User:Miniroovigilante/crakalakin

Dopamine synthesis, metabolism, degredation.......Amphetamine Neurotoxicity, Parkinson's Disease,

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KEY -MAO=Monoamine Oxidase, VMAT2=Vesicular Monamine Transporter 2, NO=Nitric Oxide, TyHy=Tyrosine Hydroxylase, ROS=Reactive Oxygen Spieces, RNS=Reactive Nitrogen Species, SOD=Superoxid Dismutase, SOC=Superoxide Catalase, MDA=Malondialdehyde, 4-NE=4-hydroxynonenal

[DISCLAIMER] ..... references are not included, because I forgot them.

Amphetamine kills your brain. It destroys brain cells…..This is how it does it. Our brains are predisposed to destruction….....we are preset to expire after a certain amount of time. For me, that time = 27 years. For most of you, I hope that time, is much longer than 27 years. The reason we are all living, having fun, with a desire to fully enjoy our existences to the upmost extent….is due, to a chemical, called dopamine. Ok disregard the last paragraph, I temporarily forgot who my audience was…..LoL. If you are reading this, you most likely already know what Dopamine is. You are reading this article, I assume, to discover the mechanism by which Amphetamine causes neurotoxicity….Im gonna get to that, eventually. The problem is, my brain is really really messed up, I think, especially my prefrontal cortex (is totally screwed) due to intake of Amphetamine, such, combined with my OCD, results in a rather undecipherable mess…..I will attempt my best, however, to get to the point. Amphetamine induces the release of Dopamine into the synaptic cleft. That is pretty much, the reason it is so reinforcing…..more Dopamine in the synaptic cleft is good, at least, as long as it activates DA receptors. Amphetamine Inhibits VMAT2, subsequently dramatically increasing cytoplasmic DA levels. This is a problem…….why? Because, DA doesn’t do any good, if its just in the cytoplasm, floating around, but not activating any receptors. Whats worse, is MAO is free to metabolize DA into DOPAL, cuz DA isn’t protected by vesicles. Wow, Im almost unable to write this paper. But I will continue to try……..maybe I should stop listening to music and writing at the same time…..or get some different music. Currently, I am listening to Marky Mark and the Funky Bunch……I am SO totally feeling the good vibrations!!! Its totally coursing through my whole body right now…..sort of. It was better about 3 hours ago, but anyways, we shall now discuss more issues related to the ability of Dopamine to directly destroy the brain.

Dopamine in the cytoplasm of presynaptic nerve terminals, is metabolized by MAO into DOPAL. DOPAL is neurotoxic, by what means, I am unsure, all I know, is that, it is neurotoxic to DA neurons/cells. DOPAL is metabolized to DOPAC by Aldehydye Dehydrogenase, DOPAC being much safer than DOPAL, presumably. Dopamine can also be metabolized by COMT, moreso in the prefrontal cortex (while MAO mediating metabolism in other areas of the brain). Both COMT and MAO metabolize DA ultimately into the end product HVA (Homovanillic Acid). Dopamine can also be metabolized into Norepinephrine by Dopamine-beta-hydroxylase.

Of principal importance, is the ability of Dopamine to metabolize into a different substance, without the presence of any enzyme. Dopamine autoxidizes into Aminochrome. What is autoxidation? Autoxidation is when a compound loses an electron, and turns into a different compound, by itself…..all that is necessary for this reaction, is Oxygen. Hence, the problem…..oxygen is obviously going to be prevalent in significant amounts, in the brain. Dopamine is oxidized by Oxygen……Thus dopamine loses elctron(s), and Oxygen gains electron(s). Oxygen, upon gaining such, turns into SuperOxide. SuperOxide is an extremely dangerous, oxidizing compound, capable of reacting with numerous targets, and oxidizing them. Aminochrome is then reduced, by two different mechanisms. Aminochrome undergoes 1-electron reduction (gains an electron) by NADPH (which donates the electron to Aminchrome). NADPH, upon losing an electron, is known as NADP+. Aminochrome, when 1-electron reduced, results in Aminochrome o-semiquinone radical…….which then autoxidizes (using Oxygen) back into Aminochrome. This REDOX cycle will continue until either Oxygen, NADPH, or NADP+ is depleted. Thus, enormous quantities of Superoxide (and possibly Hydrogen Peroxide) are produced from this REDOX reaction. Superoxide then reacts with Nitric Oxide (NO) to form Peroxynitrite. Peroxynitrite shall be discussed later**. Aminochrome also undergoes 2-electron reduction, by DT-Diaphorase. This results in Aminochrome-o-hydroquinone…..which is MUCH less toxic than the semiquinone radical. Thus, DT-Diaphorase plays a significant neuroprotective role, by indirectly preventing the excess synthesis of Superoxide and the consequent production of Peroxynitrite.

The reaction of Superoxide and Nitric Oxide yields peroxynitrite. Peroxynitrite is the principal toxin involved in the pathogenesis of Amph-induced DA neurotoxicity. Peroxynitrite causes lipid peroxidation, cellular membrane damage, mitochondrial dysfunction, and damages many other cellular mechanisms. Of particular interest is the ability of Peroxynitrite to cause lipid peroxidation, and inactivate Tyrosine hydroxylase. Lipid Peroxidation is the process of Lipids (such as cell membranes) becoming oxidized, setting off a chain reaction in which byproducts of lipid peroxidation cause the peroxidation of other lipids, and so on. Lipid peroxidation, in addition to destroying membranes and many other lipid-derived structures, also inactivates Tyrosine Hydroxylase. TyHy is responsible for converting L-tyrosine into L-DOPA. Thus, inactivation of TyHy results in the inability of DA cells to produce DA from Tyrosine, rendering the DA neuron quite useless, and unable to perform its intended function.

Lipid Peroxidation results in neurotoxic byproducts, including 4-NE and MDA. Both of these compounds inhibit Aldehyde Dehydrogenase from converting DOPAL into DOPAC, thus causing the excess buildup of DOPAL levels, and consequent DA neurotoxicity (DOPAL is extremely neurotoxic). Thus, Lipid Peroxidation through multiple pathways, leads to overall toxicity. The brain possesses many mechanisms by which to reduce neurotoxicity caused by the endogenous toxins Hydrogen Peroxide, Superoxide, Peroxynitrite, DOPAL, Hydroxyl Radical, ect. One of the most important of these protective mechanisms, are the enzymes Superoxide Dismutase and Superoxide Catalase. These enzymes both inactive Superoxide, preventing its reaction with NO and oxidation of various materials. Distinct Isoforms of SOD and SOC exist, notably the copper/zinc isoform, and the manganese isoform. The Manganese appears to be present in the mitochondria of cells, specifically, however. Nevertheless, overexpression of copper/zinc SOD/SOC inhibits strongly (but not completely) oxidative damage caused by ROS, specifically Superoxide.

DA activates Ionotropic Glutamate receptors (such as NMDA), which induces the activity of NOS (Nitric Oxide Synthase). NOS produces Nitric Oxide (NO). NO plays an extremely important role in the effects of Amphetamine. Increased Glutamate raises NO levels. NO inhibits the DAT, and enhances the release of DA from DA neurons. NOS inhibitors inhibit the expression of Hyperlocomotion induced by Amph, NOS inhibitors also inhibit Amph-induced Hyperthermia, as well as preventing the development of Behavioral sensitization to repeated Amph administration. At high concentrations, NO may inhibit NMDA receptor function, however, this effect may not be significant, as Glutamate and NMDA function stimulate NO production/activity, and Amphetamine induces a significant increase in Glutamate release and NMDA activity. A key mechanism of NO in facilitating DA/Glutamate-induced toxicity, is the ability of NO and other ROS/RNS to inhibit specific processes (known as “complexes”) of the ETC (Electron Transport Chain). The ETC of mitochondria is responsible for the production of ATP, and subsequently, providing energy to the rest of the cell. Under normal conditions, the ETC is only partially efficient, and releases/leaks harmful byproducts, notably Superoxide. When specific complexes of the ETC are inhibited by ROS/RNS/NO, the ETC becomes much less effective, and overall output of ATP is reduced, while Superoxide leakage and production is increased. This results in a chain reaction, of insufficient ATP to fuel the cell, insufficient antioxidant/protective mechanisms against oxidative stress, and significantly enhanced Oxidative stress to the cell. Oxidative stress eventually results in necrosis and/or aptosis of the cell, rendering the cell and neuron underfunctional, if not un-functional (or completely dead). Now….that I have bombarded you with an excess of neurotoxic information, I will proceed to discuss the real question: How do we prevent Amph-induced DA neurotoxicity? The basic concept, is to reduce Oxidative Stress. Antioxidants reduce oxidative stress to cells/neurons, mainly by being oxidized themselves, and thus preventing Oxidants from oxidizing and damaging cellular components. Some antioxidants, unfortunately, can function as pro-oxidants in some conditions, due to their ability to enter REDOX reactions, where they can be oxidized, but also facilitate oxidative processes and damage. Thus, the correct Antioxidants should be taken to ensure more damage is not done. Other neuroprotective mechanisms include: Inhibition of NOS, Antixoidants/Free radical scavengers (not all of them help though), Peroxynitrite scavengers/decomposition catalysts, VMAT2 inducers/enhancers, DAT blockade, NAT blockade, mAChR-1 antagonism, Depletion of DA, increasing/inducing the vesicular uptake of DA (inducing/enhancing VMAT2), Inhibition of MAO-A/B activities, Inhibition of COMT, Blockade/antagonism of Glutamate receptors/glutamate release/mGluR1/NMDA activity, enhancement of Glutamate Reuptake, inhibition/reduction of NOS (nitric oxide, nitric oxide synthase), antioxidants, increasing cellular ATP stores/synthesis/availability, prevention/reduction of Hyperthermia, blockade of excess calcium Ca2+ levels, increasing expression/activity of Superoxide Dismutase and Catalase, increasing expression/activity of DT-Diaphorase.

The most likely mechanisms to prevent DA neurotoxicity include: Peroxynitrite Scavengers, Peroxynitrite Decompostion Catalysts (i have no idea what these are), Antioxidants (such as Alpha Lipoic Acid, possibly Acetyl L-Carnitine, Selenium……[Vitamin E and Vitamin C may be effective but can also be toxic in some cases] ), NMDA/MgluR1 receptor Blockade, Inhibition of Glutamate release/activity, Enhancement of Glutamate Reuptake, Increasing cellular/mitochondrial ATP production/stores/availability (L-Carnitine),  DAT inhibition/blockade, possibly reducing Ca2+ activity/blocking Ca2+ channels, inducing/enhancing VMAT2, Increasing expression/activity of SOD/SOC (Rasagiline, Selegiline, other propargylamines?).

Amphetamine requires PKC to reverse the DAT, and inhibitors or PKC appear to block the Amph-induced reverse Dopamine Transport. PKC activators such as Diglyceride/diacylglycerol may enhance Amphetamine-induced reverse DA transport.



DA-(MAO)-DOPAL-(aldehyde dehydrogenase)-DOPAC.......oxidative stress producs 4HNE and MDA inhibit aldehyde dehyrogenase DA-(MAO)-DOPAL-([cytosolic] aldehyde and/or aldose reductase)-DOPET DA-COMT DA-(peroxynitrite and/or NO2)-DA quinones 4HNE/MDA = lipid peroxidation products DA+H2O2/O2- = DA quinone + Superoxide (O2-) + H202 (hydrogen peroxide) = ONOO- (peroxynitrite) DA (oxidation) - Dopamine o-quinone (aminochrome) Aminochrome (1-electron reduction by NADPH cytochrome P450 reductase) = aminochrome-o-semiquinone Aminochrome-o-semiquinone = constant Redox cycle, dependent on NADPH and Oxygen, = Hydrogen peroxide and Superoxide Aminochrome (2-electron reduction via DT Diaphorase) = aminochrome-o-hydroquinone [much less toxic]