PARKINSON'S DISEASE
Freddy Powers Parkinson's Foundation - FPPF
Patient Summary:
Parkinson's Disease affects the central nervous system. Symptoms of this disease include stiffness of muscles, tremors, slowness of movement, and lack of balance. The walk of many Parkinson's Disease patients often has a decreased arm swing with short, shuffling steps. The presence of depression prior to any traditional symptoms of Parkinson's Disease is so common that many physicians are now considering depression as an early sign of Parkinson's Disease.
Physician Summary:
Clinical experience has shown that STS treatments are effective in decreasing the morbidity of Parkinson's Disease. This is probably mostly due to an increase of VIP (Vasoactive Intestinal Polypeptide). As demonstrated in a case study below, the patient not only subjectively improved but also objectively improved. The plasma VIP level was increased, handwriting normalized, tremors decreased, walking normalized, memory functions improved, the Parkinson's Unified Rating Scale decreased dramatically, and the heart rate variability normalized.
A Case Study of a recent Parkinson's Disease Patient
The patient related that shortly following his retirement from work in 1990, he became extremely depressed. Several years later, he began to notice tremors and was diagnosed as having Parkinson's Disease in 1996, by his neurologist. He was given oral medications and his tremors decreased. However, the patient continued to have tremors and other autonomic nervous system dysfunction symptoms became increasingly apparent. Overall, he began to have a decreasing quality of life.
The patient was seen in our clinic and objective testing (noninvasive vascular testing, Neurometer testing, and X-Rays) all showed changes consistent with an autonomic nervous system dysfunction. The heart rate variability testing was performed before and after his first treatment. This test was repeated approximately 8 weeks later. Although the first treatment did not show a decrease in the heart rate variability, the follow-up testing showed a significant decrease. Most significantly, a Unified Parkinson's Disease Rating Scale was determined as of 8/12/02 and a follow-up on 10/8/02. The rating prior to beginning treatment was 17. After 10 weeks of treatment the rating was 6. The improvement was as follows:
8/12/02 10/8/02- Moderate intellectual impairment Mild intellectual impairment
- Periods of depression No depression
- Disinterest in elective activities Normal
- Occasional choking Normal swallowing
- Moderately small handwriting Slight handwriting abnormality
- Somewhat slow cutting food Normal
- Hand tremor slight Tremor absent
- Slow arising from chair Normal
- Dyskinesias 1-25% No Dyskinesias
- Abnormal sleep Normal sleep
MEDICAL JOURNAL BACKGROUND INFORMATION
STS treatments are designed to create vasoactive intestinal polypeptide (VIP) (40)(52)(53)(54)(55)(56), insulin-like growth factor (IGF), and cyclic adenosine monophosphate (cAMP) (60)(80)(102). VIP, IGF, and cAMP have been shown to be effective in protecting dopaminergic neurons from oxidative stress.
It has been demonstrated that STS treatments increase and normalize skin temperatures. (40) It has been shown the type of electrical stimulation utilized in the STS increased the plasma VIP 60%. Since VIP is not a blood-borne hormone, an increase in plasma VIP in the systemic circulation represents an overflow from synapses. (52)(53)(54)(55)(56) VIP, over a wide concentration range provided significant neuroprotection against oxidative stress mediated through raising cellular resistance. VIP protective activity is likely mediated by femtomolar-acting glial proteins such as activity-dependent neurotrophic factor (ADNF), activity-dependent neuroprotective protein (ADNP), peptide derivatives ADNF-9 (9aa) and NAP (8aa), respectively. Dopamine and its oxidation products are thought to trigger dopaminergic nigral cell death in Parkinson's disease. However, remarkably low concentrations of VIP protected against dopamine toxicity. (81) To exert neuroprotective activity, VIP requires glial cells secreting neuroprotective proteins (activity-dependent neurotrophic factor (ADNF), a fourteen-amino-acid fragment of ADNF (ADNF-14), and the more potent, nine-amino-acid derivative (ADNF-9). (35)(36)
Oxidative stress is a common associative mechanism that is part of the pathogenesis of many neurodegenerative diseases. (90) Brown showed that VIP is essential for astrocytes to regulate clearance of glutamate from the vicinity of neurons. In addition, VIP enhanced the expression of the high-affinity VIP receptor, increased astrocytic release of interleukin-6, and indirectly reduced the toxicity of glutamate in neuronal-conditioned astrocyte medium. (22)(23) VIP and ADNF-9 were found to cause significant protection from oxidative stress from H2O2. (104) An increased production of H2O2 is thought to be critical to the pathogenesis of Parkinson's disease. (78)
VIP stimulates glycogenolysis in the cerebral cortex. Studies in primary cultures indicate that the glycogenolysis elicited by neurotransmitters may take place in astrocytes, which are glial cells and where glycogen is predominantly stored in the nervous system. These observations suggest that the primary function of certain neuronal circuits may be to regulate the availability of energy substrates within discrete neuronal ensembles. (71)
VIP also causes an induction of glycogen resynthesis, resulting, within 9 hours, in glycogen levels that are 6-10 times higher than those measured before the application of VIP. Dibutyryl-cAMP application also results in enhanced glycogen resynthesis. This strongly suggests that the long-term effect of VIP is mediated by the cAMP second-messenger pathway. (103) VIP tightly regulates glycogen metabolism in astrocytes. In this cell type VIP regulates the expression of a number of genes related to energy metabolism, such as glycogen synthase. These effects of VIP involve the transcription factor family C/EBP and result in the induction of at least seven new proteins by astrocytes. The actions of VIP on neurons appear to be of a modulatory nature: thus VIP enhances glutamate-mediated neurotransmission by potentiating the effects of glutamate on arachidonic acid formation and on the induction of c-fos and on BDNF expression. These effects indicate that VIP can actually increase the strength of glutamate-mediated neurotransmission. (72)
Recent evidence supports the significance of IGF-I in the maintenance of the integrity and homeostasis of the nervous system. The widespread distribution of its receptor allows IGF-I to affect the survival of numerous populations of neurons and glial cells in both the CNS and the PNS. Most recently, a clinical trial has revealed the beneficial effects of IGF-I in amyotrophic lateral-sclerosis (ALS). Clinical information suggests the potential usefulness of IGF-I in the treatment of certain neurodegenerative diseases, including ALS and Alzheimer's disease. IGF-I acts on a variety of neuronal cells providing a general means of reducing or slowing down neuronal losses. (31) Mucus of the olfactory epithelium of Parkinson's disease patients contained significantly reduced levels of IGF-I in comparison with those of controls. (34) Offen et al showed that IGF-1 possesses a neuroprotective effect against DA-induced toxicity, caused by oxidative stress. (82)
Insulin and IGF-1 promote the growth of rat neuronal cells in primary culture. (27)
Hulley et al showed that cAMP was able to prevent the degeneration of dopaminergic neurons in situations of stress. (43)(48) Apparently, cAMP-dependent signaling may be particularly crucial for the maturation and long-term survival of mesencephalic dopaminergic neurons. (76) Treatment of mesencephalic cells with dibutyryl-cAMP not only promoted the survival of tyrosine hydroxylase expressing (TH+) neurons but also increased the proportion of these cells that were immunopositive for BDNF. (77)
The current major hypothesis is that nigral neuronal death in PD is due to excessive oxidative stress generated by auto and enzymatic oxidation of the endogenous neurotransmitter dopamine (DA), the formation of neuromelanin (NM) and the presence of a high concentration of iron. (7) It has been shown that the dopaminergic neurons in the substantia nigra, which degenerate in PD, are the neurons, which are particularly sensitive to oxidative stress and rise in intracellular calcium concentrations. Because both events seem to occur in Parkinson's disease this may explain why some dopaminergic neurons degenerate and other do not. (44)
The cause of dopaminergic nerve cell death in Parkinson's disease includes an oxidative stress resulting from an overproduction of free radicals or a decreased metabolism of the mitochondrial respiratory chain. (2) Human corneal endothelium(CE), a neural crest-derived tissue, has a very limited regenerative capacity and may depend on trophic factors for its survival throughout life, as well as after injury and during storage before transplantation. VIP significantly increased CE survival protecting it from hydrogen peroxide (H2O2) and other oxidative insults. (61) It should be noted that H2O2 is also produced during reperfusion following ischemia. (79)
A superactive VIP lipophilic analog (Stearyl-Norleucine17-VIP; SNV) provided a regulatory mechanism for activity-dependent neuroprotective protein (ADNP) synthesis during glycolytic stress. (97) 1-methyl-4-phenyl-pyridinium ion (MPP+) is the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Rhesus monkeys treated with MPTP exhibited behavioral and neuropathological changes that closely paralleled those in human Parkinson's disease. Glucose utilization was significantly reduced in portions of the brain. (88) It was found that in MPTP neurotoxicity, (MPP+) enters nigral neurons by the dopamine uptake system and binds to neuromelanin, which serves as a depot, continuously releasing MPP+ until it destroys the cells. (28)
VIP has neuroprotective properties, including the prevention of cell death associated with excitotoxicity (NMDA), beta-amyloid peptide, and gp120, the neurotoxic envelope protein from the human immunodeficiency virus. The neurotrophic and neuroprotective properties are mediated in part through the action of glial-derived substances released by VIP. These substance include cytokines, protease nexin I, and ADNF, a novel neuroprotective protein with structural similarities to heat-shock protein 60. (15)
Subnanomolar concentrations of VIP elicit a survival-producing action in CNS cultures composed of both astroglia and neurons. This neurotrophic action is mediated by a complex array of substances released by VIP from astrocytes. Included in this glial protein mixture are a cytokine (interleukin-1 alpha), a serine protease inhibitor (protease nexin I), and an extracellular stress protein (activity-dependent neurotrophic factor). In dissociated spinal cord cultures, all of these substances exhibit neuroprotection from neuronal cell death produced by electrical blockade with tetrodotoxin. All these substances produce neuronal cell death when test cultures are treated with neutralizing antisera to any one of them. They are all apparently necessary for the survival of a subpopulation of neurons that are dependent on spontaneous, excitatory neurotransmission. (13)(16)(18)(20)
Vasoactive intestinal peptide (VIP) increases neuronal survival in dissociated spinal cord cultures during a critical period of development. Two mechanisms contributing to this action of VIP have been observed: 1) VIP was shown to be a secretagogue for neuron survival-promoting activity; and 2) VIP was found to be an astroglial mitogen. It was found that 5 days of treatment with (VIP) increased astroglial mitosis. This effect was specific for astroglia. The dual action of VIP may regulate glial-derived trophic substances that are important for neuronal survival during the course of development. (3)(14)(19)(21)
VIP enhanced the expression of the high-affinity VIP receptor, increased astrocytic release of interleukin-6, and indirectly reduced the toxicity of glutamate in neuronal-conditioned astrocyte medium. These results indicate that VIP is essential to the molecular interaction of neurons and astrocytes and is involved in the regulation of the protective effects of astrocytes for neurons. (22)
Clinical studies suggest that gut disorders are common in Parkinson's disease. (99)
Marmosets developed features typical of Parkinson's disease following treatment with MPTP for four days. The effects of MPTP treatment on the concentrations of dopamine and neuropeptides were determined and changes compared with those reported for Parkinson's disease. It was found that within the substantia nigra, substance P concentrations doubled following treatment with MPTP; in contrast, concentrations of VIP and neuropeptide Y were significantly reduced. (4) Studies show that VIP facilitates the DA metabolism in the brain. (50) The formation of extracellular or intracellular deposits of amyloid-like protein fibrils is a prominent pathological feature of PD. In PD, the alpha-synuclein protein accumulates within neurons inside the Lewy bodies and Lewy neurites. It has been shown that solutions of Abeta 1-40, Abeta 1-42, Abeta 25-35, alpha-synuclein and non-Abeta component (NAC; residues 61-95 of alpha-synuclein) all liberate hydroxyl radicals upon incubation in vitro followed by the addition of small amounts of Fe(II). Study results suggest that hydrogen peroxide accumulates during the incubation of Abeta or alpha-synuclein, by a metal-dependent mechanism, and that this is subsequently converted to hydroxyl radicals, on addition of Fe (II), by Fenton's reaction. Consequently, one of the fundamental molecular mechanisms underlying the pathogenesis of cell death in AD and PD, and possibly other neurodegenerative or amyloid diseases, could be the direct production of hydrogen peroxide during formation of the abnormal protein aggregates. (107)
The disruption of calcium homeostasis by AbetaP-channels may be the molecular basis of the neurotoxicity of AbetaP, and the development of Alzheimer's disease. It is also proposed that the constituents of membrane lipids may play important roles in the process of this channel formation. (57) It has been shown that elevated levels of extracellular Alzheimer's beta-amyloid protein alter the homeostasis of free [Ca(2+)](i) in different cell types of the mammalian. These results suggest that unregulated Ca(2+) entry across amyloid channels may be a common mechanism causing cell death, not only in diseases of the third age, including Alzheimer's disease and type 2 diabetes mellitus, but also in prion-induced diseases. (58) Recent studies suggest that Alzheimer's disease and non-insulin-dependent (type 2) diabetes mellitus may share a common cell death mechanism, related to the toxicity of beta-amyloid (Abeta) and amylin, respectively. (67)(68)(69)(70)(112)
It has been shown that in ischemic cerebrovascular diseases (ICVD) electro-acupuncture produced significant increases in the low CSF levels of VIP so that the level was equivalent of the controls. Interestingly, the level of plasma VIP showed no significant difference between the ICVD and control groups. (118)
Many investigators have suggested therapies using the strong bronchodilatory effects and neuroprotective aspects of VIP. However, the rapid inactivation of the peptide by peptidases has prevented effective VIP-based drugs so far and non-peptide VIP-agonists did not reach clinical use. (15)(16)(17)(20)(28)(37)(43)(48)(81)(82)(90)
Many of the concomitant medical problems seen in CRPS patients are the same autonomic dysfunction symptoms as seen in PD. Hundreds of peer review journal medical articles show that autonomic dysfunctions such as GERDS, constipation, increased salivation, frequency of dysphagia, orthostatic hypotension, defecatory dysfunction necessitating increased straining and resulting in incomplete evacuation are all associated with PD. (73)(87)(96)
One study showed that 89% of PD patients had at least one of the following autonomic symptoms, compared to 43% of control subjects. These symptoms included erectile dysfunction (60.4 vs. 37.5%), sensation of incomplete bladder emptying (41.6 vs. 15.6%), urgency (45.8 vs. 3.125%), constipation (43.9 vs. 6.25%), dysphagia (22.9 vs. 6.25%) and orthostatic dizziness (21.95 vs. 0%). (100)
Another study showed that the GI symptoms in PD patients did not correlate with the type of treatment but instead correlated with disease severity. The authors stated that the GI symptoms of PD reflect direct involvement in the GI tract by the primary disease process. (32)
The frequency of sleep complaints in patients with Parkinson's disease (PD) is estimated to be between 60-90%. (5)(42)(47)(105)(106)(109) During a recent study of STS treatment of peripheral neuropathy patients, it was found that even once a day treatment with STS resulted in 80% of the participants having markedly improved sleep. (40) In addition, it has been found that more than 95% of the patients receiving STS treatments twice a day experience improved sleep.
The following autonomic dysfunctions, which are commonly seen in Parkinson's Disease patients, are caused by insufficient amounts of VIP and all of these have been treated, successfully, utilizing STS therapy. These include:
- Acid reflux (GERDS) (30)(101)(113)(114)
- Increased (and occasionally decreased) saliva (10)(29)(89)
- Dysphagia (1)(9)(38)(39)(54)
- Erectile dysfunction (41)(91)(108)
- Sensation of incomplete bladder emptying (64)(86)(93)(110)
- Constipation (25)(26)(33)(92)
- Altered tear secretion (6)(45)(46)(63)(94)(95)
- Diminished quality of sleep (12)(24)(85)(98)(117)
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