Oxidopamine

Last updated
Oxidopamine
6-Hydroxydopamine.svg
Oxidopamine-3D-balls.png
Names
Preferred IUPAC name
5-(2-Aminoethyl)benzene-1,2,4-triol
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.013.493 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 214-842-3
KEGG
PubChem CID
UNII
  • InChI=1S/C8H11NO3/c9-2-1-5-3-7(11)8(12)4-6(5)10/h3-4,10-12H,1-2,9H2 Yes check.svgY
    Key: DIVDFFZHCJEHGG-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C8H11NO3/c9-2-1-5-3-7(11)8(12)4-6(5)10/h3-4,10-12H,1-2,9H2
    Key: DIVDFFZHCJEHGG-UHFFFAOYAG
  • c1c(c(cc(c1O)O)O)CCN
Properties
C8H11NO3
Molar mass 169.18 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Oxidopamine, also known as 6-hydroxydopamine (6-OHDA) or 2,4,5-trihydroxyphenethylamine, is a neurotoxic synthetic organic compound used by researchers to selectively destroy dopaminergic and noradrenergic neurons in the brain.

Contents

The main use for oxidopamine in scientific research is to induce Parkinsonism in laboratory animals by lesioning the dopaminergic neurons of the substantia nigra pars compacta, in order to develop and test new medicines and treatments for Parkinson's disease.

History

The neurotoxin oxidopamine has first been described in 1959. Years later, in 1968 the first model exploiting oxidopamine neurotoxicity was developed by Ungerstedt, obtaining an animal model of akinesia with a very high mortality rate. Ever since, oxidopamine has become an abundantly used neurotoxin for making animal models with Parkinson's disease. [1]

Usage

The toxin oxidopamine is an antagonist of the neurotransmitter dopamine, and is commonly used for making experimental animal models in Parkinson's disease. Parkinson disease leads to degeneration of dopaminergic midbrain neurons resulting in dopamine depletion. Therefore oxidopamine can induce Parkinson disease in animal models. These models can be used to do research for treatments for Parkinson's disease. [2] The toxin is also used for experimental models of attention-deficit hyperactivity disorder and Lesch-Nyhan syndrome. [3] [4]

Structure and reactivity

Structure

Oxidopamine is a neurotoxic, solid and organic compound, derived from dopamine. It is a benzenetriol which is phenethylamine, where the hydrogens on the phenyl ring at positions 2, 4 and 5 are replaced by hydroxyl groups. Oxidopamine is a primary amino compound, a benzenetriol and a catecholamine. The molecular weight of this oxidopamine is 169.18 and has the following molecular formula; C8H11NO3. The melting point of oxidopamine is 232 degrees celsius. [5]

Reactivity and reactions

The toxin oxidopamine is a relatively unstable compound. In certain experimental conditions, oxidopamine will undergo autoxidation. This may result in the production of reactive oxygen species (ROS), mainly superoxide and hydrogen peroxide. ROS generation is also increased by oxidopamine via inhibition of complex I and IV of the electron transport chain. [3]

It has no rapid reactions with air or water. The reactive groups for oxidopamine are the phenol-, and amine-group. [5] Oxidopamine primarily interacts with structures containing norepinephrine, but also with structures containing dopamine. However the interactions with dopamine-containing structures are to a lesser extent. [6]

Synthesis

Oxidopamine was long ago characterized and synthesized, starting from 2,4,5-trimethoxy and 2,4,5-tribenzyloxybenzaldehyde respectively, by Harley-Mason and Lee and Dickson. The multistep synthesis of Senoh and Witkop involves the addition of Methanol to become an applicable o-quinone intermediate. In consequence of the general low yields and the relatively involved procedures, it is wished to report an alternate scheme for the synthesis of this pharmacon. In about 60% of the overall yield phenethylamine 3 is prepared via nitrostyrene by starting with isovanillin. The central step in synthesising oxidopamine is a Fremy's salt oxidation of 3-hydroxy-4-methoxyphenethylamine forming the corresponding p-quinone. The Teuber reaction only succeeds when the amino function is protected by acetylation, carbobenzoxylation or formylation. With the derivatives N-carbobenzoxy and N-acetyl almost quantitative yields of the p-quinone can be obtained. [7]

Available forms

Oxidopamine is directly injected into the nigrostriatal pathway, targeting the dopamine transporters (DAT). This can be done through stereotaxic injections whereas bilateral as unilateral is experimentally permitted. It will cause loss of dopamine terminals in the striatum by affecting the nigrostriatal pathway and causes loss of dopamine neurons in the Substantia nigra pars compacta (SNpc). [8]

Mechanisms

Oxidopamine is taken up by and accumulates in catecholaminergic neurons. This uptake is facilitated by dopamine and noradrenaline membrane receptors due to the structural similarity with dopamine and noradrenaline. Within the neuron, oxidopamine is oxidized by monoamine oxidase producing the toxic products hydrogen peroxide (H2O2), catecholamine quinones and reactive oxygen species (ROS). These quinones can attack endocellular nucleophillic groups. [9]

6-hydroxidopamine + O2 → quinones + H2O2. [9]

In order to induce Parkinsonism in animals, around 70% of the dopaminergic neurons in the substantia nigra of the brain must be destroyed, and this is often achieved either with oxidopamine or another neurotoxin MPTP. Both these agents likely destroy neurons by generating reactive oxygen species such as superoxide radicals. However, recent research suggests that 6-OHDA modifies proteins via cysteine modification, implying an additional cause of neuronal cell death. [10]

Metabolism

6-OHDA is thought to enter the neurons via the dopamine and noradrenaline (norepinephrine) reuptake transporters. Oxidopamine is often used in conjunction with a selective noradrenaline reuptake inhibitor (such as desipramine) to selectively destroy dopaminergic neurons. [10]

Efficacy and side effects

Efficacy

Oxidopamine is administered via an injection and causes an increase of outflow, and a decrease for intraocular pressure (IOP), lasting for a few days up to two weeks. The real purpose of 6-hydroxydopamine is to increase sensitivity to alpha- and beta-adrenergic agonists. The supersensitivity phase lasts for up to 6 months, and can be maintained by repeated injections. [11]

Adverse effects

There are several effects linked to the usage of 6-hydroxydopamine. The most common adverse effects caused by injections are hyperemia, subconjunctival hemorrhage, transient mydriasis, chemosis, lid edema, and ptosis (which may last for a few weeks). [11]

Toxicity

There are several ways in which oxidopamine may cause toxicity, however it is often difficult what mechanism causes cell damage after exposure. [3] It is also thought that toxic effects of 6-OHDA are caused by the uptake of the substance into the catecholaminergic nerve endings. This happens because the catecholaminergic transport system has a high affinity for 6-OHDA. Cell death by oxidopamine can be induced by three main mechanisms; ROS generation, H2O2 generation, or direct inhibition of mitochondria. [9]

The reaction to oxidopamine is often very site specific, making it important to inject it at the location it has to function. In order to cause toxicity in the brain, the oxidopamine has to be injected directly into the brain, since it is not able to cross the blood brain barrier. [3]

See also

Related Research Articles

<span class="mw-page-title-main">Substantia nigra</span> Structure in the basal ganglia of the brain

The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. Substantia nigra is Latin for "black substance", reflecting the fact that parts of the substantia nigra appear darker than neighboring areas due to high levels of neuromelanin in dopaminergic neurons. Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta.

<span class="mw-page-title-main">Dopamine</span> Organic chemical that functions both as a hormone and a neurotransmitter

Dopamine is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% of the catecholamine content in the brain. It is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical, L-DOPA, which is synthesized in the brain and kidneys. Dopamine is also synthesized in plants and most animals. In the brain, dopamine functions as a neurotransmitter—a chemical released by neurons to send signals to other nerve cells. Neurotransmitters are synthesized in specific regions of the brain, but affect many regions systemically. The brain includes several distinct dopamine pathways, one of which plays a major role in the motivational component of reward-motivated behavior. The anticipation of most types of rewards increases the level of dopamine in the brain, and many addictive drugs increase dopamine release or block its reuptake into neurons following release. Other brain dopamine pathways are involved in motor control and in controlling the release of various hormones. These pathways and cell groups form a dopamine system which is neuromodulatory.

<span class="mw-page-title-main">Neurotoxin</span> Toxin harmful to nervous tissue

Neurotoxins are toxins that are destructive to nerve tissue. Neurotoxins are an extensive class of exogenous chemical neurological insults that can adversely affect function in both developing and mature nervous tissue. The term can also be used to classify endogenous compounds, which, when abnormally contacted, can prove neurologically toxic. Though neurotoxins are often neurologically destructive, their ability to specifically target neural components is important in the study of nervous systems. Common examples of neurotoxins include lead, ethanol, glutamate, nitric oxide, botulinum toxin, tetanus toxin, and tetrodotoxin. Some substances such as nitric oxide and glutamate are in fact essential for proper function of the body and only exert neurotoxic effects at excessive concentrations.

<span class="mw-page-title-main">MPTP</span> Chemical compound

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is an organic compound. It is classified as a tetrahydropyridine. It is of interest as a precursor to the neurotoxin MPP+, which causes permanent symptoms of Parkinson's disease by destroying dopaminergic neurons in the substantia nigra of the brain. It has been used to study disease models in various animals.

Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifically, a neurotoxin or neurotoxicant– alters the normal activity of the nervous system in such a way as to cause permanent or reversible damage to nervous tissue. This can eventually disrupt or even kill neurons, which are cells that transmit and process signals in the brain and other parts of the nervous system. Neurotoxicity can result from organ transplants, radiation treatment, certain drug therapies, recreational drug use, exposure to heavy metals, bites from certain species of venomous snakes, pesticides, certain industrial cleaning solvents, fuels and certain naturally occurring substances. Symptoms may appear immediately after exposure or be delayed. They may include limb weakness or numbness, loss of memory, vision, and/or intellect, uncontrollable obsessive and/or compulsive behaviors, delusions, headache, cognitive and behavioral problems and sexual dysfunction. Chronic mold exposure in homes can lead to neurotoxicity which may not appear for months to years of exposure. All symptoms listed above are consistent with mold mycotoxin accumulation.

<span class="mw-page-title-main">Nigrostriatal pathway</span> Bilateral pathway in the brain

The nigrostriatal pathway is a bilateral dopaminergic pathway in the brain that connects the substantia nigra pars compacta (SNc) in the midbrain with the dorsal striatum in the forebrain. It is one of the four major dopamine pathways in the brain, and is critical in the production of movement as part of a system called the basal ganglia motor loop. Dopaminergic neurons of this pathway release dopamine from axon terminals that synapse onto GABAergic medium spiny neurons (MSNs), also known as spiny projection neurons (SPNs), located in the striatum.

<span class="mw-page-title-main">Neuromelanin</span> Dark pigment found in the brain

Neuromelanin (NM) is a dark pigment found in the brain which is structurally related to melanin. It is a polymer of 5,6-dihydroxyindole monomers. Neuromelanin is found in large quantities in catecholaminergic cells of the substantia nigra pars compacta and locus coeruleus, giving a dark color to the structures.

<span class="mw-page-title-main">Hypokinesia</span> Decreased movement due to basal ganglia dysfunction

Hypokinesia is one of the classifications of movement disorders, and refers to decreased bodily movement. Hypokinesia is characterized by a partial or complete loss of muscle movement due to a disruption in the basal ganglia. Hypokinesia is a symptom of Parkinson's disease shown as muscle rigidity and an inability to produce movement. It is also associated with mental health disorders and prolonged inactivity due to illness, amongst other diseases.

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The pars compacta (SNpc) is one of two subdivisions of the substantia nigra of the midbrain ; it is situated medial to the pars reticulata. It is formed by dopaminergic neurons. It projects to the striatum and portions of the cerebral cortex. It is functionally involved in fine motor control.

MPP<sup>+</sup> Chemical compound

MPP+ (1-methyl-4-phenylpyridinium) is a positively charged organic molecule with the chemical formula C12H12N+. It is a neurotoxin that acts by interfering with oxidative phosphorylation in mitochondria by inhibiting complex I, leading to the depletion of ATP and eventual cell death.

<span class="mw-page-title-main">Brain mitochondrial carrier protein 1</span> Protein-coding gene in the species Homo sapiens

Brain mitochondrial carrier protein 1 is a protein that in humans is encoded by the SLC25A14 gene.

<span class="mw-page-title-main">Quinolinic acid</span> Dicarboxylic acid with pyridine backbone

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References

  1. ↑ Simola, Nicola; Morelli, Micaela; Carta, Anna R. (2007-09-01). "The 6-Hydroxydopamine model of parkinson's disease" . Neurotoxicity Research. 11 (3): 151–167. doi:10.1007/BF03033565. ISSN   1476-3524. PMID   17449457. S2CID   25556004.
  2. ↑ Höglinger, Günter U.; Rizk, Pamela; Muriel, Marie P.; Duyckaerts, Charles; Oertel, Wolfgang H.; Caille, Isabelle; Hirsch, Etienne C. (July 2004). "Dopamine depletion impairs precursor cell proliferation in Parkinson disease". Nature Neuroscience. 7 (7): 726–735. doi:10.1038/nn1265. ISSN   1546-1726. PMID   15195095. S2CID   952173.
  3. 1 2 3 4 Pantic, Igor; Cumic, Jelena; Skodric, Sanja Radojevic; Dugalic, Stefan; Brodski, Claude (2021-02-25). "Oxidopamine and oxidative stress: Recent advances in experimental physiology and pharmacology" . Chemico-Biological Interactions. 336: 109380. doi:10.1016/j.cbi.2021.109380. ISSN   0009-2797. PMID   33450287. S2CID   231622597.
  4. ↑ Breese GR, Knapp DJ, Criswell HE, Moy SS, Papadeas ST, Blake BL (2005). "The neonate-6-hydroxydopamine-lesioned rat: a model for clinical neuroscience and neurobiological principles". Brain Res. Brain Res. Rev. 48 (1): 57–73. doi:10.1016/j.brainresrev.2004.08.004. PMID   15708628. S2CID   22599841.
  5. 1 2 PubChem. "Oxidopamine". pubchem.ncbi.nlm.nih.gov. Retrieved 2022-03-04.
  6. ↑ "Oxidopamine - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2022-03-04.
  7. ↑ Wehrli, Pius A.; Pigott, F.; Chu, V. (1972-09-15). "A New Synthesis of 6-Hydroxydopamine". Canadian Journal of Chemistry. 50 (18): 3075–3079. doi:10.1139/v72-488. ISSN   0008-4042.
  8. ↑ Hernandez-Baltazar, Daniel; Nadella, Rasajna; Jesus Rovirosa-Hernandez, Maria de; Zavala-Flores, Laura Mireya; Jarquin, Christian de Jesus Rosas (2017-12-20). Animal Model of Parkinson Disease: Neuroinflammation and Apoptosis in the 6-Hydroxydopamine-Induced Model. IntechOpen. ISBN   978-1-78923-165-6.
  9. 1 2 3 Saito, Yoshiro; Nishio, Keiko; Ogawa, Yoko; Kinumi, Tomoya; Yoshida, Yasukazu; Masuo, Yoshinori; Niki, Etsuo (2007-03-01). "Molecular mechanisms of 6-hydroxydopamine-induced cytotoxicity in PC12 cells: Involvement of hydrogen peroxide-dependent and -independent action". Free Radical Biology and Medicine. 42 (5): 675–685. doi:10.1016/j.freeradbiomed.2006.12.004. ISSN   0891-5849. PMID   17291991.
  10. 1 2 Farzam, Ali; Chohan, Karan; Strmiskova, Miroslava; Hewitt, Sarah J.; Park, David S.; Pezacki, John P.; Özcelik, Dennis (January 2020). "A functionalized hydroxydopamine quinone links thiol modification to neuronal cell death". Redox Biology. 28: 101377. doi:10.1016/j.redox.2019.101377. PMC   6880099 . PMID   31760358.
  11. 1 2 "Oxidopamine - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2022-03-04.
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