6-Hydroxydopamine neurotoxicity

Borlongan, C.V., et al. 2002. Bradykinin receptor agonist facilitates low-dose cyclosporine-A protection against 6-hydroxydopamine neurotoxicity. Brain Res 956 211. 

Glinka Y,GassenM, YoudimMBH. 1997. Mechanism of 6-hydroxydopamine neurotoxicity. J. Neural Transm. 50 55-66... 

Neurotoxins such as mercaptopyrazide pyrimidine (MPP+) and 6-hydroxydopamine are also taken up by transporters, and this is required for their neurotoxic effects. Mice have been prepared with their transporter genes knocked out . Extensive studies with these mice confirm the important role of transporters (Table 12-1). Once an amine has been taken up across the neuronal membrane, it can be taken up by intracellular adrenergic storage vesicles as described above. 

Neurotoxins produced by the body. Some normal body constituents are neurotoxic in excess. These incluse quinolinic acid (Fig. 25-11),889 3-hydroxykynurenine (Fig. 25-11 p. 1444),890 and homocysteine.891 Elevated levels of homocysteine are also associated with vascular disease and stroke (Chapter 24). 3-Hydroxykynurenine is a precursor to ommochrome pigments of insects and an intermediate in conversion of tryptophan into the nicotinamide ring of NAD in humans (Fig. 25-11). 6-Hydroxydopamine (Fig. 30-26), which may be formed in the body, is severely toxic to catecholaminergic neurons.892... 

A stereotyped compulsive behavior is induced both in humans and in laboratory animals by amphetamines. This provided the basis for a method that has been used to measure the action of drugs on amphetamine-sensitive centers of the brain. A lesion in the nigrostriatal bundle on one side of a rat brain was made by injection of a neurotoxic compound such as 6-hydroxydopamine. This caused degeneration of dopamine-containing neurons on one side of the brain. When rats that had been injured in this way were given amphetamines, they developed a compulsive rotational behavior. Administration of chlorpromazine and several other antipsychotic drugs neutralized this behavior and in direct proportion to the efficacy in clinical use, an observation that also supports the theory that schizophrenia involves overactivity of dopamine neurons. 

Soto-Otero R, Mendez-Alvarez E, Hermida-Ameijeiras A, Munoz-Patino AM, Laban-deira-Garcia JL. 2000. Autoxidation and neurotoxicity of 6-hydroxydopamine in the presence of some antioxidants Potential implication in relation to the pathogenesis of Parkinson s disease. J Neurochem 74 1605-1612. 

Palumbo A, Napolitano A, Barone P, d Ischia M (1999) Nitrite- and peroxide-dependent oxidation pathways of dopamine 6-nitrodopamine and 6-hydroxydopamine formation as potential contributory mechanisms of oxidative stress- and nitric oxide-induced neurotoxicity in neuronal degeneration. Chem Res Toxicol 12 1213-1222... 

In addition lipid peroxidation can result from action of active oxygen species. This leads to destruction of metabolically necessary lipid molecules and damage to the structural integrity of cellular membranes. Damage from oxidative stress can occur with excessive production of active oxygen species, inadequate protection against such species, or both. Examples of toxicity from active oxygen species include the pancreatic beta-cell destruction by alloxan, the neurotoxicity of 6-hydroxydopamine, the cardiotoxicity of the anthracy-cline antibiotics, and the pulmonary toxicity of the herbicide paraquat. 

Hydroxydopamine is a selectively neurotoxic compound which damages the sympathetic nerve endings. It can be seen from Figure 7.29 that 6-hydroxy dopamine is structurally very similar to dopamine and noradrenaline, and because of this it is actively taken up into the synaptic system along with other catecholamines. Once localized in the synapse the 6-hydroxy dopamine destroys the nerve terminal. A single small dose of 6-hydroxydopamine destroys all the nerve terminals and possibly the nerve cells as well. 

Hydroxydopamine. This selectively neurotoxic compound damages the sympathetic nerve endings. Due to its structural similarity to dopamine it is actively taken up into the synaptic system. Once taken... 

It has been stated that if 6-hydroxydopamine and 6-aminodopamine are to be selective in their neurotoxic behavior the damaging process must occur intraneuronally following uptake and hence concentration of the neurotoxin within the neuron. In vivo electrochemical measurements have shown that about 20% of 6-hydroxydopamine is converted to its p-quinone within a few minutes after injection into rat brain. " The redox equilibrium between 6-hydroxydopamine and its p-quinone or 6-aminodopamine and its p-quinoneimine is apparently maintained by an active redox buffer, probably ascorbate-dehydroascorbate, which exists in brain tissue. The potential of this redox buffer is apparently close to -0.200 V vs. SCE. 

Liang and co-workers have proposed that fast chemical interactions of the p-quinone, formed on oxidation of 6-hydroxydopamine, with ubiquitous thiol groups of nerve terminal proteins and membrane constituents could be mainly responsible for the neurotoxicity of 6-hydroxydopamine. 

NoeUcer, C. Bacher, M. Gocke, P. Wei, X. Klockgether, T. Du, Y Dodel, R. The flavanoide caffeic acid phenethyl ester blocks 6-hydroxydopamine-induced neurotoxicity. Neurosci. Lett. 2005, 383, 39-43. 

X. Klockgether, T Du, Y Dodel, R. The flavanoide caffeic acid phenethyl ester blocks 6-hydroxydopamine-induced neurotoxicity. 

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