Neuromelanin is a type of melanin found in human as well as some primate body. By this term “Neuromelanin”, we can easily understand that it is related to nervous system. Unlike other two melanin (Eomelanin and Pheomelanin) that are present on the skin as a protection of a few unwanted factors, neuromelanin is located in the mid-brain area. It was first noticed in 1837 by Purkyne and the term “Neuromelanin” was introduced by Lillie in 1957.
Two parts of mid brai , subtantia nigra and locus coeruleus , are that parts where the most of the neuromelanin is present . Being occurance of high concentration of neuromelanin in these parts, it looks very much dark in magnetic resonance imaging.
For science, it was always a mystery that why a component, structurally resembles to melanin, present in the inner part of body? For a very long time, it was believed that it is functionally negligible component. But after 1990, it became a valuable research topic and in last decade the research work on neuromelanin has been done very thoroughly.
Now come to the significance of the NM. NM structurally resembles to the other two melanin of human body. Eomelanin and Pheomelanin are responsible for our pigmentation on peripheral parts. Along with That EM and PM also responsible for protection of our skin for UV rays, and at sometimes, they prevent infections come through the skin. Unlike the two others neuromelanin , NM does not occur on the periphery of our body skin. It has different role. In 1919, Konstantin Tretiakoff put some light on NM remarkably for the first time. He noticed a relation between Parkinson’s disease and NM. He reported that a marked loss of pigmented neurons in the substantia nigra (SN), visible with the naked eye, in the brains of Parkinson's disease (PD) patients.
After that, till the date, very few researches have been done on this and it can be concluded that the concentration maintenance of NM is a vital key for prevention of PD. Subtantia nigra has a vital role in functioning of motor actions and in PD the NM get decreased. That means it might have an important role in the motor action initiation as well as acceleration.
Later on research, another interesting fact has been discovered. Heavy metals like Pd, Cd, are toxic for brain. If they enter in the CNS, it causes severe problems and even death could be possible if the toxicity goes at very higher level. NM detoxifies these heavy metals and it undergoes self-degeneration. This is a protective role that plays by NM in our body and on the contrary, just a century earlier it was first considered as a research topic.
Parkinson’s
disease and Neuromelain
Parkinson’s disease is a disease of CNS ( central nervous system) where the motor function(movement of hands, legs and other activities that we do by our control) of human body get partially uncontrolled. The term “Parkinson’s” is named after an English doctor James Parkinson. In 1817, he published a report on the symptoms of this disease for the first time. In his report, An Essay on the Shaking Palsy, he described the various symptoms of this disease. The term “Parkinson’s disease” or simply “Parkinson’s” was given by Jean-Martin Charcot who studied this disease between 1868 to 1861. His study is a landmark in understanding the Parkinson’s . By understanding the Parkinson’s in details, we can draw the co-relation between Neuromelanin and Parkinson’s in easier way.
Symptoms of Parkinson’s:-
This disease is a compilation of
various symptoms of malfunction.
1.
Motor
2.
Cognitive
and neurobehavioral abnormalities.
3.
Psychosis
Etc.
1. Motor
Motor malfunction is one of most common symptoms in
parkinson’s . It includes tremor, Postural instability, slowness of movement
and rigidity.
Tremor is the involuntary movement of various body
parts, like hands, legs, eye, face, vocal folds, arms and trunk, in rhythmic
contraction and relaxation of muscles. It brings from one hand and
proportionally gets increased by the stages of Parkinson’s resulting both of
the hands along with other possible body parts that are mentioned above. The
frequency of Parkinson’s tremor is 4-6Htz/s (cycle per second). This outcome of
the symptom is called “Pill rotating”. Pill rotating is the tendency of touch
and performs of index finger and thumb in a circular movement.
Slowness of movement, also known as Bradykinesia , Is
one of the most common problem found in Parkinson’s patients. It is the
malfunction where the motor movements do not happen sequentially. From planning
of a movement, to initiation to execution , this sequence does not occur
smoothly. Bradykinesia gets more privileged while the patient go through any
emotional stress.
Rigidity is that stage where
the muscles of limbs get stiff as well as rigid. The rigidity of limb muscles
is increased with the time . There is two type of rigidity found in
Parkinsonism – “Lead-pipe rigidity” and “ Cogwheel rigidity”. Uniform rigidity is
called the “Lead-pipe rigidity” and ratchet type rigidity if called “Cogwheel
rigidity”.
Postural instability is a
symptoms bring out in the developed stage of Parkinsonism. The misbalance of
the movement of the patient is called Postural instability. The patient falls
oftenly at the ignition of tis stage and fallinf of patient get more and more
often while the Parkinsonism gets increase.
2. Cognitive and neurobehavioral abnormalities:-
Along with the motor dysfunctions,
cognitive and behavioural abnormalities also have been shown in Parkinsonism.
Almost 84% of patient face the cognitive declination and approx 48% go through
Dementia . Dementia is very common psychiatric disorder , in better words a sum
of disorders, that can be seen in Parkinson’s patients and on an approx , the
chance of dementia get increased up to 6 times. In addition to cognitive and affective
disorders, many patients with PD exhibit features of obsessive–compulsive and
impulsive behavior, such as craving (especially for sweets),101 binge eating,
compulsive foraging, hyper-sexuality, pathological gambling, compulsive
shopping and punding, characterized by intense fascination with repetitive
handling, examining, sorting and arranging of objects.
4.
Psychosis:-
Psychosis is also a integral part of symptoms of
Parkinsonism. The psychosis affect patient’s percentage varies from 26%-83%.
Almost 50% patients face both of Hallucination and Delusion. Hallucination also
varies a range from minor to major. Minor hallucination includes sense of
presence(a belief that somebody/something is present behind the eye sight) or
sense of passing ( a belief of something is passing by suddenly). And major
hallucination includes visual hallucination and paranoid ideation (a thought
process which is a belief to be highly influenced by anxiety or fear).
Structure of
Neuromelanin
The structure of Neuromelanin is very complicated and it consists of both of the Eomelanin and Pheomelanin. It has a outer double layered membrane that is made of lipid. At earlier stages of neurmelanin research, it was thought that neuromelanin is just a melanin-resembling component. But afterwards , it was cleared that, not only it resembles to the other two melanins, but also it is a genuine melanin because it has both free radical structure and metal chelates. It is able to interact with several organic and inorganic molecules including iron and lipids and that’s why it has complicacy in study of structure.
Neuromelanin does not
occur singularly. It is basically a polymer and occurs with some lipid and
protein molecules. The lipid molecule of Nigral Neuromelanin(isolated) is
polyprenoid dolichol. It has 14% mass of the isolated pigment.
X- Ray diffraction studies have shown that
neuromelanin has a multilayer (graphite-like) three dimensional structure
similar to synthetic and naturally occurring melanins. The three
dimensional structure is derived from planar overlapped sheets consisting of
cyclic molecules of indolebenzothiazine rings. However, these sheets are
stacked much higher in neuromelanin than in any other synthetic and naturally
occurring melanins.
The molecular structure of neuromelanin of Substantia
nigra and Locus coeruleus are almost same . Neuromelanin is also found in
others parts of human brain. Cerebellum, Putamen and Cerebral cortex has also
remarkable amount of neuromelanin. But the molecular structure of neuromelanin
of Cerebellum, Putamen and Cerebral cortex, differs from the neuromelanin found
in the Substatia nigra and Locus coeruleus.
Another interesting fact about the structure is that every part of brain where Neuromelanin is found , contains high amount of heavy metals like Fe, Mn, Ni, Mg, Ag,Au etc. here is a list of different molecules found along with neuromelanin at different parts of brain.
It shows that
Neuromelanin is just not a component to execute neural signals, but also it has
a high affinity with metals and that leads to its another important function-
Detoxification of heavy metals from human brain.
Biosynthesis of
Neuromelanin
The biosysnthesis of neuromelanin was always a mystry
and several attempts were taken by several scientists from decades after
decades. At 1837 , when the first discovery of neuromelanin was proposed, it
was neglected. But after 1865 , it was been looked at, and scientists tried to
find out the most appropriate biosynthetic pathway of this mysterious
component.
Previously, Neuromelanin was considered a component
that resembles to other two melanins(Eomelanin and Pheomelanin) structurally.
Not only it resembles to other two melanin structurally, but also it is
actually a true melanin molecule. It consist of both of the melanin . It has
both Eomelanin and Pheomelanin moety.
Previously it was believed that Neuromelanin is a
secondary metabolite derived from the dopamine oxidation or by any temporal
failure of anti-oxidant defence system in the nigral neurons. But it also found in other parts excluding
Substantia nigra , in the Locus coereleus, cerebellum , putamen and other
locations.
Another assumption is in the neuromelanin biosynthesis is that tyrosinase could have been involved. The promoter activity and mRNA that derived by the tyrosinase , are noticed in the substatia nigra. But tyrosinase is absent in the substatia nigra . So, this assumption is couldn’t be a hypothesis.
Another study proposed that some quinones can be
potential precursors for neuromelanin. These quinones are derived from the
oxidation of dopamine which is a result of oxidation of Dopa and Dopa is
oxidised fromtyrosine in presence of tyrosinase catalyst.
Neuromelanin is also been hypothesized as it can also be biosynthesized by the autooxidation of catecholes to quoins in the presence of thiol. But synthesized neuromelanin structurally differs from the natural( isolated from substantia nigra).
A recent experiment has also be done on rats
substantia nigra and PC12 cell( it is basically is a cell line present in the
adrenal medulla ). This model shows that L-dopa turns into neuromelanin
directly and the molecular structure of the synthesized neuromelanin resembles
to the natural neuromelanin. Not only structurally, this synthesized component also have a double
membrane that present in the nigral neuromelanin. Addition to this information , it has also
come out that iron is involved in the neuromelanin biosynthesis. Because an
iron chelator desfrrioxamine was introduced in this experimental process and it
inhibited the Neuromelanin synthesis from the L-dopa.
Functions of Substantia niga and Locus coereleus in Human Brain
Substantia nigra, basal ganglia structure is one of the most important partin human brain, when it comes to
motor function. It is located in the mid brain . The term “Substantia nigra “
is an Latin term and it means Black Substance. Due to presence of Neuromelanin
in dopaminergic neurons, this part looks very dark comparing to other parts of
brain.
Anatomical position of Suubstatia nigra –Substatia nigra is the top structure of the brain
stem. It is located in anterior part of cerebeller peduncles in the mid brain
area. It divides cerebeller peducles into two parts – Anterior crus crebri and
posterior tegmentum in the mid brain .
It consists of two parts. 1. Pars compacta and 2.Pars reticulata.
Substantia nigra
plays mainly two roles- motor movement and reward seeking. Not only these two functions, eye movement,
addiction and learning are also carried out by this part.
Role of Pars compacta :-
·
Comprising
of dopaminergic neurons, Pars compacta plays the vital role of mototr movement.
It doesn’t act directly on motor
control. Striatum is the mediator of mototr function and any electrical
stimulation on the Pars compacta as well as Substantia nigra doesn’t initiate
any motor movement. The Pars compacta sends excitatory inputs too Striatum and
thus the motor movement occurs through the cerebral cortex .
·
The
dopaminergic neuron activity increases when a new stimuli comes. This
stimulation also occurs via Nigrostiatal pathway. But when the stumuli comes
repeatedly , the dopamineric activity decreases.
·
Pars
compacta also control the sleep-wake cycle . As we know insomnia is a very
known symptoms of Parkinsonism, here we can see a relation between Parkinsonism
and neuromelanin ( as Pars compacta has high concentration of neuromelanin).
Role of Pars reticulata:-
·
Pars
reticulata , comprises of GABAergic neurons, is the area hwere the final singal
of absal ganglia ofare processed and conveyed to the Thalamus and Superior
colliculus.
·
This
parts continuously generates action potential to inhibit the target of basal
ganglia. In case of rats , the frequency of this action potential is 25Hz.
·
The
suthalamic nucleus gives excitatory signal to Pars reticulata and the continuous generation of action
potential goes on. But most of the potentials are autonomous in this part.
· This area is also highly responsible for Saccadic eye movement. It is the movement of both of two eyes to fixed on a subject simultaneously.
Locus
coeruleus, another
important as well as one of the two zones where neuromelanin is found in higher
concentraition, plays very vital role to maintaining cognitive abilities. If the
density of the neurons of Locus coeruleus is high, then it slows down
the declination of the cognitive ability in the later stage of life. The young
aged peoples and women have significantly less intensity of signal in the Locus
coeruleus.
Anatomical postion- It is located in the mid brai region of human brain. The actual anatomical position of Locus coereleus is – postural to the rostral pons on the lateral floor of the forth ventricle.
Functions:-
·
It
is the main source of Norepinephrine. This hormone helps to increae heart rate and
plays vital role in reflex action in
fighting.
·
Interaction between Neuromelanin and Metals
In human brain, there
are some aeas where some non-alkylic heavy metals are found in high
concentration. Like iron, zinc, manganese , magnesium, copper, chromium,
murcury, lead, cobalt, cadmium, are present in the regions like Substantia
nigra and Locas coeruleus. Among the metals, iron has the highest affinity with
neuromelanin.
When the Parkinsonism
affects, the concentration of iron in the substatia nigra region is increased
up to 30-35% than the normal condition. It also causes more vulnerability of
the nigral neuron and the neuromelanin , contains more percentage of iron in
Parkinsonism , goes under degeneration and thus the symptoms get increased and
disease condition get more complicated.
It was proposed that
the neuromelanin-gycolipid complex is good chelating agent and binds with iron
to insoluble the iron ions. But later, it seems that iron bind with catechols
in spite of lipids. Iron binds with neuromelanin to form a high spin octahedral
complex as it was shown in the EPR study.
