ dopaminergic cells – located in the substantia nigra
zona compacta (SNZC)- to gradually reduce their dopamine production,
or on what brings this substance to be transformed into inactive products.
The
substantia nigra is connected to the striatum at the
brain’s base through nerve fibres, whose ends secrete the
neurotransmitter dopamine. The latter helps the striatum in
controlling movements. The
progressive death of substantia nigra cells is followed by a
reduction in dopamine availability. Normally,
dopamine is stocked in inert form in vesicles. When secreted, it is
metabolised by monoamine oxidase (MAO),
or is subjected to auto
oxidation processes, if need be. In both cases hydrogen peroxide (H2O2)
is formed, which can have a cytotoxic effect if not neutralised by
catalase, reduced glutathione (GSH) and glutathione
peroxidase (GPO).
The
pathological variation of the different biochemical parameters suggests
that during PD the substantia nigra is stressed by oxygenated free
radicals [43],
which leads to the degeneration of approximately 80% of dopaminergic
neurons in the substantia nigra striata, before clinical symptoms
arise [44].
As
a matter of fact, two elements can be noted: the increase in water
peroxide concentration (the basis of monoamine
oxidase B
activity), iron, ferritin, neuromelanin-connected iron, lipofuscin, the
peroxidation of membrane lipids and a decrease in oxygen peroxide
destruction systems such as reduced glutathione (GSH), glutathione
peroxidase (GPO), the I complex (NADH co-enzyme Q- reductase), mitochondrial electron transport activity and calcium chelating
proteins.
As
the disease progresses, the iron concentration in the substantia nigra
increases, while glutathione concentration diminishes. It is common
knowledge that Fenton’s reagent ionic iron together with oxygen peroxide
(H2O2) produces the hydroxyl radical (·OH),
which destroys reduced glutathione (GSH) and has a cytotoxic action, as do
all radicals.
Post-mortem
histopathological evidence in PD patients shows that this degenerative
process goes hand in hand with: a rise in the malonic dialdehyde and lipid
hydroperoxides (which are an index of lipid peroxidation) basal
concentration; a decrease in reduced glutathione (GSH) levels; a boost in
the mitochondrial super oxide dismutase (SOD) activity; an alteration in
the iron metabolism together with a contraction of ferritin amounts and an
increase in the number of ferric/ferrous ions; enhanced neuronal
phagocytary activity in the microglia.
These data support the hypothesis according to which “oxidative
stress” plays a role in the substantia nigra striata degenerative
processes observed in PD.
Such
hypothesis has theoretical grounds, as the central nervous system is
especially vulnerable to any kind of oxidative aggression, in particular
by oxygenated free radicals. The
brain contains large amounts of easily oxidisable polyunsaturated fat
acids. Through blood, it receives and uses a quantity of oxygen (O2)
disproportionate to other organs. On the other hand, it lacks anti
oxidative protection mechanisms, which are profusely diffused in other
body parts [20].
For instance, in some areas of the brain high ferritin
concentrations are to be found, though with low reduced glutathione (GSH)
and glutathione peroxidase levels and the complete absence of catalase.
Ferritin
levels in the brain of patients with PD shrink, especially in the substantia
nigra (SNZC), whilst free iron ions multiply becoming available for
possible oxidation reactions. Dopamine
plays a crucial role as a neurotransmitter and the onset of PD is linked
to its decline in the SNZC.
In
the meantime, catecholamines such as dopamine are oxidised, and H2O2
is released through a radicalic process
leading to the formation of neuromelanin.
Neuromelanin, in the presence of H2O2, can
react with Fenton’s reagent and release more hydroxyl radicals ·OH.
The latter, if not neutralised, can pursue the peroxidation of membrane
lipids, which eventually brings to a halt the mitochondrial electron
transport system. It has been recently proved that during dopamine
oxidation significant amounts of 6-hydroxidopamine form, together with its
quinone, Topamine-quinone (TQ). Both are highly cytotoxic.
Melanin
can capture consistent amounts of iron, leading to the formation of
iron-melanin, a complex that was said to be able to easily release
activated iron, considered to be more neurotoxic than normal free iron.
Significant data proving that neuromelanin is really able to release iron
easily and quick, are however still lacking. The neuromelanin binding
affinity towards iron and
other cations is in fact rather high, raising doubts about this mechanism
of action being workable in vivo.
Such
oxidative processes are catalysed by several metals and especially iron,
whose highest concentration in the brain is to be found in the substantia
nigra. In physiological
conditions, iron is present in negligible amounts in its free state
because it is stocked in ferritin and hemosiderin in an inactive form.
However, it becomes readily available according to physiologic (and
pathologic) needs. Suffice it to say that a mole of ferritin contains
4,500 atoms of iron, an amount which, even if only partially released,
reacting with hydrogen peroxide H2O2, as in
Fenton’s reagent, could generate a significant number of hydroxyl
radicals ·OH.
It should be stressed, moreover, that the binding affinities of ferritin
and neuromelanin for iron and other heavy cations are not comparable.
Ferritin/iron- ferritin represent an almost ideal reversible
system, able to easily and quickly bind and release iron, at request. The
neuromelanin/iron- neuromelanin complex is, on the contrary, much
too slow to satisfy the needs of our body’s requests.
It
has been shown that 6-hydroxydopamine can release iron from ferritin,
triggering a chain of reactions that will lead to the formation of
hydroxyl radicals ·OH,
extremely cytotoxic even for dopaminergic neurons.
·OH
radicals have a short average life span. Thus, they are likely to act
close to where they formed.
This
hypothesis is confirmed by the fact that the iron chelator desferroxamine
– which can break the oxidative chain – displays some activity in
Parkinson’s and Alzheimer patients, as clinically observed.
Post-mortem
analysis of the human brain have established, that oxidative stress and
iron content are enhanced in association with neuronal death. A possible
consequence of an overloading of neuromelanin with redox-active elements
is an increased contribution to the oxidative stress and intraneuronal
damage in patients with Parkinson’s disease [45].
Quantification
of the total iron content in iron-loaded neuromelanin and synthetic
melanin demonstrated that the iron-binding capacity of neuromelanin is
10-fold greater than that of the model melanin. These findings were
interpreted as a confirmation of the hypothesis, that neuromelanin may act
as an endogenous iron-binding molecule in dopaminergic neurons, whereby an
increased iron in the CNS is associated with increased indices of
oxidative stress [46].
In
later studies neuromelanin was identified as a genuine melanin with a
strong chelating ability for iron and affinity for several organic
compounds. The affinity for a variety of inorganic and organic toxins
appears to be consistent with the postulated protective function for
neuromelanin. Moreover, the neuronal accumulation of neuromelanin during
aging and the link between its synthesis and a high cytosolic
concentration of catechols suggest a protective role [47]. The
fact that all these complexes are de facto irreversible, is not taken
however into proper consideration by the authors.
In
a recent study, the concentration of iron, ferritin and neuromelanin in substantia
nigra from normal subjects, aged between 1 and 90 years, dissected
post mortem, was measured.. The iron levels in substantia nigra
were 20 ng/mg in the first year of age, had increased to 200 ng/mg by the
fourth decade and remained stable until the eighty decade of life.
L-Ferritin also showed an increasing trend during life, although the
concentrations were approx. 50% less than that of H-Ferritin at the age
point. Neuromelanin was not detectable during the first year, increased
continuously to 3500 ng/mg in the 80th year. Based upon these
data, it was concluded that neuromelanin is the major iron storage in substantia nigra
neurones in normal individuals [48].
Because
ferritin and neuromelanin strongly differ in their relative iron binding
affinities, this finding cannot
mean, in our view, that ferritin and neuromelanin are bio equivalent iron
storage systems.
Our
viewpoint is in fact confirmed by another paper, stating that the
overloading of neuromelanin with iron and other metals may trigger
inflammatory and degenerative processes, aggravating underlying pathologic
conditions [49].
As
shown in numerous papers, Parkinson’s disease is associated with a
significant increase in iron in the degenerating substantia nigra
and is measurable in living PD patients and in post-mortem brain. This
increase, however, occurs only in the advanced stages of the disease,
suggesting that this phenomena may be secondary, rather than a primary
initiating event, an hypothesis also supported by evidence from animal
experiments [50].
According to
these findings, the role of iron as key element in the pathogenesis of
Parkinson, appears to be significantly diminished.
Nitrogen monoxide NO has been found capable of releasing iron from ferritin, contributing to the formation of highly reactive oxygenated radicals [51]. This finding deserves further attention in view of the intriguing function of nitrogen monoxide on numerous biological functions.
Several
pharmacological agents, such as neuroleptics of the phenothiazine groups and butyrophenons
or reserpine, can induce syndromes that are similar to Parkinson’s. Both
interfere with the dopamine mechanism: the former block postsynaptic
dopaminergic receptors, the latter use reserpine to remove the available
dopamine from presynaptic neurons.
Therefore,
it can be reasonably argued that at the root of Parkinson’s disease
there is a degenerative process of dopaminergic neurons caused by the
aggression of the oxygenated radicals that formed in situ, with iron as a
catalyser.
A
person’s neuromelanin concentration in the substantia nigra
varies with age. It is virtually nil during early infancy, when the
newborn does not have full control over his/her locomotorial
functions. The neuromelanin concentration reaches its peak in adult
age, declines over the years and is at its lowest in the elderly. Its
decrease goes hand in hand
with the natural degradation of locomotorial coordination and reflex
response.
Considering
this phenomenology, it can be suspected that the substantia nigra plays some role in nervous transmission, consistently with
the electro
conductivity of
the SNM particle. It must be highlighted that post mortem examination of
patients with Parkinson’s disease in advanced stages reveals severe
depletion of the black pigment in the substantia nigra.
Neuromelanin
is produced constantly by dopaminergic neurons through the oxidation of
dopamine and its derivatives. It is subsequently metabolised through
oxidative degradation.
It
can therefore be claimed that, in normal physiological conditions, a
homeostatic balance dopamine/neuromelanin is established.
A
low dopamine concentration means smaller amounts of neuromelanin
and consequently an impoverished and in its electric functions
deranged substantia nigra
On
the other hand, an excessive formation of neuromelanin, through an
abnormal dopamine oxidation, leads to a lack of this neurotransmitter,
which in turn upsets dopaminergic functions and eventually kills the
neuron.
Fig.7
The
dopamine/neuromelanin dynamic balance is critical for the system to
perform correctly. However, it is also quite unstable as its components
are sensitive to and react to oxidation.
Yet, it must be said that doubts have arisen about the definitive aetiopathogenesis and about whether the factors that trigger the