[olsen]

Exp Neurol. 2007 Jul 17; [Epub ahead of print]

Neuroinflammatory mechanisms in Parkinson's disease: Potential environmental triggers, pathways, and targets for early therapeutic intervention.
Tansey MG, McCoy MK, Frank-Cannon TC.
Department of Physiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.

Most acute and chronic neurodegenerative conditions are accompanied by neuroinflammation; yet the exact nature of the inflammatory processes and whether they modify disease progression is not well understood. In this review, we discuss the key epidemiological, clinical, and experimental evidence implicating inflammatory processes in the progressive degeneration of the dopaminergic (DA) nigrostriatal pathway and their potential contribution to the pathophysiology of Parkinson's disease (PD). Given that interplay between genetics and environment are likely to contribute to risk for development of idiopathic PD, recent data showing interactions between products of genes linked to heritable PD that function to protect DA neurons against oxidative or proteolytic stress and inflammation pathways will be discussed. Cellular mechanisms activated or enhanced by inflammatory processes that may contribute to mitochondrial dysfunction, oxidative stress, or apoptosis of dopaminergic (DA) neurons will be reviewed, with special emphasis on tumor necrosis factor (TNF) and interleukin-1-beta (IL-1beta) signaling pathways. Epigenetic factors which have the potential to trigger neuroinflammation, including environmental exposures and age-associated chronic inflammatory conditions, will be discussed as possible 'second-hit' triggers that may affect disease onset or progression of idiopathic PD. If inflammatory processes have an active role in nigrostriatal pathway degeneration, then evidence should exist to indicate that such processes begin in the early stages of disease and that they contribute to neuronal dysfunction and/or hasten neurodegeneration of the nigrostriatal pathway. Therapeutically, if anti-inflammatory interventions can be shown to rescue nigral DA neurons from degeneration and lower PD risk, then timely use of anti-inflammatory therapies should be investigated further in well-designed clinical trials for their ability to prevent or delay the progressive loss of nigral DA neurons in genetically susceptible populations.

PMID: 17720159 [PubMed - as supplied by publisher]

[reverett123]

One of the maddening things about PD is that so much of the professionals believe it to be "simply" a neurological disease of uncertain origin. Unfortunately it is

Our Immune System (inflammatory response) + Our Endocrine System (stress response) = Neural Damage

As a result most endocrinologists and immunologists barely know we exist and the neurologists spend a lot of time scratching their heads in frustration.

I'm also becoming more and more convinced that, in addition to the longterm effects, there are short term effects due to neural disruption of the chemicals associated with stress and inflammation. So many of the botanicals that do seem to help have actions against one or both of these processes. But the disciplines seldom talk to each other, read their own journals, go to their own conferences, etc.

[indigogo]

I think you are right on the money. To continue to be pigeon holed as a "neurological" disorder does patients a disservice.

Originally Posted by reverett123

One of the maddening things about PD is that so much of the professionals believe it to be "simply" a neurological disease of uncertain origin. Unfortunately it is

Our Immune System (inflammatory response) + Our Endocrine System (stress response) = Neural Damage

As a result most endocrinologists and immunologists barely know we exist and the neurologists spend a lot of time scratching their heads in frustration.

I'm also becoming more and more convinced that, in addition to the longterm effects, there are short term effects due to neural disruption of the chemicals associated with stress and inflammation. So many of the botanicals that do seem to help have actions against one or both of these processes. But the disciplines seldom talk to each other, read their own journals, go to their own conferences, etc.

[ashleyk]

Below, is one of several papers coming from the Neuropharmacology Section of the NIH. They have long claimed that neuro-inflammation is the cause or one of the causes of many neuro-degenerative diseases through a process of over activated microglial (killer) cells. They also believe, through their experiments with rodents, that they can greatly attenuate this inflammation with low doses of several drugs that are opioid receptor antagonists such as naloxone (naltrexone), dextromethorphan and others.
I guess I've bought into their work and I have been taking 4.5mg of naltrexone (LDN, low dose naltrexone) for the past 38 months. Outside of rebalancing my meds between Sinemet and Mirapex, still at low levels, my PD seems to have not progressed. I have only been on Sinemet for 35 months so maybe I'm in the honeymoon period. But if naloxone can protect rodents from neuro-inflammation, maybe it can do the same people.
Has anyone remained at the equivalent or same dose of Sinemet and/or Mirapex for three years or longer and their PD symptoms remain about the same?
Ashley

http://www.ncbi.nlm.nih.gov/sites/en...t=AbstractPlus

Liu Y, Qin L, Wilson BC, An L, Hong JS, Liu B.Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, NC 27709, USA. liu3@niehs.nih.gov
Previously we reported that naloxone stereoisomers, in an opioid receptor-independent manner, attenuated the inflammation-mediated degeneration of dopaminergic neurons by inhibition of the activation of microglia, the resident immune cells in the brain. Recently we discovered that beta-amyloid peptide Abeta (1-42) exhibited enhanced neurotoxicity toward both cortical and mesencephalic neurons through the activation of microglia and production of superoxide. The purpose of this study was to determine whether naloxone isomers had any effect on Abeta (1-42)-induced neurodegeneration. Pretreatment of either cortical or mesencephalic neuron-glia cultures with 1 to 10 microM (-)-naloxone, prior to treatment for up to 11 days with 0.1 to 3 microM Abeta (1-42), afforded significant neuroprotection as judged by neurotransmitter uptake, immunocytochemical analysis, and cell counting. More importantly, (+)-naloxone, the ineffective enantiomer of (-)-naloxone in binding opioid receptors, was equally effective in affording neuroprotection. Mechanistically, inhibition of Abeta (1-42)-induced production of superoxide in microglia underlay the neuroprotective effect of naloxone stereoisomers. Moreover, neuroprotection and inhibition of Abeta (1-42)-induced superoxide production was also achieved with naloxone methiodide, a charged analog with quaternary amine, suggesting that the site of action for naloxone isomers is at the cell surface of microglia. These results demonstrated that naloxone isomers, through mechanisms unrelated to the opioid receptors, were capable of inhibiting Abeta (1-42)-induced microglial activation and degeneration of both cortical and mesencephalic neurons. Combined with our previous observations with inflammagen-induced neurodegeneration, naloxone analogs, especially (+)-naloxone, may have potential therapeutic efficacy for the treatment of Alzheimer's and Parkinson's disease.
PMID: 12183682 [PubMed - indexed for MEDLINE]

[indigogo]

ashleyk -

here's my drug history:

1999-2002 (3 years) mirapex only (can't remember the dosage, but it never changed)
2002-2005 (3 years) requip only (2 mg/3 times a day)
2005-2006 (1 year) sinemet (one 25/100 3 times a day added to requip)
2005-2007 (1 year) no requip; added one 100 mg amantadine/3 times a day; sinemet remains the same
2007 (2 months) added 2 mg requip once a day at bedtime for restless leg

In 8 years +, my doctor has changed drugs, but never increased, only decreased dosages. I am tremor dominant. I think my PD symptoms have progressed very little.

I also have taken 150 mg effexor for depression once a day for 8 years; depression has a far greater effect on my "tasks of daily living" than the classical pd physical symptoms.

I drink green tea but take no other supplements.

[RLSmi]

4-6 mg dextromethorphan (currently via Children's Pedia Care cough medicine)at bedtime;

2X50/200 mg carbi/levodopa (generic Sinemet)CR, plus 1/2 25/100 carbi/levo each morning and afternoon with CR (a total of 75/500 mg carbi/levodopa);

3X300 mg CoQ10;

100 mg amantadine;

Shaklee super multivitamins/minerals (spouse is a distributor);

500 mg C;

400 units E;

600 mg N-acetyl cysteine

400 mg acetyl-l-carnitine

200 mg alpha lipoic acid

occasional red panax ginseng tea

The last four were added in the last year.

No significant progression in 6 years, except for onset about 2 years ago of early AM "shuffle-steps" which disappear after carbi/levodopa kicks in.

I think the dextromethorphan (48 mos.) and CoQ10 (60 mos.) are most responsible for any slowing/preventing symptom progression.

Robert

[reverett123]

By no means exhaustive. If I were inclined to experiment I think I would combine sub-clinical doses of several for several reasons- 1) don't put it all on one horse; 2) if you happen to choose one that is harmful, your restraint minimizes risk; 3) synergy has a greater opportunity to occur; 4) it may not be a good idea to completely counter the inflammation (you may need some) and a low dose approach may be as sensible here as with the dextromethorphan. Go to Medline and paste in the ID number of those you want to follow up.

1: Chen HQ et al. Biochanin A protects dopamine...[PMID: 17399896]

2: Wang MJ et al. Silymarin protects dopaminerg...[PMID: 12473078] (Milk thistle)

3: Liu Y et al. Dextromethorphan protects dop...[PMID: 12649371]

4: Wang X et al. Genistein protects dopaminerg...[PMID: 15706233]

5: Liu B et al. Naloxone protects rat dopamin...[PMID: 10773035]

6: Zhou HF et al. Triptolide protects dopaminer...[PMID: 15755670]

7: Jung KK et al. Inhibitory effect of curcumin...[PMID: 16934299]

8: Hou RC et al. Effect of sesame antioxidants...[PMID: 14534426]

9: Wu CF et al. Differential effects of ginse...[PMID: 17276889](ginseng)

10: Moon DO et al. Inhibitory effects of eicosap...[PMID: 17178390](fish oil)

11: Lau FC et al. Inhibitory effects of blueber...[PMID: 17265471]

12: Tikka TM et al. Minocycline provides neuropro...[PMID: 11390507]

13: Gayle DA et al. Lipopolysaccharide (LPS)-indu...[PMID: 11850061]

[jeanb]

My neurologist recommends taking an anti-inflammatory every day - an ibuprophen to be specific because - there may be inflammation in the brain due to pd. She doesn't know but it's a precaution.

[VICTORIALOU]

Originally Posted by jeanb

My neurologist recommends taking an anti-inflammatory every day - an ibuprophen to be specific because - there may be inflammation in the brain due to pd. She doesn't know but it's a precaution.

I just pulled up this thread while looking for any references to Ibuprofen. In addition to other "natural" anti-inflammatories such as fish oil, curcumin, etc
I have been taking LARGE doses of this N-said for at least ten years and I believe it has helped greatly with slowing down the progression of my problems. I am aware of the potential side -effects and also take milk thistle to try to reduce the toxic load on my liver and kidneys.
I usually take 600 mg. upon rising and usually at least three doses of 600 mg daily- sometimes more. It helps keep me limber enough to move much more than I otherwise would.
I thought this was pertinent given all the new interest in brain inflammation.

[Dawn Angel]

I have just started on meloxicam for hip pain, but wonder if it has a neural anti-inflammatory effect as well.

Two weeks ago I began low-dose naltrexone (LDN). Too early to tell if there are any benefits. My neurologist (Jon Stoessl - the top PD researcher in Canada) was quite excited when I told him, and he went into PubMed and found the references by JS Hong. The book, "The Promise of Low Dose Naltrexone Therapy" by Elaine Moore and Samantha Wilkinson is a good introduction to LDN.

I take numerous neuroprotective supplements and botanicals (too many to list) in addition to exercise and regular physical therapy. So far I am over 4 years med-free with no progression of symptoms.

Dawn Angel