Recently, over the past few years, there have been numerous papers written in reputable neuro journals by reputable MDS's linking the onset of PD with cytokine inflammation, specifically tumor necrosis factor and interleukin-1.

Can someone more familiar than I with the various groups that lobby for more NIH funding or someone who knows the workings of the NPF or FOX kindly explain why, to my knowledge, there has not been ONE trial begun which explores this hypothesis?

There are tnf-a antagonists that already exist. There are also il-1 antagonists that already exist. The drugs are there. There are minimally invasive ways to get these drugs into the brain.

Why is this not being aggressively explored? Anyone know?

HI caldeerster,

Todd Scherer reply from MJFF:

I can’t add much on Il-1 but related to TNF-alpha, the biggest issue is related to potential peripheral toxicity of compounds and this has been a roadblock for development. There is some effort to develop drugs targeting these pathways, however. We have funded a group led by Malu Tansey to develop TNF alpha drugs that specifically target the brain with minimal side effects. There are also a few biotechs working in the area as well.

I do think it is still controversial as to the exact role of inflammation in PD (whether inflammation is truly involved in PD onset, for example, or is secondary part of the neurodegenerative process).

Todd

Paula

When most authors still discuss and wonder whether the pathological process that underlies Parkinson’s disease starts either in neurons or in microglia so to target future therapies, one may suggest that initial alterations start in both, or, better, because of intimate relations between neurons and microglia, require impairements of both cellular groups and regulation to initiate and external factors to amplify.

Compared to inflammation in peripheral tissues, inflammation in brain appears to follow distinct pathways and time-courses, which likely has to do with a relatively strong immunosuppression in that organ.
The central nervous system appears to be a largely immunosuppressive environment, which previously led to the hypothesis that it is an "immunologically privileged" organ. Nevertheless, microglia can be activated by various internal and external stimuli, resulting in expression of cytokines and other mediators of inflammation. The molecular mechanisms converting those signals into specific microglial responses are a field of intensive research efforts.

It turns out that microglia are extremely sensitive towards any kind of stimulus. They are probably the first cells in the brain "sensing" changes in the periphery, and the summarized data suggest that microglia may even react in a specific manner in response to a specific stimulus.

Here starts the hypothesis of several previous “attacks” on brain neurons and microglia that lead to a special status of these cells, supporting reactions shifted during decades till reaching the point of illness trigger, with no spontaneous possibility to “go back to a healthy state and typical PD cells alterations characterized the formation of proteinaceous inclusions, Lewy bodies (LBs) and Lewy neurites (LNs)), lying in both neurons and microglia, and to a lower extend in astrocytes and oligodendrocytes.

The slowness of process may explain the appearent synucleopathy in PD which may "only" be sign of intra-cellular long term dysregulation, as well as taupathies when AD is concerned.

Different events probably exist or even co-exist with repeated hits on neurons and on microglia leading to mild chronicneuronal dysfunctions and microglia inflammatory reaction, until a point where illness really starts and autoentertains, and neuronal apoptosis begins under its own internal dysfunctions and microglia factors release of inflammatory cytokines as TNF-α , MHC II proteins, iNOS , COX-2, and components of complement.......


Reboot PD thinking, think it the dynamical way....

Anne

.....

Question I have, is...does it ever stop and is it continually changing? Are we spinning our wheels? How many years does it take to replace its dynamics?

Treat some symptoms with what there is or not? We are being told [or shown] that there is nothing yet. So do we accept that and try to cope?
I hope not.....but it takes a village of patients.

Thanks for a great explanation!
paula

Sorry, I must add this:

the biggest problem is not to stop immune reactions but it would be nonsense, there is too much danger to do so, the problem is to modulate the response.......keep the good, erase the deliterious one....subtile alchemy...
but again isn't the cause of microglia activation worse than the consequences and what will happen if causes remain........or may be recurrent...

Anne

Gee...I see the logic and alpha synuclein has to be a factor; we have some serious chemicals out of whack. We're going to have to stumble onto off label hopes...I need to just concentrate on how fascinating it all is. I know, it's not about me....lol.....

But actually it is, I"m going through something heavily metabolic...fascinating so keep the information flowing. But all the more urgent.

paula

We should not discount the nutritional approach. It may be a safer way to go, with fewer dire unintended consequences. Tnfa antagonists have caused problems in patients. Maybe there is something we can eat that will prevent microglia overactivation in the first place. Overactivation leads to the microglia dying which is thought to be a self regulatory mechanism to protect other neurons. But we don't want microglia dying because our brains have a limited number of them.

"Microglia are the resident immune cells of the brain and play a role in immune surveillance under normal condition. However, microglia become readily activated in response to infections and neuronal injuries under pathological condition [5].

Activated microglia produce a wide array of factors, including cytokines such as TNF-greek small letter alpha and IL-β, reactive oxygen species, reactive nitrative species such as NO, and eicosanoids.

These factors are believed to contribute to microglia-mediated neurodegeneration [3] G.H. Jeohn, L.Y. Kong, B. Wilson, P. Hudson and J.S. Hong, Synergistic neurotoxic effects of combined treatments with cytokines in murine primary mixed neuron/glia cultures, J. Neuroimmunol. 85 (1998), pp. 1–10.

Recent studies indicated that minocycline, a tetracycline derivative, exhibits a neuroprotective effect by inhibiting microglia activation in several models of neurodegeneration [13] and [14].

Similarly, Liu et al. have shown that naloxone protects dopaminergic neurons against inflammatory damage through inhibition of microglia activation [7].

Wang et al. have demonstrated that silymarin, a polyphenol flavonoid derived from milk thistle, protects dopaminergic neurons against LPS-induced neurotoxicity by inhibiting microglia activation in mesencephalic neuron-glia cultures [17].

Moreover, Liu et al. have reported that dextromethorphan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglia activation [10].
These observations suggest that the agents which inhibit microglia activation will provide neuroprotective effects.

In the present study, we have shown that biochanin A effectively inhibited microglia activation and release of TNF-greek small letter alpha, NO, and superoxide in mesencephalic neuron-glia cultures and microglia-enriched cultures exposed to LPS treatment, indicating that the mechanism of action underlying the neuroprotective role of biochanin A, at least partially, is attributed to the inhibition of microglia activation."



From:

Biochanin A protects dopaminergic neurons against lipopolysaccharide-induced damage through inhibition of microglia activation and proinflammatory factors generation

Han-Qing Chena, b, Zheng-Yu Jina, Corresponding Author Contact Information, E-mail The Corresponding Author and Guan-Hong Li

Neuroscience Letters
Volume 417, Issue 2, 1 May 2007

Abstract

Activation of microglia and consequent release of proinflammatory factors, are believed to contribute to neurodegeneration in Parkinson's disease (PD). Hence, identification of compounds that prevent microglial activation is highly desirable in the search for therapeutic agents for inflammation-mediated neurodegenerative diseases.

In this study, we reported that biochanin A, one of the predominant isoflavones in Trifolium pratense, attenuated lipopolysaccharide (LPS)-induced decrease in dopamine uptake and the number of dopaminergic neurons in a dose-dependent manner in rat mesencephalic neuron-glia cultures.

Moreover, biochanin A also significantly inhibited LPS-induced activation of microglia and production of tumor necrosis factor-greek small letter alpha, nitric oxide and superoxide in mesencephalic neuron-glia cultures and microglia-enriched cultures.

This study suggested for the first time that biochanin A protected dopaminergic neurons against LPS-induced damage through inhibition of microglia activation and proinflammatory factors generation.


http://www.sciencedirect.com/science...9cf8010c9e3214

Thanks for checking, Paula.

I think Tansey actually wrote a study postulating that tnf-a inflammation was a trigger. It's good to hear that MJFF has funded her search for an effective antagonist.