Why no trials yet of tnf-a and il-1 antagonists?
 

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?

emailed Todd at MJFF
 

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

.....

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

everything is on hyperdrive
 

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

It can't be coincidental that the substantia nigra contains the most microglia.

Nature Reviews Neuroscience 8, 57-69 (January 2007) | doi:10.1038/nrn2038
Microglia-mediated neurotoxicity: uncovering the molecular mechanisms

Michelle L. Block1, Luigi Zecca2 and Jau-Shyong Hong1

Mounting evidence indicates that microglial activation contributes to neuronal damage in neurodegenerative diseases. Recent studies show that in response to certain environmental toxins and endogenous proteins, microglia can enter an overactivated state and release reactive oxygen species (ROS) that cause neurotoxicity. Pattern recognition receptors expressed on the microglial surface seem to be one of the primary, common pathways by which diverse toxin signals are transduced into ROS production. Overactivated microglia can be detected using imaging techniques and therefore this knowledge offers an opportunity not only for early diagnosis but, importantly, for the development of targeted anti-inflammatory therapies that might slow or halt the progression of neurodegenerative disease.



For many years, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease have been a major focus of neuroscience research, with much effort being devoted to understanding the cellular changes that underlie their pathology. Microglia, the resident innate immune cells in the brain, have been implicated as active contributors to neuron damage in neurodegenerative diseases, in which the overactivation and dysregulation of microglia might result in disastrous and progressive neurotoxic consequences. Although these concepts have been widely reviewed in recent years1, 2, 3, the characteristics defining deleterious microglial activation and the mechanisms by which neurotoxic microglial activation is initiated remain poorly understood. In the current review, we therefore focus on recent reports indicating that pattern recognition receptors (PRRs) are tools used by microglia to identify neurotoxic stimuli and that stimulation of NADPH oxidase activity is the predominant mechanism through which microglia produce neurotoxic reactive oxygen species (ROS). We further explain how the identification of these crucial participants in microglia-mediated neuronal injury could provide the insight necessary for the development of novel markers that specifically define deleterious microglial activation. Furthermore, these mechanisms might be ideal prospects for targeted anti-inflammatory therapy capable of slowing and perhaps preventing neurodegenerative diseases.

Microglia: friend and foe

........In the mature brain, microglia typically exist in a resting state characterized by ramified morphology, and monitor the brain environment7, 8. In response to certain cues such as brain injury or immunological stimuli, however, microglia are readily activated7, 9. Activated microglia undergo a dramatic transformation from their resting ramified state into an amoeboid morphology and present an upregulated catalogue of surface molecules.......


....Activated microglia are involved in regulating brain development by enforcing the programmed elimination of neural cells19, 20, and seem to enhance neuronal survival through the release of trophic and anti-inflammatory factors21, 22, 23. In addition, in the mature brain, microglia facilitate repair through the guided migration of stem cells to the site of inflammation and injury24, and might be involved in neurogenesis......

Under other circumstances, however, microglia become overactivated and can induce significant and highly detrimental neurotoxic effects by the excess production of a large array of cytotoxic factors such as superoxide29, nitric oxide (NO)30, 31 and tumour necrosis factor-alpha (TNFalpha)32, 33. The stimuli that cause microglial overactivation and dysregulation can be diverse, ranging from environmental toxins, such as the pesticide rotenone, to neuronal death or damage. In neurodegenerative disease, activated microglia have been shown to be present in large numbers, a condition termed microgliosis, strongly implicating these cells in disease pathology.

Currently, the conditions defining whether microglial activation is detrimental or beneficial to neuronal survival are poorly understood. However, it is becoming more widely accepted that although microglial activation is necessary and crucial for host defence and neuron survival, the overactivation of microglia results in deleterious and neurotoxic consequences26. It is because of this that understanding the causes and defining the characteristics of deleterious microglial activation in neurodegenerative disease has become a recent focus of research......

re: PD...

Microglial activation in this disease is not limited to the substantia nigra, but is also found in the putamen, hippocampus, transentorhinal cortex, cingulate cortex and temporal cortex51.

The selective loss of DA neurons in the substantia nigra might be due to DA neuron glutathione deficiency52 (resulting in a reduced antioxidant capacity), high content of DA (a redox active molecule) in neurons in the substantia nigra53, elevated iron concentrations54 (redox active elements) and increased numbers of microglia in the substantia nigra6, 55 compared with other regions.

So, DA neurons in the substantia nigra might be particularly vulnerable to inflammatory insult owing to their precarious redox equilibrium and colocalization with a large population of microglia.....

Several in vitro studies reveal that damaged DA neurons release several factors that seem to activate microglia and are implicated in neuronal degeneration in Parkinson's disease......

Neuromelanin is a complex molecule made of melanin, peptides and lipid components that is released in Parkinson's disease by dying DA neurons to activate microglia59. Neuromelanin is insoluble and so remains for an extended time in the extracellular space, is loaded with toxins able to activate microglia, and is localized at high concentrations in the human substantia nigra (2–4 mg g-1 tissue)59. Human neuromelanin added to neuron–glia cultures is phagocytosed and degraded by microglia with the release of inflammatory factors and ROS, which lead to neuronal death60 (L.Z., unpublished observations). So, neuromelanin seems to be a potential candidate for the establishment of the perpetuating cycle of reactive microgliosis in Parkinson's disease.

.....Microglia, inflammation and neurotoxicity.

As discussed above, microglia-mediated neurotoxicity tends to be progressive97, 98, 99, which could contribute to the progressive nature of several neurodegenerative diseases.

This has been most effectively demonstrated in models using lipopolysaccharide (LPS), the polysaccharide component of the cell walls of gram-negative bacteria. Although LPS models cannot not precisely mimic the conditions under which microglia are activated in neurodegenerative disease, these studies demonstrate that LPS is neurotoxic only in the presence of microglia, indicating that microglia can initiate neuronal damage100, 101.

For example, LPS is reported to induce microglial activation in vivo and in vitro and cause the progressive and cumulative loss of DA neurons over time100, 102, 103. Furthermore, embryonic exposure to LPS has an impact on microglial activation and neuron survival into adulthood103, 104. Interestingly, once overactivated, microglia can remain in this state, as evidenced by the chronic neuroinflammation that continues years after brief MPTP exposure in humans50 and primates98.

http://www.nature.com/nrn/journal/v8...l/nrn2038.html

Fortunately, endogenous protective regulatory signals in the brain have been identified that inhibit microglial overactivation, such as neuropeptides121, 122, 123, cannabinoids124, 125, anti-inflammatory cytokines (that is, IL-10 and transforming growth factor-beta (TGFbeta))126, 127, oestrogen128, glucocorticoids129, 130, 131 and even microglial apoptosis132, 133. However, it has been proposed that when the ability to activate these protective mechanisms fails, or when they are overwhelmed by an excessive inflammatory response, microglia initiate neuronal death and drive the progressive nature of neurodegenerative disease26, 121. A full understanding of the mechanisms underlying microglial dysregulation and overactivation is of pressing interest because of the valuable insight it will provide into the aetiology, pathogenesis and treatment of neurodegenerative diseases.

So, microglial activation is present in diverse neurodegenerative diseases and is closely associated with pathology. Previously, the microglial response to neuronal damage was believed to be passive. However, recent reports indicate that microglial activation is capable of both initiating additional neuronal loss and amplifying ongoing neuronal damage, indicating that microglia might be crucial to the aetiology and the progressive nature of neurodegenerative diseases. Current work is therefore beginning to focus on the stimuli necessary to initiate deleterious microglial function, where studies have revealed several triggers of inflammation-mediated neurodegeneration are present in the environment.....

This we can all do! Exercise and enrich our environment!

"Another appealing strategy, on both the biological and economical fronts for the treatment of PD, involves harnessing endogenous mechanisms to complement, if not supplant, gene therapeutic strategies.

Beyond the perhaps more “subjective” benefits of exercise to the quality of life of PD patients ([Baatile et al., 2000], [Crizzle and Newhouse, 2006], Dibble et al., 2006 L.E. Dibble, T.F. Hale, R.L. Marcus, J. Droge, J.P. Gerber and P.C. LaStayo, High-intensity resistance training amplifies muscle hypertrophy and functional gains in persons with Parkinson's disease, Mov. Disord. 21 (2006), pp. 1444–1452.

..exercise may enhance the CNS-intrinsic protective mechanisms that may prove useful as an adjunct to other therapies. Mild stressors, including exercise and dietary restriction, have been shown to be neuroprotective in a number of animal models of CNS disorders, perhaps via effects on increasing neurogenesis and/or neurotrophin levels (reviewed in Mattson et al. (2004)).

More specific to PD, both exercise ([Fisher et al., 2004], [Petzinger et al., 2007] and [Tillerson et al., 2003]) and environmental enrichment ([Faherty et al., 2005], [Steiner et al., 2006] and [Urakawa et al., 2007]) enhance functional recovery in rodent neurotoxicant models of the disease, while exercise has been shown to enhance plasma IL-10 levels in human PD patients (Cadet et al., 2003).

Thus, a more complete understanding of both the intrinsic neurogenic capabilities of the areas affected in PD and the endogenous mechanisms that can modulate these activities is necessary to further therapeutic development.

Regardless, as appears to be the case in many if not all chronic diseases, early lifestyle alterations (exercise, diet, etc.) may be an important first line of defense in either preventing or attenuating PD pathogenic processes, as well as enhancing therapeutic efficacy."

From:

Gazing into the future: Parkinson's disease gene therapeutics to modify natural history 2007

http://www.sciencedirect.com/science...aa6bc60b937357

Environmental enrichment in adulthood eliminates neuronal death in experimental Parkinsonism

Ciaran J. Faherty, Kennie Raviie Shepherd, Anna Herasimtschuk and Richard J. Smeyne


Accepted 27 August 2004.


Abstract

Idiopathic Parkinson's disease (PD) affects 2% of adults over 50 years of age. PD patients demonstrate a progressive loss of dopamine neurons in the substantia nigra pars compacta (SNpc). One model that recapitulates the pathology of PD is the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

Here we show that exposure to an enriched environment (EE) (a combination of exercise, social interactions and learning) or exercise alone during adulthood, totally protects against MPTP-induced Parkinsonism.

Furthermore, changes in mRNA expression would suggest that increases in glia-derived neurotrophic factors, coupled with a decrease of dopamine-related transporters (e.g. dopamine transporter, DAT; vesicular monoamine transporter, VMAT2), contribute to the observed neuroprotection of dopamine neurons in the nigrostriatal system following MPTP exposure. This non-pharmacological approach presents significant implications for the prevention and/or treatment of PD.


http://www.sciencedirect.com/science...94788&ref=full

What we have here is a system out of control
 

The problem is in the control systems of the immune response and the stress response and the complexity is mind numbing. So much so that I am convinced that the only factor with any chance to heal the body is the body itself. How to encourage this is the puzzle. There is some reason to think that the botanicals classified as adaptogens (ashwagandha, ginseng, etc) may offer aid. Change of lifestyle to lower stress and boost nutrition and exercise definitely. Self-hypnosis. Tai chi. Reiki. All need testing.

Some time back I wound up a white rat report on my positive experience with ginseng that had produced some noticeable improvement. Since then I have become aware of another variable that I had sort of forgotten or even dismissed. During the last three months or so of that six month period I had occasionally used a self-hypnosis disc I had made for myself. The suggestion was simple, along the lines of "Your body has the power to heal the damage of Parkinson's. You will use that power now and in the coming weeks to repair that damage." or something similar.

What are the limits of such an approach? Obviously we don't know. But the more I think about it, though, the more I picture my healing systems as a powerful giant that is literal to the point of self-harm and that just might listen to its conscious brother. I've restarted the experiment and will report backin six months. :D