Pharmacological actions of 6-hydroxydopamine

RM Kostrzewa, DM Jacobowitz - Pharmacological reviews, 1974 - ASPET
RM Kostrzewa, DM Jacobowitz
Pharmacological reviews, 1974ASPET
From the previous discussions, it is apparent that 6-OHDA produces a relatively selective
effect on sympathetic nerve terminals. The selectivity of this action appears to be related to
its accumulation within noradrenergic neurons by uptake-1 transport mechanisms. Once
inside the neuron, 6-OHDA is bound in a granular storage pool and can be released by
nerve stimulation, thus acting as a false neurotransmitter. In sufficiently high amounts,
apparently more related to the concentration in the cytoplasmic pool, 6-OHDA generates …
From the previous discussions, it is apparent that 6-OHDA produces a relatively selective effect on sympathetic nerve terminals. The selectivity of this action appears to be related to its accumulation within noradrenergic neurons by uptake-1 transport mechanisms. Once inside the neuron, 6-OHDA is bound in a granular storage pool and can be released by nerve stimulation, thus acting as a false neurotransmitter. In sufficiently high amounts, apparently more related to the concentration in the cytoplasmic pool, 6-OHDA generates highly reactive products, suggested to be peroxides, superoxides, hydroxyindoles, and quinones. These products react nonspecifically with neuronal structures and eventually destroy the neuron. MAO appears to be important in the metabolism of the 6-OHDA molecule and this enzyme, as well as granule storage, may serve as protective mechanisms. The actual subcellular component most altered by 6-OHDA, and most involved with maintaining neuronal function, is not known. However, the endoplasmic reticulum, outer limiting membrane, nucleus, mitochondrion and other structures have been suggested as sites for the primary lesion, and 6-OHDA has been shown in vitro to uncouple oxidative phosphorylation in mitochondria. During the process of degeneration the nerves first lose their ability to conduct action potentials, NE stores become depleted and sympathomimetic responses may be observed. Uptake mechanisms become incapacitated and the nerve membrane ultimately is phagocytized, as evidenced by the intense neuroglia reaction. Accompanying the loss in the adrenergic nerve active amine uptake mechanism is the appearance of presynaptic supersensitivity at a host of sites. Development of postsynaptic supersensitivity has been suggested to occur with time in certain structures. In the peripheral nervous system the terminals regenerate, and it has been observed that functional activity is restored at early times, when the amine levels are still reduced and while the terminal network is far from being fully regenerated.
In the peripheral nervous system, 6-OHDA alters noradrenergic terminals to various degrees in different end organs. Time-course studies, following various routes of administration, have determined the threshold for terminal destruction in various organs of several species. In general, the increasing order for threshold of the destructive action of 6-OHDA in various end organs is cardiac ventricles > salivary glands > whole heart > iris > nictitating membrane > spleen > atria > blood vessels > vas deferens > sympathetic ganglia > adrenal glands. In regard to the adrenals it bears mentioning that they apparently are unaffected by direct 6-OHDA action, but respond to diminished sympathetic function by compensatorily increasing CA turnover. Terminals in all organs studied regenerate at a steady rate.
In the CNS of mature animals 6-OHDA produces marked alterations of both noradrenergic and dopaminergic neurons after injection into the parenchyma of the brain or into one of the brain cavities. Early studies showed that 6-OHDA in moderate doses could deplete the brain of NE in the absence of ultrastructural damage. Also, DA stores are initially increased after 6-OHDA and are depleted only as a consequence of damage to dopaminergic neurons. The regional effects of 6-OHDA on noradrenergic neurons in the brain vary according to the parameter under study. Different regional variations are found when either NE content, NE uptake or tyrosine hydroxylase activity is measured. The degeneration of the central noradrenergic neurons occurs in different phases, classified as primary and secondary …
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