|
In 1969 it was found that 6-hydroxydopamine is an extremely dangerous molecule, which causes “the terminal regions of peripheral adrenergic nerves to degenerate and eventually disappear."
Further conclusions were that "6-hydroxydopamine, induces changes similar to those seen after section of an adrenergic nerve, suggesting that this compound produces a chemical sympathectomy."
6-hydroxydopamine does not penetrate the blood brain barrier. It can only be synthesized inside neurons by addition of oxygen to dopamine. Experiments to test the effects of 6-hydroxidopamine must be done through systemic administration, that is direct administration by injection via the cerebrospinal fluid. Various research groups concluded that 6-hydroxydopamine produces a selective acute degeneration of dopamine and noradrenaline nerve terminals in the brain. These results increased research interest to eventually discover the biochemical and physiological paths of 6-hydroxydopamine in the central nervous system.
In 1971 it was demonstrated that 6-hydroxidopamine generates hydrogen peroxide, and that this peroxide was the main inducer of the damage observed in the adrenergic nerve, when 6-hydroxidopamine was injected into the brain. Hydrogen peroxide (H2O) is generated when 6-hydroxydopamine reacts with molecular oxygen. The research group demonstrated that "hydrogen peroxide is a toxic intermediate generated from 6-hydroxydopamine by its reaction with molecular oxygen." They concluded further that "hydrogen peroxide is responsible for the destruction of nerve terminals."13
Spontaneous and Enzymatic Oxidation
I would like to make the following observation in relation to the results presented above. To generate hydrogen peroxide, first oxygen adds spontaneously to position 6 of the carbon ring of dopamine and formed 6-hydroxydopamine. Secondly, oxygen adds again spontaneously, now to 6-hydroxydopamine to generate the toxic product hydrogen peroxide.
It seems to me, that there are interesting differences to point out between enzymatic and spontaneous, addition of oxygen to dopamine. The enzymatic reactions are programmed reactions, that is, the biosynthesis of the enzyme that will catalyze the reaction, is synthesized in accordance with genetic instructions encoded within the DNA of the cell.. These enzymatic reactions are normal physiological reactions, programmed reactions, required for normal and efficient cell function. To this group of reactions belongs the previously mentioned oxidation of dopamine to form noradrenaline.
A spontaneous reaction, like the addition of oxygen to position 6 of the carbon ring of dopamine in order to generate 6-hydroxydopamine, is not a genetically programmed enzymatic reaction.
I assume then, that spontaneous reactions are emergency-like reactions which in this particular case, might occur due to recent environmental evolutionary change, and that the body has not yet created an organized molecular adjustment or adaptation to those new circumstances. Increase in atmospheric oxygen, could be a recent evolutionary change to which no proper developmental adaptations have yet been genetically evolved. I conclude then that the non- enzymatic, spontaneous addition of oxygen to dopamine, is a detrimental reaction, caused mainly because of a sudden evolutionary increase in environmental oxygen penetrating neurons and brain tissues. (Colour Plate 15, Page 93)
Graph which follows, shows the main enzymatic and non enzymatic reactions of dopamine with oxygen.
Research to study the production of hydrogen peroxide in the dopaminergic system, as a consequence of auto-oxidation of dopamine, continued arduously. In 1975 research demonstrated that the toxic hydrogen peroxide produced by auto-oxidation of dopamine induces natural defenses to protect neurons against the harmful effect of hydrogen peroxide. It was then found that the harmful hydrogen peroxide was partially absorbed in the formation of neuromelanin, a dark colored pigment present in neurons in the substantia nigra pars compacta (SNpc).
It was then argued that neuromelanin is formed as a self defense against the detrimental effects of hydrogen peroxide. This defense reaction is enzymatic, catalyzed by the enzyme peroxidase. Peroxidase, uses hydrogen peroxide, dopa and dopamine to produce neuromelanin. The conclusion of this research was that "the substantia nigra is a melanin that could be synthesized by the oxidation of dopamine which is present in substantial amounts in these neurons." "Melanin is formed by the oxidation of tyrosine, dopa and catecholamines in the presence of hydrogen peroxide."14
The researchers found that this protective enzymatic complex is markedly decreased in Parkinsonian brains, providing us with a reasonable explanation for the fact that more than 80% of the cells of the dopaminergic system in Parkinson's Disease are damaged or dead.
In 1988, Joseph Knoll found that by inhibiting oxidations of dopamine, sexual life of experimental animals was enhanced, and life span prolonged.
The main objective of the research by Joseph Knoll is to try to maintain the synaptic concentrations of dopamine for longer periods, by delaying its catabolic pathway. In this way, improvements could be obtained in cases on which the synthetic pathways of dopamine biosynthesis have seriously deteriorated, as it occurs in Parkinson's disease, and periods of advanced age.
The treatment advocated by J. Knoll, inhibits an enzymatic oxidation of dopamine, but not a spontaneous oxidation of dopamine.
Spontaneous oxidations of dopamine occur when oxygen is in excess in the basal ganglia of the central nervous system. If oxygen is in excess in the system, inhibiting the enzymatic paths of dopamine oxidation, as proposed by J. Knoll, it will not avoid the damaging effects of spontaneous additions of oxygen. It seems to me that if the enzymatic addition of oxygen is blocked, the normal counteraction to the enzymatic blockade of oxygen, must be to increase the spontaneous additions of oxygen, expanding the formation of free radicals and hydrogen peroxide.
The inhibition of enzymatic oxidation of dopamine is possible after the introduction of (-)Deprenyl, a chemical compound which inhibits the enzyme monoamine oxidase (MAO). The compound produces an extension of the active life of dopamine in the synaptic cleft. In Parkinson's disease, there is a severe deficiency of dopamine. By retarding oxidative degradation of dopamine the Parkinsonian deficit of dopamine could be partially compensated.
My conclusion is, that if oxygen is in excess in the system, blocking oxidation-enzymatic paths, will enhance alternative paths of oxygen additions. It seems to me that improvements by decreasing oxygen damage, could only be achieved by lowering the oxygen pressure in the dopaminergic system. This could be clearly attained if environmental oxygen pressure decreases.
Neuromelanin
In 1991 the pigment neuromelanin was isolated in efforts to determine its definitive structure. It is interesting that the findings were that neuromelanin is mainly formed by a complex of the amino-acid cysteine with dopamine. The complex called 5-S-Cysteinyl-dopamine has the amino-acid cysteine bound at the position 5 of the dopamine carbon ring. (Colour Plate 16, Page 96) The amino acid cysteine has a sulfur atom at its main reactive site.
The Formation of 5-S-Cysteinyldopamine, the main isomer of neuromelanin in the substantia nigra, represents the protective mechanism of neurons against oxygen free radicals.
Since the initiation of my chemistry studies I have found it important to notice that in the periodic table, Group 16, which represents the vertical column headed by oxygen, is followed by sulfur and below it in the same column, selenium. Both sulfur and selenium have the same electron valence as oxygen and similar properties. Sulfur and selenium will react similarly to oxygen. Oxygen, sulfur and selenium have six, electrons in the outermost electron shell.
The reactive negative charges (electrons) in sulfur are further apart from the nucleus than in oxygen. This is why, the element sulfur is less reactive than oxygen (Less electronegative), although it possesses the same number of electron charges as oxygen. In selenium the negatives charges are even further apart from the nucleus than in sulfur. Selenium and sulfur, because of their similarities to oxygen electron-valence, might replace oxygen when reacting with another molecule. Sulfur might react with dopamine instead of oxygen, because both atoms have similar electron shell configurations.. It seems to me that if dopamine reacts with sulfur instead of oxygen, it will avoid the creation of the free radicals superoxide and hydrogen peroxide, as by products of the reaction. For these reasons, sulfur and selenium are important free radical scavengers. Their presence interferes with oxygen and the creation of oxygen free radicals.
I have noticed that in the formation of neuro-melanin, the sulfur atom of cysteine reacts at position 5 of the carbon ring of dopamine. This block nearby position 6, to react with oxygen to form 6-hydroxydopamine and toxic hydrogen peroxide.
The recent elucidation that one of the main compounds forming neuromelanin is 5-S-Cysteinyl-dopamine is in accordance with essential chemical principles. The defense against neuronal auto-oxidation is provided by sulfur, an element with similar binding reactive properties to oxygen, but with no damaging free radicals by products, like hydrogen peroxide, or superoxide radical.
|
