Depression cause and risk
factors-pathophysiology The
Parkinson's Disease Model
Insights into the
pathophysiology of depression
can be gained from understanding
another monoamine
neurotransmitter disease,
Parkinsons Disease. Parkinsonism
is caused by damage to the
dopamine post-synaptic neurons
of the substantia nigra at
levels which result in clinical
compromise of fine motor
movement.
Parkinson’s disease has a study
model of neurotoxin damage.49
A great deal of
understanding about Parkinson’s
disease has resulted from
research and case studies
involving the neurotoxin MPTP
(1-methyl 4-phenyl
1,2,3,6-tetrahydropyridine). In
1982, the first writings on MPTP
appeared in the medical
literature after several heroin
addicts administered synthetic
heroin (MPPP) that contained the
byproduct of synthesis, MPTP.
9 Since that time, the
MPTP mechanism of |
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action has
become the prototype in the study of
Parkinson’s disease. At present, most
medical school students study the
ability of MPTP to quickly induce
advanced Parkinson’s symptoms in
patients without prior history of the
disease.
MPTP
is a free radical neurotoxin, which
interferes with mitochondrial metabolism
and leads to cell death (apoptosis). It
freely crosses the blood brain barrier
and has an affinity for the
post-synaptic dopamine neurons of the
substantia nigra which it destroys.
MPTP is chemically similar to MPPP
(synthetic heroin) and may be produced
as a by-product during the illegal
manufacturing of MPPP and other
narcotics.9 The MPTP model of
Parkinson’s disease has taught us a lot
about the dopamine neurons of the
substantia nigra. The main point being
that if enough dopamine neurons are
damaged, the flow of electrical impulses
is compromised and Parkinson’s symptoms
will occur. The way to compensate for
neurotoxin-induced damage is to increase
neurotransmitter levels higher than is
normally found in the system.9
Consistent with the findings of the MPTP
model, the pharmacologic treatment is
dopamine agonists which raise the
existing levels of this neurotransmitter
above population norms in order to boost
damaged neurons. Dopamine agonists, such
as
bromocriptine,
pergolide,
ropinirole,
pramipexole, and
cabergoline can be used as a
monotherapy or in combination with
L-dopa. L-dopa crosses the blood brain
barrier and is freely synthesized into
dopamine without biochemical regulation.3
The elevation of dopamine in the central
nervous system stimulates the remaining
viable dopamine neurons of the
substantia nigra by increasing the
electrical flow, which results in
restoration of the regulator function of
the dopamine bundles and improvement of
disease symptoms.7 The
shortcoming is tachyphylaxis, where the
dopamine agonist and/or L-dopa become
ineffective.
Consistent with the findings of the MPTP
model, the pharmacologic treatment is
dopamine agonists which raise the
existing levels of this neurotransmitter
above population norms in order to boost
damaged neurons. Dopamine agonists, such
as
bromocriptine,
pergolide,
ropinirole,
pramipexole, and
cabergoline can be used as a
monotherapy or in combination with
L-dopa. L-dopa crosses the blood brain
barrier and is freely synthesized into
dopamine without biochemical regulation.3
The elevation of dopamine in the central
nervous system stimulates the remaining
viable dopamine neurons of the
substantia nigra by increasing the
electrical flow, which results in
restoration of the regulator function of
the dopamine bundles and improvement of
disease symptoms.7 The
shortcoming is tachyphylaxis, where the
dopamine agonist and/or L-dopa become
ineffective.
With
Parkinson’s patients, establishing
dopamine levels in the reference range
reported by the laboratory does not
provide relief of symptoms. For
example, the reference range of urinary
dopamine reported by the laboratory is
40-390 micrograms of dopamine per gram
of creatinine (the
neurotransmitter-creatinine ratio
compensates for dilution of the urine).
In our years of research, we have not
observed a Parkinson’s patient able to
achieve relief of symptoms with dopamine
levels in this range. For treatment of
Parkinson’s patients, the therapeutic
range of urinary dopamine is 6,000 to
8,000 micrograms of dopamine per gram of
creatinine. Dopamine levels of this
magnitude can be achieved by
administration of the amino acid
precursor, L-dopa. Amino acid
supplementation can reduce the
tachyphylaxis generally associated with
pharmacologic interventions. Once the
synaptic levels of dopamine are high
enough and the flow of electricity is
once again adequate to regulate fine
motor control clinical resolution of the
Parkinsonian tremor and other symptoms
are seen.40
Just
as with Parkinsonism, the damage to
other neuron bundles of the
serotonin/catecholamine pathways such as
with depression can be dealt with
effectively by increasing the
neurotransmitter levels higher than is
normally found in the system. This has
led our group to propose the Bundle
Damage Theory of Depression.
Depression cause and risk
factors-pathophysiology The
Parkinson's Disease Model
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