Oxidopamine

The neurontoxin 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 akineasia with a very high mortality rate. Ever since, oxidopamine has become an abundantly used neurotoxin for making animal models with Parkinson’s disease.[1]

The toxin oxidopamine, 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]

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]

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]

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.[9]

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

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

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]

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]

• 5,7-Dihydroxytryptamine
• DSP-4
• MPTP
• Norsalsolinol
• Rotenone
• FAUC50