19 replies to this topic

[tunt01]

Parkinson's: Neurons Destroyed By Three Simultaneous Strikes

http://www.scienceda...90429132222.htm

Researchers had previously suspected dopamine, alpha-synuclein and calcium channels were involved in killing the neurons, but could not pin the deaths on any single molecule.The new paper, along with previous studies with Dr. Ana Maria Cuervo at Albert Einstein College of Medicine, shows that it is the combination of all three factors that kills the neurons.

The studies found that neurons die because calcium channels lead to an increase of dopamine inside the cell; excess dopamine then reacts with alpha-synuclein to form inactive complexes; and then the complexes gum up the cell's ability to dispose of toxic waste that builds up in the cell over time. The waste eventually kills the cell.

The neurons will survive if just one of the three factors is missing, Drs. Sulzer and Mosharov also found. "It may be possible to save neurons and stop Parkinson's disease by interfering with just one of the three factors," Dr. Mosharov says.

That means that one drug already in clinical trials – which blocks the culprit calcium channel – may work to slow or stop the progression of the disease, an achievement none of the current treatments for Parkinson's disease can accomplish.


Anyone know the name of the drug offhand?


EDIT: looks like it is called Isradipine and it is already in generic form.

http://news.bbc.co.u...lth/6740109.stm

http://en.wikipedia....wiki/Isradipine

Edited by prophets, 29 April 2009 - 06:52 PM.

[tunt01]

http://clinicaltrial...how/NCT00753636

here is the clinical trial notice for Isradipine CR. I have a cousin with Parkinsons and he's ordering it.

Edited by prophets, 29 April 2009 - 08:17 PM.

[Luna]

http://clinicaltrial...how/NCT00753636

here is the clinical trial notice for Isradipine CR. I have a cousin with Parkinsons and he's ordering it.

omg!

Can you please share if there is any improvement? I have an uncle with this devil!

Edited by Winterbreeze, 30 April 2009 - 02:51 AM.

[Lufega]

Awsome post prophets. Many of my problem revolve around dopamine and I have many dopamine related problems. I suspect that I will fall victim to Parkinson's disease later in life (or maybe sooner than I think) If I don't take measures right now.

Magnesium is a natural calcium-channel blocker. Are there any links in Parkinson's disease to magnesium deficiency?

This compares isradipine and magnesium in a diff. function.

Effects of magnesium and isradipine on contractile activation induced by the thromboxane A2 analog U46619 in human uteroplacental arteries in term pregnancy.

The effects of Mg++ and the dihydropyridine calcium channel blocker isradipine on contractions induced by the thromboxane A2 mimetic U46619 were studied in isolated human uteroplacental arteries. In all preparations investigated U46619 10(-10) to 10(-6) mol/L induced concentration-related contractile responses. In maternal vessels U46619 produced a biphasic concentration-response curve, whereas the compound in fetal vessels produced a sigmoid concentration-response curve parallel to that of prostaglandin F2 alpha. Mg++ (1.0 to 6.0 mmol/L) and isradipine (10(-10) to 10(-5) mol/L) both relaxed U46619-induced contractions by up to about 40%. In preparations precontracted by U46619 and exposed to isradipine 10(-6) mol/L, addition of Mg++ 6.0 mmol/L consistently produced a further small relaxation. Removal of the endothelium or pretreatment with indomethacin 10(-6) mol/L or digoxin 10(-6) mol/L did not influence the inhibition produced by Mg++ or isradipine. In vessels pretreated in Ca(++)-free medium Mg++ 6.0 mmol/L depressed and isradipine abolished responses to Ca++ (0.01 to 4.0 mmol/L) after depolarization with K+ 124 mmol/L. In maternal and fetal arteries stimulated with U46619, however, Mg++ 6.0 mmol/L and isradipine 10(-6) mol/L produced a similar, partial inhibition of responses to Ca++ (0.01 to 4.0 mmol/L). Mg++ seems to inhibit transmembrane Ca++ influx, although less efficiently than the dihydropyridine calcium antagonist isradipine. In addition, Mg++ may interfere with Ca++ at intracellular binding sites. Provided that preeclampsia comprises enhanced vascular actions of thromboxane A2, the present results support the established use of Mg++ in the treatment of this condition and suggest that calcium antagonists are of potential benefit.

This says that isradipine may enhance magnesium levels in the body. This is important for those with an unretractable Mg def.

Study of in vitro and in vitro effects of isradipine in skeletal muscles and interaction with some drugs.

The effects of the calcium channel blocker isradipine were studied in the indirectly and directly stimulated mouse diaphragm and in the anesthetized rat to determine its potency, reversibility and interaction with a number of drugs. Initially, it potentiated both indirect and direct twitches followed by a reduction. With tetanic contractions, no potentiation was obtained, only a reduction, which was complete or near complete at the highest concentration tested (10(-4) M). In combination, isradipine reduced the IC50 and IC90 values for the antibiotics gentamicin, polymyxin B and clindamycin, d-rubocurarine and magnesium ions. Depression of contraction caused by isradipine or in combination could be reversed to varying degrees by washout, elevated calcium ions, neostigmine or 4-aminopyridine. Spontaneous recovery from the effects of isradipine alone or in combination was slow and usually incomplete. For in vivo experiments, severe cardiovascular depressant effects of isradipine limited its exposure to lower concentrations and for shorter periods. Under these conditions, it had no effect on heart rate. However, both systolic and diastolic blood pressure were significantly reduced, while pulse pressure was increased. After an initial potentiation muscle contraction was maximally reduced to 55% of control. This study indicates that acute administration of isradipine may aggravate neuromuscular effects of antibiotics, muscle relaxants or hypermagnesemia, although it is unlikely that spontaneous recovery or reversibility of muscular activity by suitable reversal agents will be affected. However, prolonged use of the drug may be more difficult to reverse.

edit: My grandfather has Parkinson's. If I can convince him to test his magnesium levels, serum, RBC, etc., I'll post the results.

Edited by Lufega, 01 May 2009 - 03:32 AM.

[Lufega]

The neurons will survive if just one of the three factors is missing, Drs. Sulzer and Mosharov also found. "It may be possible to save neurons and stop Parkinson's disease by interfering with just one of the three factors," Dr. Mosharov says.

Seems like magnesium alone can inhibit 2/3 factors. Although, a sygergism between the drug and mag. is probaby best.

Magnesium inhibits spontaneous and iron-induced aggregation of alpha-synuclein.

Multiple studies implicate metals in the pathophysiology of neurodegenerative diseases. Disturbances in brain iron metabolism are linked with synucleinopathies. For example, in Parkinson's disease, iron levels are increased and magnesium levels are reduced in the brains of patients. To understand how changes in iron and magnesium might affect the pathophysiology of Parkinson's disease, we investigated binding of iron to alpha-synuclein, which accumulates in Lewy bodies. Using fluorescence of the four tyrosines in alpha-synuclein as indicators of metal-related conformational changes in alpha-synuclein, we show that iron and magnesium both interact with alpha-synuclein. alpha-Synuclein exhibits fluorescence peaks at 310 and 375 nm. Iron lowers both fluorescence peaks, while magnesium increases the fluorescence peak only at 375 nm, which suggests that magnesium affects the conformation of alpha-synuclein differently than iron. Consistent with this hypothesis, we also observe that magnesium inhibits alpha-synuclein aggregation, measured by immunoblot, cellulose acetate filtration, or thioflavine-T fluorescence. In each of these studies, iron increases alpha-synuclein aggregation, while magnesium at concentrations >0.75 mm inhibits the aggregation of alpha-synuclein induced either spontaneously or by incubation with iron. These data suggest that the conformation of alpha-synuclein can be modulated by metals, with iron promoting aggregation and magnesium inhibiting aggregation.

[Lufega]

The effects of the flavonoid baicalein and osmolytes on the Mg 2+ accelerated aggregation/fibrillation of carboxymethylated bovine 1SS-alpha-lactalbumin.

Many protein conformational diseases arise when proteins form alternative stable conformations, resulting in aggregation and accumulation of the protein as fibrillar deposits, or amyloids. Interestingly, numerous proteins implicated in amyloid protein formation show similar structural and functional properties. Given this similarity, we tested the notion that carboxymethylated bovine alpha-lactalbumin (1SS-alpha-lac) could serve as a general amyloid fibrillation/aggregation model system. Like most amyloid forming systems, Mg2+ ions accelerate 1SS-alpha-lac amyloid fibril formation. While osmolytes such as trimethylamine N-oxide (TMAO), and sucrose enhanced thioflavin T detected aggregation, a mixture of trehalose and TMAO substantially inhibited aggregation. Most importantly however, the flavonoid, baicalein, known to inhibit alpha-synuclein amyloid fibril formation, also inhibits 1SS-alpha-lac amyloid with the same apparent efficacy. These data suggest that the easily obtainable 1SS-alpha-lac protein can serve as a general amyloid model and that some small molecule amyloid inhibitors may function successfully with many different amyloid systems.

Wiki- Baicalein (5,6,7-trihydroxyflavone) is a flavonoid(flavones) originally isolated from the roots of Scutellaria baicalensis.

Wiki- Scutellaria baicalensis (or Baikal Skullcap, as opposed to Scutellaria lateriflora, a Skullcap native to North America)

Most of the skullcap supps. I found on Iherb are of the Scutellaria lateriflora variety. Only this one is the scutellaria baicalensis type.

[Lufega]

One more...

This one shouldn't be a surprise to anyone

Curcumin inhibits aggregation of alpha-synuclein.

Pandey N, Strider J, Nolan WC, Yan SX, Galvin JE.
Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MO 63110, USA.
Aggregation of amyloid-beta protein (Abeta) is a key pathogenic event in Alzheimer's disease (AD). Curcumin, a constituent of the Indian spice Turmeric is structurally similar to Congo Red and has been demonstrated to bind Abeta amyloid and prevent further oligomerization of Abeta monomers onto growing amyloid beta-sheets. Reasoning that oligomerization kinetics and mechanism of amyloid formation are similar in Parkinson's disease (PD) and AD, we investigated the effect of curcumin on alpha-synuclein (AS) protein aggregation. In vitro model of AS aggregation was developed by treatment of purified AS protein (wild-type) with 1 mM Fe3+ (Fenton reaction). It was observed that the addition of curcumin inhibited aggregation in a dose-dependent manner and increased AS solubility. The aggregation-inhibiting effect of curcumin was next investigated in cell culture utilizing catecholaminergic SH-SY5Y cell line. A model system was developed in which the red fluorescent protein (DsRed2) was fused with A53T mutant of AS and its aggregation examined under different concentrations of curcumin. To estimate aggregation in an unbiased manner, a protocol was developed in which the images were captured automatically through a high-throughput cell-based screening microscope. The obtained images were processed automatically for aggregates within a defined dimension of 1-6 microm. Greater than 32% decrease in mutant alpha-synuclein aggregation was observed within 48 h subsequent to curcumin addition. Our data suggest that curcumin inhibits AS oligomerization into higher molecular weight aggregates and therefore should be further explored as a potential therapeutic compound for PD and related disorders.

[tunt01]

- my cousin is pretty far progressed in PD, to the point where he needs daily assistance from nursing in assisted living facility. even if Isradipine stabilizes him, he has serious existing damage. So i'm not entirely sure whether his overt results will be very useful as a datapoint, but I will follow up with him after he has taken it for a month.

- I'm not an expert on PD, but this study seems to lend support to Lufega's thoughts on the value of magnesium and PD.

http://www.ncbi.nlm....pubmed/18242592

Magnesium exerts both preventive and ameliorating effects in an in vitro rat Parkinson disease model involving 1-methyl-4-phenylpyridinium (MPP+) toxicity in dopaminergic neurons.
Hashimoto T, Nishi K, Nagasao J, Tsuji S, Oyanagi K.

Department of Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan.

A study was conducted to clarify the effects of magnesium (Mg) administration in a rat Parkinson disease (PD) model involving culture of ventral mesencephalic-striatal cells with 1-methyl-4-phenylpyridinium (MPP+), based on recent evidence for significant loss of dopaminergic neurons exclusively in the substantia nigra of 1-year-old rats after exposure to low Mg intake over generations [Oyanagi, K., Kawakami, E., Kikuchi-Horie, K., Ohara, K., Ogata, K., Takahama, S., Wada, M., Kihira, T., Yasui, M., 2006. Magnesium deficiency over generations in rats with special references to the pathogenesis of the parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. Neuropathology 26, 115-128.]. The results indicated that Mg might protect dopaminergic neurons in the substantia nigra from degeneration. The concentration of Mg in the culture medium varied from 0.8 mM, corresponding to the control condition, to 4.0 mM. Effects were estimated by counting the number of surviving dopaminergic neurons immunopositive for tyrosine hydroxylase and measuring the length of dopaminergic neurites. An increase in the concentration of Mg to 1.2 mM significantly inhibited the toxicity of MPP+, and a concentration of 4.0 mM completely prevented any decrease in the number of dopaminergic neurons. The length of dopaminergic neurites was significantly preserved in the presence of Mg at 1.2 and 4.0 mM. An increase in the concentration of Mg to 1.2 and 4.0 mM led to a significant amelioration in the length of dopaminergic neurites after MPP+ toxicity. This is the first report to document a significant and striking effect of Mg for prevention of neurite and neuron pathology, and also amelioration of neurite pathology in a PD model.

Edited by prophets, 01 May 2009 - 12:47 PM.

[Lufega]

Calcium-channel blockade and depressive illness

Calcium-channel antagonists (calcium blockers) act on muscles to prevent the constriction of blood vessels and also slow the passage of nerve signals through heart muscle. Initially prescribed to treat high blood pressure, there has been an increasing interest in their use for psychiatric disorders. One calcium blocker, verapamil, has been used to treat mania, while another, nifedipine, is reported to produce a paradoxical effect and induces mania or an elevated mood. A case is presented of a 67-year-old woman with a long history of recurrent depression and many hospitalizations who responded well when nifedipine was discontinued. A few days after her last admission to a psychiatric hospital, the woman had a sudden and unexplained spontaneous recovery. A review of the records showed that on the third day of hospitalization nifedipine was withdrawn because the patient developed low blood pressure. Clinical improvement was very rapid, and she was able to return home, where her mood remained quite elevated, but was still within a normal range; she was not hypomanic or manic. This rapid 'switch' from depression to elevated mood was also noted in another patient after nifedipine was withdrawn. A subsequent review of 45 patients admitted to the hospital with severe affective disorder revealed that four were taking nifedipine. Three recovered when the drug was withdrawn, but remained on various drug treatments. The fourth patient recovered after withdrawal of nifedipine alone. Various calcium-channel blockers are structurally different. The fact that verapamil does not bind to the same receptor as nifedipine would seem to explain why one stabilizes mood, while the other may precipitate a mood disorder. The data suggests that patients with treatment resistant depression who are being treated with nifedipine should be withdrawn from this drug. (Consumer Summary produced by Reliance Medical Information, Inc.)

author: Eccleston, Donald, Cole, Andrew J.
Publisher: Royal College of Psychiatrists (UK)
Publication Name: British Journal of Psychiatry
Subject: Health
ISSN: 0007-1250
Year: 1990

[Chaos Theory]

The studies found that neurons die because calcium channels lead to an increase of dopamine inside the cell; excess dopamine then reacts with alpha-synuclein to form inactive complexes; and then the complexes gum up the cell's ability to dispose of toxic waste that builds up in the cell over time. The waste eventually kills the cell.

Is it possible that deprenyl use in healthy individuals over time could lead to increased dopamine within the cells?

[tham]

The standard drug for Parkinson's, Sinemet,
which is levodopa plus carbidopa, actually
accelerates the disease eventually because
dopamine causes massive free radical damage
in the substantia nigra.

[lojzenov]

so why is sinemet prescribed if it just accelerates the disease?

[tham]

so why is sinemet prescribed if it just accelerates the disease?

For symptomatic replacement of the dopamine deficiency.

Just observe any Parkinson's patient on Sinemet.
While he may improve initially, he eventually deteriorates
with time.

Treatment of Parkinson's, as with the treatment of
virtually all degenerative diseases in any standard allopathic
medical textbook, is all about symptomatic management.

It basically involves replenishing dopamine, or reducing
excess acetylcholine with anticholinergics such as Artane.

Doctors are just trained to prescribe certain drugs for a
certain disease. They are not going to tell you that the
drug causes oxidative damage (even if they do know this)
in the very area which it is meant to treat, nor would
they know what to do about it, even if they wanted to.

That's why Annetta Freeman had such a comprehensive regimen.

http://www.ceri.com/annett4.htm

[Lufega]

http://clinicaltrial...how/NCT00753636

here is the clinical trial notice for Isradipine CR. I have a cousin with Parkinsons and he's ordering it.

Update ? I'm thinking of getting my father on this.

[abelard lindsay]

Have you guys heard about the DOPAL? It's what dopamine is metabolized into by MAO-B. Some scientists think it's what's responsible for Parkinsons when it builds up.

http://www.ncbi.nlm....pubmed/19537779

Abstract

Dopamine (DA) has been implicated as an endogenous neurotoxin to explain selective neurodegeneration, as observed for Parkinson's disease (PD). However, previous work demonstrated that 3,4-dihydroxyphenylacetaldehyde (DOPAL) was more toxic than DA. DOPAL is generated as a part of DA catabolism via the activity of monoamine oxidase, and the mechanism of DOPAL toxicity is proposed to involve protein modification. Previous studies have demonstrated protein reactivity via the aldehyde moiety; however, DOPAL contains two reactive functional groups (catechol and aldehyde), both with the potential for protein adduction. The goal of this work was to determine whether protein modification by DOPAL occurs via a thiol-reactive quinone generated from oxidation of the catechol, which is known to occur for DA, or if the aldehyde forms adducts with amine nucleophiles. To accomplish this objective, the reactivity of DOPAL toward N-acetyl-lysine (NAL), N-acetyl-cysteine (NAC), and two model proteins was determined. In addition, several DOPAL analogues were obtained and used for comparison of reactivity. Results demonstrate that at pH 7.4 and 37 degrees C, the order of DOPAL reactivity is NAL >> NAC and the product of NAL and DOPAL is stable in the absence of reducing agent. Moreover, DOPAL will react with model proteins, but in the presence of amine-selective modifiers citraconic anhydride and 2-iminothiolane hydrochloride, the reactivity of DOPAL toward the proteins is diminished. In addition, DOPAL-mediated protein cross-linking is observed when a model protein or a protein mixture (i.e., mitochondria lysate) is treated with DOPAL at concentrations of 5-100 microM. Protein cross-linking was diminished in the presence of ascorbate, suggesting the involvement of a quinone in DOPAL-mediated protein modification. These data indicate that DOPAL is highly reactive toward protein nucleophiles with the potential for protein cross-linking.

[Lufega]

Magnesium deficiency over many generations is what causes Parkinson's according to this study. So, could giving magnesium threonate to someone with PD partially halt the progression ??

Magnesium deficiency over generations in rats with special references to the pathogenesis of the Parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam.
Oyanagi K, Kawakami E, Kikuchi-Horie K, Ohara K, Ogata K, Takahama S, Wada M, Kihira T, Yasui M.
Source
Department of Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Japan. k123ysm@tmin.ac.jp


Abstract
Parkinsonism-dementia complex (PDC) and amyotrophic lateral sclerosis (ALS) are fatal neurological diseases. The incidence on Guam was very high between 1950 and 1965 but decreased dramatically after 1965. It is thought that drinking water containing low levels of calcium (Ca) and magnesium (Mg), and high levels of aluminum and of a plant excitatory neurotoxin are involved in the pathogenesis of these diseases. The present experiment was performed in rats that were exposed to low Ca and/or Mg intake over two generations, thus simulating the conditions of human life on Guam, where several generations live continuously in the same environment. Significant loss of dopaminergic neurons was identified exclusively in the substantia nigra in 1-year-old rats that had been exposed continuously to low Mg intake (one-fifth of the normal level) over generations. The present study suggests that low Mg intake over generations may be involved in the pathogenesis of substantia nigra degeneration in humans.

PMID:16708544 [PubMed - indexed for MEDLINE]

[VidX]

Interesting.

Edited by VidX, 30 May 2011 - 09:30 PM.

[tham]

Last night, I happened to visit this tea lady who
worked in my office during the early 90s. Now 75,
she was bedridden with Parkinson's.



" A potential clue to the vulnerability of these neurons
is their increasing reliance on Ca(2+) channels to
maintain autonomous activity with age. This reliance
could pose a sustained metabolic stress on
mitochondria, accelerating cellular ageing and death.

The Ca(2+) channels underlying autonomous activity
in dopaminergic neurons are closely related to the
L-type channels found in the heart and smooth muscle.
Systemic administration of isradipine, a dihydropyridine
blocker of L-type channels, forces dopaminergic neurons
in rodents to revert to a juvenile, Ca(2+)-independent
mechanism to generate autonomous activity. "


http://www.ncbi.nlm....t_uids=17884683

http://www.ncbi.nlm....t_uids=20187241



Which brings us back to the mitochondrial theory of aging.

http://www.ceri.com/mito.htm

Edited by tham, 05 June 2011 - 08:53 PM.

[tham]

Citicholine.

http://www.ncbi.nlm....st_uids=7162583


" Improvements on the tests were shown by more
patients who received half their levodopa dose
plus citicoline than by those who continued to
receive their usual levodopa dose plus the citicoline.

It is concluded that the levodopa-saving effect of
citicoline could be used to decrease the incidence
of side effects and retard the loss of efficacy of
levodopa in long-term treatment. "

http://www.ncbi.nlm....st_uids=2289218


http://www.ncbi.nlm....st_uids=1863939

http://www.ncbi.nlm....st_uids=8709678

http://www.ncbi.nlm....st_uids=7790146

[tham]

This replaces the last Medline link above which
was erroneous.

Citicholine stimulates growth hormone release
in the elderly.


http://www.ncbi.nlm....st_uids=2028709