Oxidopamine, also known as 6-hydroxydopamine (6-OHDA) or 2,4,5-trihydroxyphenethylamine, is a

neurotoxic 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 – specificall ...

synthetic

organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The ...

used by researchers to selectively destroy

dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate d ...

and

noradrenergic Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...

neurons in the brain. The main use for oxidopamine in scientific research is to induce

Parkinsonism Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), rigidity, and postural instability. These are the four motor symptoms found in Parkinson's disease (PD), after which it is named, dementia with Lewy bo ...

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 Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

History

The neurontoxin oxidopamine has first been described in 1959. Years later, in 1968 the first model exploiting oxidopamine

neurotoxicity 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 – specificall ...

was developed by Ungerstedt, obtaining an animal model of akineasia with a very high mortality rate. Ever since, oxidopamine has become an abundantly used neurotoxin for making animal models with Parkinson’s disease.

Usage

The toxin oxidopamine, an antagonist of the neurotransmitter

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...

, 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. The toxin is also used for experimental models of attention-deficit hyperactivity disorder and Lesch-Nyhan syndrome.

Structure and reactivity

Structure

Oxidopamine is a neurotoxic, solid and organic compound, derived from dopamine. It is a

benzenetriol The trihydroxybenzenes (or benzenetriols) are organic compounds with the formula C6H3(OH)3. Also classified as polyphenols, they feature three hydroxyl groups substituted onto a benzene ring. They are white solids with modest solubility in water. ...

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.

Reactivity and reactions

The toxin oxidopamine is a relatively unstable compound. In certain experimental conditions, oxidopamine will undergo

autoxidation Autoxidation (sometimes auto-oxidation) refers to oxidations brought about by reactions with oxygen at normal temperatures, without the intervention of flame or electric spark. The term is usually used to describe the gradual degradation of organi ...

. This may result in the production of

reactive oxygen species In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen () p ...

(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. It has no rapid reactions with air or water. The reactive groups for oxidopamine are the phenol-, and amine-group. 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.

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.

Available forms

Oxidopamine is directly injected into the

nigrostriatal pathway 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 (i.e., the caudate nucleus and putamen) in the forebrain. It is one of the f ...

, 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).

Mechanisms

Oxidopamine operates though a two-step mechanism. The first step is the accumulation of the oxidopamine in neurons, whereas the second is the oxidation of oxidopamine. Oxidopamine is taken up into catecholaminergic neurons by dopamine or noradrenaline membrane receptors, and stored intracellular. The toxin is easily taken up because its structure is similar to dopamine and noradrenaline. After the uptake, oxidation of oxidopamine takes place by monoamine oxidase and hydrogen peroxide (H₂O₂) is generated. Hydrogen peroxide can cause oxygen radicals to be released. Oxidopamine gets oxidized and generates, beside the toxic hydrogen peroxide, reactive oxygen species (ROS) and catecholamine quinones. These quinones can attack endocellular nucleophilic groups. 6-hydroxidomapine + O₂ → quinones + H₂O₂. In order to induce this condition in animals, around 70% of the dopaminergic neurons in the

substantia nigra 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 app ...

of the brain must be destroyed, and this is achieved either with oxidopamine or

MPTP MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a prodrug 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 d ...

. Both these agents likely destroy neurons by generating reactive oxygen species such as

superoxide In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of the ...

radical. However, recent research suggests that 6-OHDA modifies proteins via cysteine modification, implying an additional cause of neuronal cell death.

Metabolism

6-OHDA is thought to enter the neurons via the

and noradrenaline (

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...

) reuptake transporters. Oxidopamine is often used in conjunction with a selective noradrenaline reuptake inhibitor (such as

desipramine Desipramine, sold under the brand name Norpramin among others, is a tricyclic antidepressant (TCA) used in the treatment of depression. It acts as a relatively selective norepinephrine reuptake inhibitor, though it does also have other activiti ...

) to selectively destroy dopaminergic neurons.

Efficacy and side effects

Efficacy

Oxidopamine is administered via an injection and causes an increase of outflow, and a decrease for

intraocular pressure Intraocular pressure (IOP) is the fluid pressure inside the eye. Tonometry is the method eye care professionals use to determine this. IOP is an important aspect in the evaluation of patients at risk of glaucoma. Most tonometers are calibrated to ...

(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 An adrenergic agonist is a drug that stimulates a response from the adrenergic receptors. The five main categories of adrenergic receptors are: α1, α2, β1, β2, and β3, although there are more subtypes, and agonists vary in specificity between t ...

. The supersensitivity phase lasts for up to 6 months, and can be maintained by repeatingly injections.

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).

Toxicity

There are several ways in which oxidopamine may cause

toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subst ...

, however it is often difficult what mechanism causes cell damage after exposure. 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. 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 Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the Cell (biology), cells, and transports Metabolic waste, metabolic waste products away from th ...

References

{{Phenethylamines Catecholamines Neurotoxins