7 replies to this topic

[BioFreak]

So, as we all know, long term high l-dopa intake results in neurotoxicity.

Why is this important?

Dopamine is a major factor in memory, motivation, problem solving, complex thinking etc. Meaning to increase dopamine, within limits, would improve these factors. Too much of something is never a good thing and this holds true for dopamine as well. Side effects from too much dopamine include hypersexuality, psychosis, ... you get the picture. So what we want to do is raise dopamine as much as possible without getting negative side effects in short or middle term.

However, even modest increases in dopamine could mean more oxidative stress that long term could lead to parkinson or other mental illnesses. So it would be extremely important to lower toxicity by dopamine, even when only increasing it modestly.

The question now is, how does this happen in detail? Only if we know enough about dopamine toxicity we can find appropriate countermeasures, and increase dopamine related mental effects without long term side effects.

I wanna discuss this with you guys, so we can hopefully come to a broader understanding of the subject.

I think there are three main questions:
HOW does dopamine lead to neuronal death?
WHERE does it have a toxic effect - intracellular, or extracellular as well?
WHAT natural defenses does the body have to cope with dopamine?

So... I'll start:

Evidence for Dopamine Toxicity in Neurodegeneration

Linan Chen, Yunmin Ding, Barbara Cagniard, Amber D. Van Laar, Amanda Mortimer, Wanhao Chi, Teresa G. Hastings, Un Jung Kang, and Xiaoxi Zhuang

The symptoms of Parkinson's disease are caused by loss of dopaminergic neurons in the substantia nigra; therefore, it seems somewhat counterintuitive that dopamine may be a vulnerability factor in the disease. But Chen et al. now provide strong evidence for this hypothesis. Dopamine metabolites are highly reactive species that cause oxidative damage, leading ultimately to degeneration. Dopaminergic neurons sequester dopamine into vesicles, thus protecting these cells from damage. To examine the potential toxic effects of dopamine, Chen et al. engineered transgenic mice to conditionally express the dopamine transporter (DAT) in striatal neurons: targets of dopaminergic neurons that lack the ability to sequester dopamine. When DAT was turned on, the mice exhibited motor dysfunction and neurodegeneration within weeks. These effects depended on the presence of dopamine: if the dopaminergic inputs to the striatum were unilaterally severed, motor function on the contralateral side was spared. In contrast, L-DOPA accelerated neurodegeneration.

So what does this mean... Not used dopamine gets stored in neuron vesicles. As long as dopamine is there, it will have no effect, but no toxicity either.

They hypothesize that not dopamine, but dopamine metabolites cause a lot of oxidative stress. Now dopamine that is outside the cell is also subject to processes that metabolize dopamine(probably comt, mao?), thus generating those metabolites. DOPAL(by mao-b) is one of those.

Interestingly, parkinson is also a risk factor for anyone using amphetamines (i.e. ritalin). They make the cell release dopamine from its vesticle(http://www.jneurosci...5/4102.full.pdf). So that would fit into the picture. Once higher then normal levels are active, they can be metabolized by mao-b and comt.

Dopamine Induced Neurodegeneration in a PINK1 Model of Parkinson's Disease

We investigated the mechanism of dopamine induced cell death in transgenic PINK1 knockout mouse neurons. We show that dopamine results in mitochondrial depolarisation caused by mitochondrial permeability transition pore (mPTP) opening. Dopamine-induced mPTP opening is dependent on a complex of reactive oxygen species production and calcium signalling. Dopamine-induced mPTP opening, and dopamine-induced cell death, could be prevented by inhibition of reactive oxygen species production, by provision of respiratory chain substrates, and by alteration in calcium signalling.
actually the whole study can be found at http://www.plosone.o...al.pone.0037564

Very interesting study. I think I will read it thoroughly and then report back.

Coincidentally I already would at least know about 2 substances who can go the 2 paths(calcium signalling and ROS reduction): NAC and lasea (lavandula extract, inhibits calcium channels in the brain). Anyone knows more?

Although in the case of calcium signaling I wonder if there would be undesirable side effects from blocking calcium channels in the brain. It should have an anxiety lowering effect, though.

Edited by BioFreak, 16 May 2013 - 02:04 PM.

[gail2]

Thanks for this post BioFreak. This is such an important topic and I look forward to hearing more about your research.

[gail2]

BioFreak - any more thoughts on this subject? Any other studies you know of? Any studies specifically looking at toxicity from l-tyrosine?

[brainslugged]

Hi, there are a lot of very good mega-threads on bluelight about this.

In a very basic sense, [meth]amphetamine toxicity can be reduced or possibly eliminated by combination with one or more of

MAOIs, specifically MAO-B inhibitors (Selegiline)
NMDA-antagonists (such as Memantine)
DRIs (ritalin)
Some SSRIs (Prozac and some others)
Reduction of body temperature (such as by lowering ambient temperature or use of benzos)

www.acnp.org/g4/gn401000166/ch162.htm (STIMULANT TOXICITY section)

What is most interesting is that selegiline and memantine both potentate amphetamine and/or reduce tolerance. Selegiline may even reduce the cardio-vascular effects of amphetamine. These two would probably be the best choice in combination with keeping cool. However, you should NEVER take a MAOI with amphetamine without close doctor supervision. It is known for triggering hypomania and, presumably, psychosis. Memantine seems to be a fairly safe and effective combination, though. An amphetamine user with both of these substances would most likely be taking a very, very small dose of amphetamine, maybe in the range of micrograms. Too high doses could result in psychosis or even severe cardio-vascular effects (selegiline's modifications to them are not well understood) and death.

DRIs and SSRIs will likely reduce effects of amphetamine. Since they act through competing mechanisms, the dose needed for full harm-reduction would likely be enough to mostly cancel most of the effects of amphetamine. This is because amphetamine works (primarily) by reversing the actions of DAT(and I think SERT too), and thus causing them to put dopamine into the synapse. DRIs and SSRIs would negate these effects by deactivating DAT/SERT. Thus, although effective at reducing the toxicity, it would likely reduce the effects at effective levels.

Memantine would really be the best choice. It is safe, well tolerated, may be valuable to ADHD treatment itself, and prevents sensitization to amphetamine[1][2] (which is instrumental in dopamine psychosis) while also helping prevent tolerance(anecdotal, check Medieval's posts and here as well as MindAndMuscle and socialanxietysupport forum) to prosocial effects and decrease Ca+ ion influx (which is a bad thing in general).

[BioFreak]

I completely forgot about this thread, after having a really stressful time in real life. Anyways... Now seems to be as good as any to revive it.

Brainslugged, I think the only way an ssri could protect the brain from dopamine related neurotoxicity would be through lowering dopamine by increasing serotonin. While this should work to decrease neurotoxicity, any dopaminergic effects will also be lost. So this would be a bad idea, imho.

High dose magnesium could be a (natural) start for NMDA antagonism, magnesium deficiency should be avoided in any case.

Quercetin could be neuroprotective through (weak) mao inhibition.
http://www.bluelight...ic-side-effects

Although they say it has only 1/30 of the strength of selegiline, dosage for selegiline is normally 5mg, and quercetin comes often in dosages of 500mg, which would make 500mg quercetin as strong as 17mg selegiline, if I calculated it right? (500mg/30). That is, if you can make up for weaker inhibition by higher dosage.

in addition it could be neuroprotective through its antioxidant effects, and through mitochondrial biogenesis:
http://www.ncbi.nlm....pubmed/19211721

It also normalizes Corticotropin-releasing hormone:
http://www.wellnessr...and_depression/
And could therefore benefit those who need more dopamine, but get anxiety on substances that increase dopamine, but catecholamines too.

On a personal note, I am right now combining 500mg quercetin with very low dose mucuna pruriens seed powder (340mg which comes down to maybe 17mg l-dopa) and dl-phenylalanine and I am having very positive effects. When I used mucuna alone, I would use 5x the dose 3 times a day for a similar effect, and I am even thinking about further reducing my now low dose mucuna because I feel like it might be too much(which is quite an accomplishment for my normally catecholamine deficient brain).

Dopamine- or L-DOPA-induced neurotoxicity: the role of dopamine quinone formation and tyrosinase in a model of Parkinson's disease.
http://www.ncbi.nlm....pubmed/12835121

Dopamine (DA)- or L-dihydroxyphenylalanine-(L-DOPA-) induced neurotoxicity is thought to be involved not only in adverse reactions induced by long-term L-DOPA therapy but also in the pathogenesis of Parkinson's disease. Numerous in vitro and in vivo studies concerning DA- or L-DOPA-induced neurotoxicity have been reported in recent decades. The reactive oxygen or nitrogen species generated in the enzymatical oxidation or auto-oxidation of an excess amount of DA induce neuronal damage and/or apoptotic or non-apoptotic cell death; the DA-induced damage is prevented by various intrinsic and extrinsic antioxidants. DA and its metabolites containing two hydroxyl residues exert cytotoxicity in dopaminergic neuronal cells mainly due to the generation of highly reactive DA and DOPA quinones which are dopaminergic neuron-specific cytotoxic molecules. DA and DOPA quinones may irreversibly alter protein function through the formation of 5-cysteinyl-catechols on the proteins. For example, the formation of DA quinone-alpha-synuclein consequently increases cytotoxic protofibrils and the covalent modification of tyrosine hydroxylase by DA quinones. The melanin-synthetic enzyme tyrosinase in the brain may rapidly oxidize excess amounts of cytosolic DA and L-DOPA, thereby preventing slowly progressive cell damage by auto-oxidation of DA, thus maintainng DA levels. Since tyrosinase also possesses catecholamine-synthesizing activity in the absence of tyrosine hydroxylase (TH), the double-edged synthesizing and oxidizing functions of tyrosinase in the dopaminergic system suggest its potential for application in the synthesis of DA, instead of TH in the degeneration of dopaminergic neurons, and in the normalization of abnormal DA turnover in the long-term L-DOPA-treated Parkinson's disease patients.

So they say that dopamine itself can be neurotoxic when it gets oxidized, through reactive oxygen or nitrogen species. I suppose this is primarily the case when dopamine is within the cell but not stored in the vesticle? This would happen when there is more dopamine then can be stored in the vesticle, and/or there are not enough enzymes for transportation of dopamine into the vesticle.

However, this is not necessarily a thing to panic about - as long as dopamine is within physiological levels (which is not the case for parkinson patients on high dose l-dopa, I assume), it is a natural process with natural defenses. The question is:
Can we increase the brains defense from reactive oxygen and nitrogen species with glutathione through NAC? If so, we would not have to worry about oxidative stress from dopamine itself. Also, dosage makes the poison, it would always be the goal to use the lowest effective dose of l-dopa or similar possible.

The second highlighted part is interesting also: tyrosinase can both oxidize DA and L-DOPA to prevent neurotoxicity, but also convert tyrosine into l-dopa when there is not enough tyrosine hydroxylase(!).
Now I am speculating here, but could this not mean that if one supplements with tyrosine, and there is not enough tyrosine hydroxylase to convert it into l-dopa, tyrosinase would jump in and do it instead? If this is the case, then we would use up tyrosinase, and by that, increase autooxidation of DA and L-DOPA (if there is excess in the cell). And as we know, tyrosine->l-dopa conversion is limited, so we could easily enter territory where we deplete both enzymes. Hmmm...

On the other side, if we could increase tyrosine hydroxylase, we could spare tyrosinase. What comes to mind? vitamin d. Someone said that dl-phenylalanine would increase tyrosine hydroxylase, but I can't find references doing a quick search.

[BioFreak]

DOPAL and DOPEGAL are neurotoxic metabolites from catecholamines dopamine and noradrenaline, adrenaline respectively.
They both seem to be neurotoxic through free radical formation primarily:

The monoamine oxidase (MAO) metabolites of norepinephrine (NE) or epinephrine (EPI) and of dopamine (DA) are 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) and 3,4-dihydroxyphenylacetaldehyde (DOPAL), respectively. The toxicity of these catecholamine (CA) MAO metabolites was predicted over 50 years ago. However, until our recent chemical synthesis of these CA aldehyde metabolites, the hypothesis about their toxicity could not be tested. The present paper reviews recent knowledge gained about these compounds. Topics to be reviewed include: chemical synthesis and properties of DOPEGAL and DOPAL; in vitro and in vivo toxicity of CA aldehydes; subcellular mechanisms of toxicity; free radical formation by DOPEGAL versus DOPAL; mechanisms of accumulation of CA aldehydes in Alzheimer's disease (AD) and Parkinson's disease (PD) and potential therapeutic targets in Alzheimer's disease and Parkinson's disease.

http://www.ncbi.nlm.nih.gov/pubmed/14697885

So if we increase catecholamines in general, we also have to worry about neurotoxic metabolites of adrenaline and noradrenaline.

If oxidative stress is also the primary cause of dopamine's metabolites, antioxidants would be the best way to protect the brain.

So we would have 3 primary ways of protection:

• use the lowest dose of dopamine increasing drugs possible that has the right therapeutic effect
• inhibit enzymes that produce the most toxic metabolites of dopamine
• increase antioxidant capacity where it matters, in the brain within the cells.

Edited by BioFreak, 03 January 2014 - 01:57 PM.

[BioFreak]

Dopamine metabolites can damage mitochondria, but this effect is being prevented by Glutathione:
http://www.ncbi.nlm....pubmed/10461904
Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria: implications for Parkinson's disease.

Both reactive dopamine metabolites and mitochondrial dysfunction have been implicated in the neurodegeneration of Parkinson's disease. Dopamine metabolites, dopamine quinone and reactive oxygen species, can directly alter protein function by oxidative modifications, and several mitochondrial proteins may be targets of this oxidative damage. In this study, we examined, using isolated brain mitochondria, whether dopamine oxidation products alter mitochondrial function. We found that exposure to dopamine quinone caused a large increase in mitochondrial resting state 4 respiration. This effect was prevented by GSH but not superoxide dismutase and catalase. In contrast, exposure to dopamine and monoamine oxidase-generated hydrogen peroxide resulted in a decrease in active state 3 respiration. This inhibition was prevented by both pargyline and catalase. We also examined the effects of dopamine oxidation products on the opening of the mitochondrial permeability transition pore, which has been implicated in neuronal cell death. Dopamine oxidation to dopamine quinone caused a significant increase in swelling of brain and liver mitochondria. This was inhibited by both the pore inhibitor cyclosporin A and GSH, suggesting that swelling was due to pore opening and related to dopamine quinone formation. In contrast, dopamine and endogenous monoamine oxidase had no effect on mitochondrial swelling. These findings suggest that mitochondrial dysfunction induced by products of dopamine oxidation may be involved in neurodegenerative conditions such as Parkinson's disease and methamphetamine-induced neurotoxicity.

So they state that the primary damage is also done by oxidative stress. Whats interesting about this study is that only glutathione does prevent this from happening, which is good news for those supplementing with NAC.

This may also lead to the question if C60 may help, since it's protective effects on the mitochondria.

About NAC and l-dopa:
http://www.ncbi.nlm....pubmed/22546753
N-acetyl-cysteine in the treatment of Parkinson's disease. What are we waiting for?

Parkinson's disease is an age-related neurodegenerative disorder that is ameliorated with levodopa. However, long-term use of this drug is limited by motor complications, postural instability and dementia resulting in the progression of the disease. Insights into the organization of the basal ganglia and knowledge of the mechanisms responsible for cell death in Parkinson's disease has permitted the development of putative neuro-protective drugs that might slow the disease progression. Although no drug has yet been established to alter the rate of disease progression, recent publications have confirmed previous results and hypotheses about the probable role of thiolic antioxidants on Parkinson's disease, demonstrating a significant reduction of dopaminergic neuronal degeneration in α-synuclein over expressing mice treated with oral N-acetyl-cysteine. This thiolic antioxidant is a modified form of the natural amino acid cysteine, which is the precursor of the most potent intracellular antioxidant glutathione. Besides, increasing evidence has been accumulated in the last 10years about the beneficial effects of this thiolic antioxidant in experimental and pathologic states of the nervous system, including against neurotoxic substances. The present paper put forward the existing rationale evidence for the use of N-acetyl-cysteine alone or in combination with levodopa in the clinical management of this neurodegenerative disorder.

Edited by BioFreak, 03 January 2014 - 02:52 PM.

[dunbar]

This is a very interesting, but also scary topic.

I wonder is ritalin also neurotoxic? I think I read stuff that it's neuroprotective.

I wonder which antioxidants do we even have which also work in the brain? I guess it wouldn't be bad to take a brain antioxidant.

N-acetyl-cysteine in the treatment of Parkinson's disease. What are we waiting for?

Maybe NAC isn't profitable enough and so big pharma has no interest in it?

Edited by dunbar, 03 January 2014 - 08:25 PM.