US Provisional Patent: 60/496, 397 Methods and Composition for Modulation of The Activity of Voltage-Gated Ion Channels
ABSTRACT
BACKGROUND:
Mental
disorders are conditions that affect thinking, feeling, mood, and behavior. They
may be occasional or long-lasting (chronic). They can affect the ability to relate to others and function each
day. Mental and
neurological disorders result from a combination
of genetic, environmental and biological risk factors.
RESULTS:
Finally, we propose that when this molecule partially or totally releases from these segments in voltage-gated ion channels in some neurons in various regions of the brain due to combination of genetic vulnerability, environmental risk factors, prolonged stress, aging, and oxidative stress, altered ion concentration, impaired neuronal function, and neurotransmitter imbalance may occur, thus, many disorders are predicted to develop including but not limited to schizophrenia, bipolar disorder, depression, anxiety, and ADHD. Also, some neurological disorders including but not limited to epilepsy and irreversible Parkinson’s disease.
RESULTS:
We propose firstly, that chromium chloride (CrCl3)
is the positively charged molecule attached to the nitrogen atoms
on the amino acids lysine or arginine side chains in voltage
sensing segments S4 in all
voltage-gated ion channels with covalent bonds.
Secondly, we propose
that this molecule is the modulator of activity of voltage-gated ion channels with the contribution of S4 ( voltage
sensing segments) situated in all voltage-gated
ion channels according to changes to membrane potential.
Finally, we propose that when this molecule partially or totally releases from these segments in voltage-gated ion channels in some neurons in various regions of the brain due to combination of genetic vulnerability, environmental risk factors, prolonged stress, aging, and oxidative stress, altered ion concentration, impaired neuronal function, and neurotransmitter imbalance may occur, thus, many disorders are predicted to develop including but not limited to schizophrenia, bipolar disorder, depression, anxiety, and ADHD. Also, some neurological disorders including but not limited to epilepsy and irreversible Parkinson’s disease.
CONCLUSION:
Based on our preliminary results –
which are consistent with well established
scientific literature - we predict that chromium picolinate supplement in particular, due to its high bioavailability, serves as a
long-term and intermittent adjuvant approach that may relieve
symptoms or even cure mental disorders
including but not limited to schizophrenia, bipolar disorder, depression,
anxiety and ADHD, and some neurological disorders
like epilepsy effectively, excluding irreversible Parkinson’s disease. Also,
for some other disorders associated with the impairment of modulation of the activity of voltage-gated ion
channels. Daily dose 200 mcg orally for a limited period of 12 weeks for
adults along with standard treatment, preferably under medical supervision.
Keywords: Mental
disorders, schizophrenia, depression , bipolar
disorder, anxiety ADHD, voltage-gated ion channels, chromium picolinate.
INTRODUCTION:
Ion channels are crucial components of living cells. They are situated in the membrane of the cell and allow particular ions to pass from one side of the membrane to the other. Voltage-gated ion channels are involved in many cellular processes: initiation of action potentials, neurotransmitter release, muscle contraction, pacemaker activity, secretion of hormones and other substances. MATERIALS AND METHODS:
We
depended on this research on a published
medical study showing that diclofenac sodium drug may affect the male ejaculation process. In order to study this effect on the modulation
of the activity of voltage-gated ion channels located in
chromaffin cells at adrenals that could be involved in the ejaculation process,
100 mg of diclofenac sodium was administered daily for ten days to a
normal 35 years old male, during which
frequent ejaculations occurred. At the
end of the ten-day period, results were recorded. Then this subject was
administered 120 mcg of chromium
chloride daily for 12 weeks. At the end
of the 12 week period, these results were also recorded. We have proposed
the following hypothesis:
HYPOTHESIS No. 1:
We propose that nerve impulse resulting from
sexual stimulation travels from pelvic plexuses throughout sympathetic trunk to
suprarenal plexuses and is blocked temporarily in voltage-gated ion channels in chromaffin cells at adrenals depolarizing ion channels. When depolarization reaches the threshold of channels, these channels open and
electrolyte discharge (orgasm) occurs and nerve impulse is released throughout
suprarenal plexuses to the sympathetic trunk then through pelvic plexuses to pelvic
muscles causing contraction and squeezing
seminal vesicles thus, ejaculation process occurs.
This hypothesis
is based on a fact that nerves are connected to voltage-gated
ion channels located in chromaffin cells at adrenals, so there should be a function for these nerves. Also, it is based on
an in vitro experiment stating that: ( By using fluorescent dye to detect
Calcium ions influx it was noticed that
there is a blocking of calcium ions influx in
Adrenal chromaffin cells).
Also, this
evidence comes from anatomy: " The suprarenal plexus supplies the suprarenal
gland, being distributed chiefly to its medullary portion; its branches are remarkable for their large
size in comparison with that of the organ they supply " (Gray, Henry.
1918. Anatomy of the human body).
·
So, if nerve impulse is not blocked temporarily in voltage-gated ion channels located in
chromaffin cells at adrenals, due to
voltage-gated ion channels gating mechanism malfunction, then premature
ejaculation will occur.
In order to
test this hypothesis, we conducted the following case study:
CASE STUDY No. 1:
100 mg of diclofenac sodium was administered daily for ten days to a normal 35 years old male,
during which frequent ejaculations occurred.
At the end of the ten days, results
were recorded.
RESULTS OF CASE STUDY NO. 1:
·
It was observed
that the subject suffered from premature ejaculation followed by administering
100 mg of diclofenac sodium daily for ten days during which frequent
ejaculations occurred.
HYPOTHESIS No. 2:
Also,
we propose that: “ There should be molecules in the
structure of voltage-gated ion channels located in chromaffin cells at adrenals vital for the function of these channels. The release of these molecules
leads to a failure in these channels thus they no more can block nerve impulse
resulting from sexual stimulation leading to premature ejaculation. And valency of
these molecules should be higher than
sodium valency (i.e higher than1+) because diclofenac sodium drug
absorbed it causing failure in ion channels
leading to premature ejaculation.
Since
sodium atom lies at the end of the molecular
structure of this drug, so the sodium atom could be substituted by another atom with
a valency higher than 1+. The
molecular structure of diclofenac sodium is
C14H10Cl2No2Na.
Since
chromaffin cells are stained with chromium chloride it gives them brownish color due to oxidation of catecholamines so, (CHROMIUM CHLORIDE) could be the molecules vital for the function of voltage-gated ion channels in chromaffin cells in adrenals, since
valency of chromium is Cr +3 and it's
higher than valency of Sodium (Na
1+ ) .
·
So, if male
suffering from premature ejaculation is given
chromium chloride for a limited period of time, which is implicated in voltage-gated ion channels gating mechanism located in
chromaffin cells, then he will be free
from premature ejaculation.
To test this hypothesis, we have conducted the following case
study:
CASE
STUDY No. 2:
In a case study in the same subject who had
been given diclofenac sodium and caused him premature ejaculation, the subject
was given 120 mcg of chromium chloride daily for 12 weeks. At the end of the 12 weeks,
results were recorded.
RESULTS OF CASE
STUDY No. 2
·
It was observed
that the subject was free from premature ejaculation followed by administering
120 mcg chromium chloride daily for 12 weeks:
ANALYSIS OF CASE
STUDIES:
In the first case study:
It was
observed that the subject suffered from premature ejaculation followed by administering 100 mg of diclofenac
sodium daily for ten days during which frequent ejaculations occurred. Because
diclofenac sodium absorbed chromium chloride from voltage-gated ion channels located in a chromaffin cell at adrenals which are involved in the ejaculation
process thus, gating mechanism in these ion channels malfunctioned and could
not block temporarily nerve impulse
resulting from sexual stimulation, thus, the subject suffered from premature
ejaculation.
Hence,
providing an answer to hypothesis No. 1. ( Mutations introduced in the positive residues of S4
segments alter the voltage dependence of
channel activation) N. Davidson, 1989.
Strong
evidence supporting these case studies
and proves that chromium chloride is a modulator
of activity of voltage-gated ion channels
and supporting that diclofenac sodium drug absorbs chromium chloride from voltage-gated ion channels in chromaffin cells
leading to malfunction of gating mechanism, thus permanent premature
ejaculation will occur according to the
following formula:
In the second case study:
It
was observed that the subject was free
from premature ejaculation followed by administering 120 mcg chromium chloride
daily for 12 weeks. Because of chromium
chloride attached with S4 ( voltage sensing segments) in the same voltage-gated ion channels located in
chromaffin cells at adrenals and restored totally released chromium chloride in
first case study so, gating mechanism in
these ion channels restored its proper
functionality and could block
temporarily nerve impulse resulting from sexual stimulation thus, the
subject recovered from premature ejaculation.
Hence, providing an answer to hypothesis No. 2.
RESULTS:
Here we summarize our results that mental and some neurological disorders are predicted to develop due to the following risk factors
respectively:
1.
Genetic vulnerability.
2.
Prolonged stressful situations and environmental risk factors.
3. Partial or total release of chromium chloride from voltage-gated ion channels in some neurons in various regions of
the brain is proposed and predicted to cause altered ion
concentration and impaired neuronal function.
4. Neurotransmitter imbalance.
5.
Development of mental and some neurological disorders.
SCHIZOPHRENIA:
Schizophrenia is a chronic disabling mental disorder. There are five types of symptoms characteristic of schizophrenia: delusions, hallucinations, disorganized speech, disorganized behavior, and the so-called “negative” symptoms like lack of emotional expression, lack of interest or enthusiasm, problems with motivation, lack of self-care, lack of interest in the world, apparent unawareness of the environment, social withdrawal, speech difficulties and abnormalities, inability to carry a conversation; short and sometimes disconnected replies to questions and speaking in monotone.
One of the famous hypothesis speculating on the causes of this disorder is the dopamine hypothesis. The dopamine hypothesis proposes that certain parts of the schizophrenic brain produce more of the monoamine, dopamine than normal brains.
One of the famous hypothesis speculating on the causes of this disorder is the dopamine hypothesis. The dopamine hypothesis proposes that certain parts of the schizophrenic brain produce more of the monoamine, dopamine than normal brains.
What supports this hypothesis is that the mode of action of current medications of schizophrenia is by targeting and blocking dopamine receptors in dopaminergic neurons in the limbic system in the brain to diminish the effect of excessive dopamine levels. Thus, alleviating symptoms of schizophrenia.
Proposed pathophysiology of schizophrenia is, when chromium chloride is proposed to totally release from voltage-gated calcium channels in terminal buttons in some dopaminergic neurons in the limbic system in brain, a continuous calcium ions influx diffuses into these terminals leading to continuous secretion of dopamine neurotransmitter from synaptic vesicles into synaptic cleft via exocytosis process thus, dopamine levels become higher than normal, so schizophrenia is predicted to develop.
“ Chromium is an essential trace element that potentiates the action of insulin and enhances the activity of neurotransmitters in the brain. Hence increased level of Cr may lead to increase the activity of neurotransmitters in the brain. Thus, suggesting its role in the aetiopathogenesis of schizophrenia “. Ganiyu Arinola et, all, J Res Med Sci. 2010 Sep-Oct; 15(5): 245–249. ( www.ncbi.nlm.nih.gov/pmc/articles/PMC3082825/ ).
CASE STUDY:
In a case study in one 30 years old male diagnosed with schizophrenia, the subject was given 120 mcg of chromium picolinate daily for 12 weeks orally. At the end of the 12 weeks, the subject showed a significant improvement in the negative and positive symptoms of this condition. But he continued to take the monthly maintenance injection zuclopenthixol due to addiction to this injection.
DEPRESSION:
Depression is a mood disorder that causes a persistent feeling of sadness and loss of interest. It affects how you feel, think and behave and can lead to a variety of emotional and physical problems. You may have trouble doing normal day-to-day activities, and sometimes you may feel as if life isn't worth living.
The monoamine hypothesis of depression predicts that the underlying pathophysiologic basis of depression is a depletion in the levels of serotonin, norepinephrine, and/or dopamine in the central nervous system. This hypothesized pathophysiology appears to be supported by the mechanism of action of antidepressant agents that elevate the levels of these neurotransmitters in the brain that have all been shown to be effective in the alleviation of depressive symptoms. ( Journal of Clinical Psychiatry. 2000;61 Suppl 6:7-11).
It is well documented that when any of these above-mentioned neurotransmitters levels deplete, consequently, the rest of neurotransmitters levels deplete too. On the other hand, when any of these a/m neurotransmitters elevate, consequently, the rest of neurotransmitters levels elevate too. GABA levels are expected to be lower than normal in clinical depression.
It is well documented that when any of these above-mentioned neurotransmitters levels deplete, consequently, the rest of neurotransmitters levels deplete too. On the other hand, when any of these a/m neurotransmitters elevate, consequently, the rest of neurotransmitters levels elevate too. GABA levels are expected to be lower than normal in clinical depression.
We shall consider the depletion of serotonin neurotransmitter levels as an example of the proposed pathophysiology of depression. What applies to serotonin depleted levels also, applies to norepinephrine and dopamine-depleted levels too, since they are implicated in depression pathophysiology.
MECHANISM OF SEROTONIN SECRETION:
TERMINATION OF SEROTONIN SECRETION:
Action potentials also activate ( with delay ) voltage-gated potassium channels in the membrane of the terminal buttons thus, potassium ions efflux diffuses outside these terminals, leading to repolarization of the cell membrane at -70 mv, thus voltage-gated calcium channels inactivate and serotonin secretion terminates.
The proposed pathophysiology of depression is when chromium chloride is proposed to partially release from voltage-gated calcium ion channels in terminal buttons in some serotonergic neurons in specific regions of the brain, their threshold becomes low. So the duration of their activation decreases, they will repolarize and inactivate on a current before rest potential current, i.e over - 70 mv. So, voltage-gated calcium channels close faster than normal and calcium ions influx terminates thus, exocytosis process stops and serotonin secretion terminates, so secreted levels of serotonin in synaptic cleft are predicted to become lower than normal.
The depletion of serotonin levels leads to depletion of norepinephrine and dopamine levels according to the monoamine hypothesis. As it is well known, there are grades of depression, when the release of chromium chloride is little depression is mild when the release is high, depression becomes severe.
In summary, we propose that the above-mentioned impairments are implicated in the pathogenesis of depression.
The depletion of serotonin levels leads to depletion of norepinephrine and dopamine levels according to the monoamine hypothesis. As it is well known, there are grades of depression, when the release of chromium chloride is little depression is mild when the release is high, depression becomes severe.
Finally,
stress-induced HPA-Axis hyperactivity leads to overexpression of glucocorticoid
and cortisol which causes depletion of serotonin neurotransmitter, thus
contributing to the development of depression.
In summary, we propose that the above-mentioned impairments are implicated in the pathogenesis of depression.
In a clinical trial, chromium picolinate shows promising antidepressant effects in atypical depression. Its mechanism of action may relate to 5HT2A downregulation, increased insulin sensitivity, or to other effects. ( Davidson JR et al. Biol Psychiatry 2003).
BIPOLAR DISORDER:
Bipolar disorder is classified as a Bipolar affective disorder, or manic-depressive illness (MDI), is a common, severe, and persistent mental illness. This condition is a serious lifelong struggle and challenge.
The bipolar affective disorder is characterized by periods of deep, prolonged, and profound depression that alternate with periods of an excessively elevated or irritable mood known as mania. Mania is characterized by elation, irritability, a diminished need for sleep, excessive talking or pressured speech, racing thoughts … etc.,
Low serotonin levels are implicated in bipolar
disorder. So, the proposed pathophysiology of bipolar disorder is
that, when chromium chloride partially releases
from the voltage-gated calcium ion
channels in terminal buttons in some serotonergic neurons in specific regions of the brain, their threshold becomes low. So the duration of their activation decreases, they will repolarize
and inactivate on a current before rest
potential current, i.e over - 70
mv. So, voltage-gated
calcium channels close faster than normal
and calcium ions influx terminates thus,
exocytosis process stops and serotonin secretion
terminates, so secreted levels of serotonin in synaptic
cleft are predicted to become lower than normal.
Depletion
of serotonin levels leads to depletion of norepinephrine and dopamine
levels according to the monoamine
hypothesis, thus, the bipolar patient
undergoes a state of depression.
Also, low GABA neurotransmitter levels are implicated in bipolar disorder as follows, when chromium chloride is proposed to partially release from voltage-gated calcium channels in terminal buttons in some GABAergic neurons in specific regions of the brain, their threshold becomes low. So the duration of their activation decreases, they will repolarize and inactivate on a current before rest potential current, i.e over - 70 mv. So, voltage-gated calcium channels close faster than normal and calcium ions influx terminates thus, exocytosis process stops and GABA neurotransmitter secretion terminates, so secreted levels of GABA neurotransmitter in synaptic cleft are predicted to become lower than normal.
Decreased levels of GABA have been found in the brain, cerebrospinal fluid, and plasma of patients with bipolar disorder during the depression, as well as during mania. ( Berrettini et al. 1983, Petty et al. 1993).
Due
to neurotransmitter interaction and depression
medications, norepinephrine levels may
become elevated leading to elevated levels of
dopamine, while serotonin and GABA levels are low. In experimental tests, levels of
norepinephrine in patients with affective disorders were higher than patients
without disorders ( Leszczynska-Rodziewicz, 2002; Lake, 1982). Finally,
Elevated dopamine levels cause HPA-Axis hyperactivity which leads to overexpression
of glucocorticoid and cortisol thus, a patient undergoes a state of mania.
In
summary, we propose that the above-mentioned impairments are implicated in the pathogenesis of the bipolar disorder.
ANXIETY:
Experiencing occasional anxiety is a normal part of life.
However, people with anxiety disorders frequently have intense, excessive and
persistent worry and fear about everyday situations. Often, anxiety disorders
involve repeated episodes of sudden feelings of intense anxiety and fear or
terror that reach a peak within minutes (panic attacks). These feelings of
anxiety and panic interfere with daily activities.
Proposed pathophysiology of anxiety is when chromium chloride is proposed to totally release from voltage-gated calcium channels in terminal
buttons in some noradrenergic neurons in amygdala in
limbic system in brain, a continuous influx of calcium ions diffuses
into these terminals leading to continuous secretion of
norepinephrine neurotransmitter from synaptic vesicles into synaptic cleft
via exocytosis process, thus, norepinephrine levels are predicted to become higher than normal. The
role of dopamine neurotransmitters is
proposed to be minimal in anxiety.
Low serotonin levels are also implicated in
anxiety. So, we propose, when chromium chloride partially releases from voltage-gated
calcium ion channels in terminal buttons in
some serotonergic neurons in specific regions of the
brain, their threshold becomes low.
So the duration of their
activation decreases, they will repolarize and inactivate
on a current before rest potential current, i.e over - 70 mv. So, voltage-gated calcium channels close faster than normal and calcium ions influx terminates thus, exocytosis process
stops and serotonin secretion terminates,
so secreted levels of serotonin in synaptic
cleft are predicted to become lower
than normal.
Finally,
stress-induced HPA-Axis hyperactivity leads to overexpression of glucocorticoid
and cortisol, thus contributing to the development of anxiety.
ADHD:
ADHD is a mental disorder of the neurodevelopmental type. It is characterized by problems paying attention, excessive activity, or difficulty controlling behavior which is not appropriate for a person's age. The symptoms appear before a person is twelve years old, are present for more than six months, and cause problems in at least two settings (such as school, home, or recreational activities). In children, problems paying attention may result in poor school performance. Although it causes impairment, particularly in modern society, many children with ADHD have a good attention span for tasks they find interesting.
Elevated levels of serotonin are predicted to deplete norepinephrine and dopamine levels.
In summary, we propose that the above-mentioned impairments are implicated in the pathogenesis of ADHD.
DISCUSSION:
Chromium
chloride is a hydrophilic compound and is attached to the Nitrogen atom on the amino acids lysine or arginine side
chains in voltage sensing segments of VG
ion channels with covalent bonds. Chromium
chloride kernels are positively charged, so they
will be attracted by negatively charged oxygen atoms in the aqueous environment of the ion channel due to
changes to membrane potential. Thus S4
(voltage sensing segments) will change their conformation to closed or opened
states of ion channel according to changes to membrane potential.
Upon chromium chloride release from voltage sensing segments in voltage-gated ion channels in some neurons in various regions of the brain due
to combination of genetic vulnerability,
environmental risk factors,
aging, and oxidative stress, ability of these segments to change
their conformation to closed or opened states of ion
channels due to changes to membrane
potential will be affected, thus leading to altered ion concentration, impaired ion
channels function, impaired neuronal function, and neurotransmitter imbalance.
Finally, stress-induced HPA-axis hyperactivity also contributes
to the development of mental disorders like depression, anxiety, and mania via overexpression
of glucocorticoid and cortisol which interact with
neurotransmitters.
: CONCLUSION
Based on our preliminary results – which are consistent with well established scientific
literature - we predict that chromium picolinate supplement in particular, due to its high bioavailability, serves as a
long-term and intermittent adjuvant approach that may relieve
symptoms or even cure mental
disorders including but not limited to schizophrenia, bipolar disorder,
depression, anxiety and ADHD, and some neurological disorders like epilepsy effectively,
excluding irreversible Parkinson’s
disease. Also, for some other disorders associated with the
impairment of modulation of the activity of voltage-gated
ion channels. Daily dose 200 mcg orally for a limited period of 12 weeks for
adults along with standard
treatment, preferably under medical supervision.
We would like to point out that there are limitations in this research since it needs further in vitro empirical validation
: ACKNOWLEDGMENTS
We would like to extend our grateful gratitude to Dr. Mustafa Naka, and Dr. Maram Elayyan for their valuable assistance.
: FOOTNOTES
.Chromium supplementation should be for limited periods of time for kidney and liver patients
This research is based on trivalent chromium which is safe and beneficial to humans. While
.Hexavalent chromium is harmful to humans and may cause lung cancer
Abstract of this research y had been displayed as a poster at The 3rd Europe Schizophrenia Research
.Conference held in Berlin – Germany in 2011
.Conference held in Berlin – Germany in 2011
Also, the abstract of this research had been accepted to be displayed as a poster at The 9th Bipolar Disorder Conference Held in Pennsylvania – the USA in 2011
This research does not endorse any product, it is for the sake of patients all over the world.
This research does not endorse any product, it is for the sake of patients all over the world.
No potential conflict of interest exists
Written consents had been taken from all participants enrolled in case studies mentioned in this research
Six case studies utilizing chromium have been conducted for different indications, related
to chromium deficiency conditions in humans, they all gave significant results.
: REFERENCES
Gray, Henry. 1918. Anatomy
of the human body
Ganiyu Arinola et, all, J Res Med Sci. 2010 Sep-Oct; 15(5): 245–249.www.ncbi.nlm.nih.gov/pmc/articles/PMC3082825/)Journal of Clinical Psychiatry. 2000;61 Suppl 6:7-11.
Davidson
JR et al. Biol Psychiatry 2003).
Berrettini et al. 1983, Petty et
al. 1993.
Leszczynska-Rodziewicz,
2002; Lake, 1982.
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