[ol'cs]

some questions , when my brain was jogged back into thinking about PD and its etiology by a recent post by Heidi L.
I said to myself "what's the difference between the way MPTP and 6-Hyroxydopamine, insofar as the mechanism by which they induce PD in rats (the contralateral rotation paradigm)"
The mechanism's (as known), have a glaring hole in them. MPTP and 6-hydroxydopamine are "specific" to Nigral area cell death, but other molecules which aren't so specific to just nigral cells, that is compounds like rotenone which can permeate any body cell to the same degree (non-specific) still cause Parkinsonism, albeit more slowly.
This URL
http://www.springerlink.com/content/r43078h664809185/
came up after a short search and pins the underlying PD causing activity on the action of "Complex 1" a large enzyme that works at the beginning of the NADPH redox cycle in mitochondria. Do a search for complex 1 and the cellular cycle that i speak of. This, will jog a lot of questions in your brain too, if you give it some thought.
It's been implicated for a long time that this redox cycle is of primary importance for energy cycling in all cells and is based at the mitochondria in ATP production, and "recharging".
The thing that i'm getting at is why don't ALL cells that are permeated by compounds that are toxic to complex 1, throw such a wrench into the biological machinery in the mitochondria to produce apoptosis (initiated cell death). It seems that we should be compromised EVERYWHERE, in the body, in nerve, blood, bone, etc. cells, since the energy producing mechanisms in all cell mitochondria are the same.
Does anyone have a good explanation for this?. There is lots of stuff out there to look at as far as this is concerned, but to my knowledge, this question hasn't been answered yet? cs

[Heidi L]

Ow! My head!

It looks like rotenone actually targets the microtubules in dopamine neurons. However I'm not very impressed by the description of the researcher that dopamine neurons are preferentially damaged because they have long microtubules. Or is it that dopamine is more oxidative when it can't be released?
I also don't understand the parkin/microtubule interaction. Do those rats have parkin mutations?

These are all variations on the same study:

Two-Fisted Assault On Dopamine Transport System May Be Foundation Of Parkinson's Disease

researcher's home page
http://www.acsu.buffalo.edu/~jianfeng/
As microtubules play obligatory functions in the maintenance of cellular morphology and intracellular transport, their depolymerization by rotenone causes significant damages to the cell, especially for long projection neurons such as dopamine cells on the nigrostriatal pathway. This is because microtubule depolymerization causes vesicle accumulation in the soma, which leads to increased cytosolic dopamine concentration and elevated production of reactive oxygen species from dopamine oxidation. Thus, the microtubule-depolymerizing activity of rotenone significantly contributes to its selective toxicity on dopaminergic neurons. Parkin, through its ability to ubiquitinate and degrade misfolded tubulin, may protect neurons from toxic accumulation of misfolded tubulin, particularly when the cells are exposed to microtubule-depolymerizing agents such as rotenone.

Selective vulnerability of dopaminergic neurons to microtubule depolymerization
J. Biol. Chem, 10.1074/jbc.M503483200

Parkinson’s disease (PD) is characterized by the specific degeneration of dopaminergic (DA) neurons in substantia nigra and has been linked to a variety of environmental and genetic factors. Rotenone, an environmental PD toxin, exhibited much greater toxicity to DA neurons in midbrain neuronal cultures than to non-DA neurons. The effect was significantly decreased by the microtubule-stabilizing drug taxol and mimicked by microtubule-depolymerizing agents such as colchicine or nocodazole. Microtubule depolymerization disrupted vesicular transport along microtubules and caused the accumulation of dopamine vesicles in the soma. This led to increased oxidative stress due to oxidation of cytosolic dopamine leaked from vesicles. Inhibition of dopamine metabolism significantly reduced rotenone toxicity. Thus, our results suggest that microtubule depolymerization induced by PD toxins such as rotenone plays a key role in the selective death of dopaminergic neurons.


Now, I really must go grocery shopping. I'm out of half and half and my coffee intake is in peril.

[ZucchiniFlower]

Cs, other dysfunction in people with PD may account for the selective apoptosis. For example:

Mitochondrial impairment as an early event in the process of apoptosis induced by glutathione depletion in neuronal cells: relevance to Parkinson’s disease

Biochemical Pharmacology
Volume 56, Issue 5, 1 September 1998, Pages 645-655

Mansouria Merad-Boudiaa, Annie Nicolea,

Abstract

In Parkinson’s disease (PD), dopaminergic cell death in the substantia nigra was associated with a profound glutathione (GSH) decrease and a mitochondrial dysfunction. The fall in GSH concentration seemed to appear before the mitochondrial impairment and the cellular death, suggesting that a link may exist between these events.The relationships between GSH depletion, reactive oxygen species (ROS) production, mitochondrial dysfunction and the mode of cell death in neuronal cells remain to be resolved and will provide important insights into the etiology of Parkinson’s disease. An approach to determine the role of GSH in the mitochondrial function and in neurodegeneration was to create a selective depletion of GSH in a neuronal cell line in culture (NS20Y) by inhibiting its biosynthesis with Image-buthionine-(S,R)-sulfoximine (BSO), a specific inhibitor of γ-glutamylcysteine synthetase. This treatment led to a nearly complete GSH depletion after 24 hr and induced cellular death via an apoptotic pathway after 5 days of BSO treatment.

By using the reactive oxygen species-sensitive probe 2′,7′-dichlorofluorescin, we observed that the rapid GSH depletion was accompanied, early in the process, by a strong and transient intracellular increase in reactive oxygen species evidenced after 1 hr with BSO, culminating after 3 hr when the GSH level decreased to 30% of normal. GSH depletion induced a loss of mitochondrial function after 48 hr of BSO treatment. In particular, the activities of complexes I, II and IV of the respiratory chain were decreased by 32, 70 and 65%, respectively as compared to controls. These results showed the crucial role of GSH for maintaining the integrity of mitochondrial function in neuronal cells. Oxidative stress and mitochondrial impairment, preceding DNA fragmentation, could be early events in the apoptotic process induced by GSH depletion. Our data are consistent with the hypothesis that GSH depletion could contribute to neuronal apoptosis in Parkinson’s disease through oxidative stress and mitochondrial dysfunction.

[ZucchiniFlower]

Also, a reminder that we differ from the animals in experiments:

Recent clinical failures in Parkinson's disease with apoptosis inhibitors underline the need for a paradigm shift in drug discovery for neurodegenerative diseases

Understanding the mechanisms of neuronal death in concert with the identification of drugable molecular targets key to this process has held great promise for the development of novel chemical entities (NCEs) to halt neurodegenerative disease progression. Two key targets involved in the apoptotic process identified over the past decade include the mixed lineage kinase (MLK) family and glyceraldehyde phosphate dehydrogenase (GAPDH). Two NCEs, CEP-1347 and TCH346, directed against these respective targets have progressed to the clinic. For each, robust neuroprotective activity was demonstrated in multiple in vitro and in vivo models of neuronal cell death, but neither NCE proved effective Parkinson's disease (PD) patients. These recent clinical failures require a reassessment of both the relevance of apoptosis to neurodegenerative disease etiology and the available animal models used to prioritize NCEs for advancement to the clinic in this area.

ANOTHER ARTICLE:

http://www.sciencedirect.com/science...06a473ba#SECX1

"Cytoplasmic hybrid cells (cybrids) from patients with sporadic PD have revealed that expression of PD mitochondrial genes generates multiple detrimental consequences for cell survival and these correlate with changes in PD brain. The consequences include decreased complex I activity (Dawson and Dawson, 2003, Schapira et al., 1998 and Swerdlow et al., 1996), increased production of ROS (Swerdlow et al., 1996), altered intracellular calcium homeostasis (Sheehan et al., 1997), increased levels of antioxidant enzymes (Cassarino and Bennett, 1999), nuclear translocation and increased levels of the transcription factor NF-κB (Cassarino et al., 2000), increased levels of survival-promoting Bcl-2 and Bcl-XL proteins (Veech et al., 2000), increased numbers of morphologically abnormal mitochondria (Trimmer et al., 2000) as well as spontaneous production of true Lewy body inclusions (Trimmer et al., 2004). These multiple changes demonstrate both the pervasive cellular consequence of expressing PD mitochondrial genes and the dualistic responses (pro-apoptotic and pro-survival) they induce.".....

....."The anti-oxidant N-acetylcysteine (NAC) has been reported to promote cell survival through a number of mechanisms (Cotgreave, 1997) including enhancement of intracellular glutathione levels, anti-oxidant activity (Aruoma et al., 1989), and regulation of transcription (Fujisawa et al., 1996 and Keogh et al., 1998). Although the precise mechanism by which NAC protects neurons from cell death is unknown, it is widely assumed to be due to its anti-oxidant properties and its ability to elevate glutathione.

In the present study, we sought to systematically investigate the relative contributions of ERK, JNK, p38, and NF-κB to cell survival in PD cybrids under basal conditions and after treatment with NAC. We found that under basal replicating conditions, PD cybrids have increased JNK and p38 activity that leads to increased caspase-mediated processing and decreased survival. This increased vulnerability to cell death is eliminated by incubating the cells in NAC. Thus, expression of PD mitochondrial genes in PD cybrids results in the activation of signal transduction pathways leading to apoptotic death, an effect attenuated by pharmacologically reducing intracellular oxidative stress."....

....."The antioxidant NAC decreased JNK activity and increased NF-κB activity downstream of the ERK and PI3-K pathways, thus eliminating caspase-mediated PARP cleavage. Using specific inhibitors, we found that blocking the PI3K pathway significantly decreased viability, whereas inhibition of either JNK or p38 activity significantly enhanced survival. Taken together, our findings support the concept that PD mitochondrial gene expression drives oxidative stress-mediated changes in intracellular signaling that promote caspase-requiring apoptosis."...

....."These results reflect a complex interplay of pro- and anti-apoptotic pathways elicited by the amplification of PD mitochondrial genes in cybrid cells (Fig. 9). It is likely that the dynamic balance among forces promoting cell death and forces promoting cell survival determines the ultimate fate of the cell. This study has outlined a few of what may turn out to be multiple signaling pathways mediating cell survival/death in this cellular model. These fundamental regulatory pathways are influenced by PD mitochondria, apparently due to increased oxidative stress. It seems likely that in the more complex whole brain, additional inputs from external and internal events would also contribute to the balance between survival and cell death. A primary goal of future study will be to identify critical points which tip the balance toward survival and normal function"

[ZucchiniFlower]

CYTOKINES!!

p53 protein, interferon-γ, and NF-κB levels are elevated in the parkinsonian brain

Makio Mogia,

Received 29 June 2006; revised 21 October 2006; accepted 5 December 2006. Available online 29 December 2006.

Abstract

We and other workers found markedly increased levels of proinflammatory cytokines and apoptosis-related proteins in parkinsonian brain. Although the pathogenesis of Parkinson's disease (PD) remains enigmatic, apoptosis might be involved in the degeneration of dopaminergic neurons in PD. To investigate the possible presence of other inflammatory cytokines and/or apoptosis-related protein, the levels of p53 protein, interferon-γ, and NF-κB were measured for the first time in the brain (substantia nigra, caudate nucleus, putamen, cerebellum, and frontal cortex) from control and parkinsonian patients by a highly sensitive sandwich enzyme-linked immunosorbent assay.

The p53 protein level in the caudate nucleus was significantly higher in parkinsonian patients than in controls (P < 0.05), whereas this protein in the substantia nigra, putamen, and cerebral cortex showed no significant difference between parkinsonian and control subjects. The interferon-γ level was significantly higher in the nigrostriatal dopaminergic regions (substantia nigra, caudate nucleus, and putamen) in parkinsonian patients than in the controls (P < 0.05), but was not significantly different in the cerebellum or frontal cortex between the two groups.

In accordance with previous immunohistochemical analysis, the NF-κB level in the nigrostriatal dopaminergic regions was significantly higher in parkinsonian patients than in the controls (P < 0.05). These data suggest that the significant increase in the levels of p53 protein, interferon-γ, and NF-κB reflect apoptosis and the inflammatory state in the parkinsonian brain and that their elevation is involved in the degeneration of the nigrostriatal dopaminergic neurons.

Neuroscience Letters
Volume 414, Issue 1, 27 February 2007, Pages 94-97'

*******************

This article talks about autophagy (eating itself up with enzymes), instead of apoptosis and it's connection to protein kinases:

http://ajp.amjpathol.org/cgi/reprint/170/1/16

[reverett123]

ZF, your mention of cytokines brings my current area of mucking about.

Cytokines are the chemicals associated with the immune system just as hormones are associated with the endocrine system. The former is to infection what the latter is to stress (I know that is a little simplified).

Prenatal bacterial toxin exposure sensitizes us to future exposure. Even normal immune systems monitor the levels of the bacterial toxins to detect early infections. We react sooner than normal. The reaction is, in part, to produce cytokines.

The body does not want too many cytokines so it regulates them by producing natural steroids such as cortisol. Just as a doctor might give you a shot of steroids to bring down inflammation.

So we have a see-saw effect between the two systems and a shifting tide of cytokines and steroid hormones. Which finally brings me to my point.

Both families of chemicals and their breakdown products function as neurotransmitters!

Now, that's as far as I've gotten so far, but it sure seems relevant to me.

[reverett123]

An excellent overview with full text available-

Neurodegeneration from mitochondrial insufficiency: nutrients, stem cells, growth factors, and prospects for brain rebuilding using integrative management.
Kidd PM.

University of California, Berkeley, USA. dockidd@dockidd.com

Degenerative brain disorders (neurodegeneration) can be frustrating for both conventional and alternative practitioners. A more comprehensive, integrative approach is urgently needed. One emerging focus for intervention is brain energetics. Specifically, mitochondrial insufficiency contributes to the etiopathology of many such disorders. Electron leakages inherent to mitochondrial energetics generate reactive oxygen free radical species that may place the ultimate limit on lifespan. Exogenous toxins, such as mercury and other environmental contaminants, exacerbate mitochondrial electron leakage, hastening their demise and that of their host cells. Studies of the brain in Alzheimer's and other dementias, Down syndrome, stroke, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, Friedreich's ataxia, aging, and constitutive disorders demonstrate impairments of the mitochondrial citric acid cycle and oxidative phosphorylation (OXPHOS) enzymes. Imaging or metabolic assays frequently reveal energetic insufficiency and depleted energy reserve in brain tissue in situ. Orthomolecular nutrients involved in mitochondrial metabolism provide clinical benefit. Among these are the essential minerals and the B vitamin group; vitamins E and K; and the antioxidant and energetic cofactors alpha-lipoic acid (ALA), ubiquinone (coenzyme Q10; CoQ10), and nicotinamide adenine dinucleotide, reduced (NADH). Recent advances in the area of stem cells and growth factors encourage optimism regarding brain regeneration. The trophic nutrients acetyl L-carnitine (ALCAR), glycerophosphocholine (GPC), and phosphatidylserine (PS) provide mitochondrial support and conserve growth factor receptors; all three improved cognition in double-blind trials. The omega-3 fatty acid docosahexaenoic acid (DHA) is enzymatically combined with GPC and PS to form membrane phospholipids for nerve cell expansion. Practical recommendations are presented for integrating these safe and well-tolerated orthomolecular nutrients into a comprehensive dietary supplementation program for brain vitality and productive lifespan.

PMID: 16366737 [PubMed - indexed for MEDLINE]

[ZucchiniFlower]

It's all so murky. Things change as PD progresses, and it's often the balance between things that matters in PD.

"We conclude that the cytokines from activated microglia in the SN and putamen may be initially neuroprotective, but may later become neurotoxic during the progress of PD."

http://www.springerlink.com/content/nh185v3276230515/

Rick, I don't get your steroid connection yet. I'll need to study it more.

http://www.e-emm.org/article/article...064-review.pdf

[ZucchiniFlower]

Rick, it seems norepinephrine helps regulate migroglia cells!

"In addition to DA neurons in the SNc postmortem patients with PD showed that norepinephrine (NE) neurons in the locus coeruleus (LC) also degenerate (not, vert, similar70% loss). The loss of NE neuron has been overlooked in PD."

Maybe the loss of NE leads to DEPRESSION and explains why newer antidepressants that affect both NE and serotonin (without side effects of the old drugs) are so effective in PD depression.

http://www.sciencedirect.com/science...53447fb82f1ff3

[lou_lou]

Brain abnormalities found in 1 of 8 healthy people
Wed Oct 31, 2007 5:11pm EDT
By Gene Emery

BOSTON (Reuters) - Thirteen percent of healthy adults were found to have some type of undiagnosed -- but likely harmless -- abnormality in the brain, according to a Dutch study published on Wednesday.

The research, led by Meike Vernooij of the Erasmus MC University Medical Center in Rotterdam, is important because brain scans are becoming more common and more detailed, and doctors need to know whether to be concerned if they stumble onto something unexpected.

Vernooij and colleagues looked at MRI scans of 2,000 volunteers over the age of 45. Magnetic resonance imaging or MRI can give a detailed picture of physical brain structures.

Just over 7 percent showed evidence of a brain clot, but the clots were too small to produce symptoms and seemed to be more common with age.

Nearly 2 percent had a brain aneurysm, which is a bulge in a blood vessel that can burst if it becomes too big, causing a stroke. But 32 of the 35 aneurysms were so small, the researchers did not suggest follow-up medical treatment.

The younger volunteers were just as likely to have them as older ones.

The scans also uncovered 32 tumors. All but one were benign.

Thirteen people had more than one abnormality, Aad van der Lugt, another member of the team, said.

As MRI scans become more sensitive, they "will probably increase the number of small brain abnormalities detected" and doctors will need to know which ones can be safely ignored, the researchers wrote in the New England Journal of Medicine.

"Unfortunately, we know little of the natural course of these asymptomatic findings," Van der Lugt wrote in an e-mail.

"It may well be that the clinical course and relevance of these unexpected asymptomatic findings differ from those of similar symptomatic findings for which persons seek medical treatment," he added.

Tracking such "incidental" abnormalities "will hopefully provide more information on this that will be useful for both researchers and clinicians," he said.


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