Hello Ron and Debi,
Thanks again to Ron for introducing new concepts and initiating discussions.
Debi, its great to have you here and I thank you! MJFF's out of the box thinking is so refreshing and encouraging to think freely. I am optimistic there will be a cure for PD with such diverse areas of research going on in the field of PD.

My personal bias is that inflammation is one of the major causes of neuronal cell death contributing to PD. Having said that, I just want to explain why inflammation is a good thing too. It is a double edged sword sort of thing. It has to be the right amount, right combination of cytokines and at the right place for it to be useful.

Acute inflammation brings immune cells to the site of infection and prevents the pathogen from spreading. Proinflammatory cytokines are made in response to infection. This is sort of an alarm for the body to know that there are intruders and to get ready to defend the body. Without inflammation and subsequent activation of cells, pathogens will not be cleared, vaccines will not work. Most vaccines contain what are called adjuvants and their purpose is to induce pro inflammatory cytokines. This process of acute inflammation is short lived, dependent on (in general) external stimuli, localized to the site of injury or infection and is considered a good response.

On the contrary, chronic inflammation is a different story. If it is sytemic, you can imagine the damage it can do to the body. Immune cells everywhere, where they should not be, vascular permeability increases making cells,factors and toxins enter into previously forbidden areas.....and the list of negative effects of inflammation goes on.

This is how I see inflammation. Hope it makes sense and explains some of the discussion points.

Thanks
Girija

Surprisingly, they are not exactly the same thing but very close. The following is by P.S. Whitton's team, the group that Tom Isaacs is buying amorous gila monsters for. The report has full text available for free, too.


1: Br J Pharmacol. 2007 Apr;150(8):963-76. Epub 2007 Mar 5.

Inflammation as a causative factor in the aetiology of Parkinson's disease.

Whitton PS.

1Department of Pharmacology, The School of Pharmacy, London, UK.
peter.whitton@pharmacy.ac.uk

Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting
mainly the elderly, although a small proportion of PD patients develop the
illness at a much younger age. In the former group, idiopathic PD patients, the
causes of the illness have been the subject of longstanding debate with
environmental toxins, mitochondrial dysfunction, abnormal protein handling and
oxidative stress being suggested. One problem has been that the epidemiology of
PD has offered few clues to provide evidence for a single major causative factor.
Comparatively recently it has been found that in both patients and experimental
models of PD in animals neuroinflammation appears to be a ubiquitous finding.
These cases present with all of the classical features of inflammation including
phagocyte activation, increased synthesis and release of proinflammatory
cytokines and complement activation. Although this process is vital for normal
function and protection in both the CNS, as in the periphery, it is postulated
that in the aetiology of PD this process may spiral out of control with over
activation of microglia, over production of cytokines and other proinflammatory
mediators as well as the release of destructive molecules such as reactive oxygen
species. Given that dopaminergic neurons in the substantia nigra are relatively
vulnerable to 'stress' and the region has a large population of microglia in
comparison to other CNS structures, these events may easily trigger
neurodegeneration. These factors are examined in this review along with a
consideration of the possible use of anti-inflammatory drugs in PD.

PMCID: PMC2013918
PMID: 17339843 [PubMed - indexed for MEDLINE]

I guess ever since I've been in this Forum, I've been posting articles on research done at the NIH by Dr. J S HONG and his group. Over about the past ten years, they have worked with rodents that have been induced with a drug causing PD and then treated with various opioid type drugs at very low doses. Two of these drugs are naloxone (naltrexone) and dextromethorphan, DM. Their work has shown that these opioid drugs reduce the increased microglial activity in the brain caused by the bad drug. They claim that neuro-inflamation, which is the result of out of control microglial activity, is a major cause of PD. My brief unscientific explanation.
While I take 4.5 mg of naltrexone and don't seem to have progressed?, others may want to try 1/2 teaspoon of cough syrup, DM, each night.

* Neuropharmacology Section, Laboratory of Pharmacology and Chemistry and
the National Center for Toxicogenomics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA;
Pathology & Lab Medicine, University of North Carolina at Chapel Hill, North Carolina, USA; and
Departments of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan


1Correspondence: Neuropharmacology Section NIEHS/NIH, PO BOX 12233, MD: F1-01 111 Alexander Dr., Research Triangle Park, NC 27709, USA. E-mail: hong3@niehs.nih.gov; guorongl@med.unc.edu
Inflammation in the brain has increasingly been recognized to play an important role in the pathogenesis of several neurodegenerative disorders, including Parkinson’s disease (PD). Progress in the search for effective therapeutic strategies that can halt this degenerative process remains limited. We previously showed that micromolar concentrations of dextromethorphan (DM), a major ingredient of widely used antitussive remedies, reduced the inflammation-mediated degeneration of dopaminergic neurons through the inhibition of microglial activation. In this study, we report that femto- and micromolar concentrations of DM (both pre- and post-treatment) showed equal efficacy in protecting lipopolysaccharide (LPS) -induced dopaminergic neuron death in midbrain neuron-glia cultures. Both concentrations of DM decreased LPS-induced release of nitric oxide, tumor necrosis factor-, prostaglandin E2 and superoxide from microglia in comparable degrees. The important role of superoxide was demonstrated by DM’s failure to show a neuroprotective effect in neuron-glia cultures from NADPH oxidase-deficient mice. These results suggest that the neuroprotective effect elicited by femtomolar concentrations of DM is mediated through the inhibition of LPS-induced proinflammatory factors, especially superoxide. These findings suggest a novel therapeutic concept of using "ultra-low" drug concentrations for the intervention of inflammation-related neurodegenerative diseases.—Li, G., Cui, G., Tzeng, N.-S., Wei, S,.-J., Wang, T., Block, M. L., Hong, J.-S. Femtomolar concentrations of dextromethorphan protect mesencephalic dopaminergic neurons from inflammatory damage.

I didn't mean to send the email address's in my previous post.
Sorry
But, while I'm back, here is the paper with the comments.
http://www.fasebj.org/cgi/content/full/19/6/489.

JS Hong and fellow NIH alumnus Bin Liu have pretty much mapped out the first steps that lead to PD. Pre-natal "priming" of the microglia leads to a defensive reaction that can continue for months after a single exposure. The result is a constant assault on the brain.

That results in dead neurons in the substantia nigra and accounts for most of our motor problems. The ground work for our non-motor problems, however, lies elsewhere and is not really recognized yet. It is in the normal response of our bodies to inflammation, namely the production of natural steroids such as cortisol by the endocrine system. Dobbs and others have documented elevated cortisol levels in PWP.

This sets up a "see-saw" effect. Inflammation increases. Steroids calm it down. Body cuts back on steroids. Inflammation increases. Steroids go back up. Up and down. After thirty or forty years, system fatigue begins to take a toll from the constant stress. The spinning top begins to wobble.

That two-part explanation (known modestly as the Frobert-Everett Hypothesis) holds up under scrutiny rather well and explains much.

I have been taking low-dose DM for four of the eight years since my PD diagnosis. I spoke to Dr. Hong in Washington at the World Parkinsons Congress in February of 2006 and told him that I had been using LDDM for about a year. His response indicated that he knew of at least one LDDM trial in progress at that time, in Taiwan, I think. He also cautioned me to choose DM preparations that do not contain polystyril, such as Delsym, as this additive has the effect of slowing the release of the DM. Apparently a rapid "spike" in the brain concentration of the drug is most effective in achieving the neuroprotective effect.
For easiest measurement of my 3.5 to 4mg nightly dose, I choose pediatric preparations that contain the lowest DM concentrations, typically 7.5 mg of DM hydrobromide per 5 milliliters (ml) or 1 teaspoon. I take just slightly over one-half teaspoon of Pedia Care Long Acting Cough distributed by McNeill Laboratories. As I have repeatedly posted, my progression has been extremely slow with only modest increases in PD meds; currently one 25/100 carbi/levo plus one 50/200 carbi/levo CR first thing in the morning, then one-half 25/100 plus another 50/200 CR at 2-3 PM, for a total of 550mg of levodopa each day. As I have also previously reported, my Neuro is delighted with my status, saying "Keep doing what you are doing now."
Incidentally, I have also been taking a tonic called VIVIX since August of last year. This preparation contains high levels of natural resveratrol and other polyphenols isolated from muscadine grape seeds and peels and some other vegetable sources. Resveratrol, the miracle anti-aging drug recently featured in several TV news interviews of Dr. David Sinclair at the Harvard Medical School, has also shown powerful neuroprotective effects in animal models of several neurodegenerative diseases. Dr. Sinclair collaborated with scientists at the company which markets VIVIX in perfecting the preparation of this product.
If anyone is interested in more information on this, please PM me.

Robert

If you can remember, could you share how your progression was BEFORE you began the LDDM? In other words, in the four years between dx and your commencement of LDDM, were you progressing at one pace, and then once began LDDM, notice a change of pace? I know how hard it is to tell, just curious. Thanks.

lurking, As you obviously recognize, it is so subjective to make such a comparison that I am hesitant to try. I mostly rely on the assesment of my neurologist for how I am doing. I can say that, although I am aware of some progression both BEFORE and AFTER beginning LDDM, it SEEMS to be slower since starting DM use.

In February of 2006, just before the WPC, I was given a 125I CIT SPECT scan of my remaining substantia nigra dopamine transporters as part of a research program on familial PD at the Institue for Neurodegenerative Diseases in New Haven CT. I have not had another such test to provide a truly objective determination of my progression over time. At any rate, the data in such programs is not provided to participants because of rules of the funding agencies. I think tests of that sort are the only way to objectively measure progression.
Robert

Hope things stay slow for you!

I'm aware that a clinical trial looking at these compounds failed (see reference below) but the opiate receptor target is still being actively pursued (we funded something at the Parkinson's Institute a few years ago and have a current grant looking at specific utility as it relates to digestive issues in PD.) In general, the focus for these compounds remains primarily on more selective targeting to overcome/avoid side effects.

Debi


1: Mov Disord. 1994 Jul;9(4):437-40. Links
Naltrexone, an opiate antagonist, fails to modify motor symptoms in patients with Parkinson's disease.
Rascol O, Fabre N, Blin O, Poulik J, Sabatini U, Senard JM, Ané M, Montastruc JL, Rascol A.
Department of Clinical Pharmacology (INSERM U317), University Hospital, Toulouse, France.
One month of adjunct treatment with naltrexone (100 mg/day) was compared with placebo in a double-blind, randomized, cross-over design in two groups of patients with Parkinson's disease. The first group was composed of 10 patients with a moderate motor impairment insufficiently controlled by monotherapy with bromocriptine. The second group was composed of eight patients with L-dopa-induced peak-dose dyskinesia. Naltrexone as compared with placebo did not demonstrate any significant change in motor function in either group. These negative clinical results do not support a significant role of endogenous opioid systems in the pathophysiology of motor impairment in Parkinson's disease.