6-hydroxy-dopamine induced degeneration of central monoamine neurons

Ungerstedt, Urban

doi:10.1016/0014-2999(68)90164-7

Cited by 2,076 publications

(499 citation statements)

References 14 publications

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“…31 These rats produce contralateral rotations away from the lesioned side when they are challenged with direct-acting dopamine agonists. This model is considered to be one of the standard preclinical models for the early screening of PD drugs.…”

Section: ■ Discussionmentioning

confidence: 99%

D-512 and D-440 as Novel Multifunctional Dopamine Agonists: Characterization of Neuroprotection Properties and Evaluation of In Vivo Efficacy in a Parkinson’s Disease Animal Model

Santra

Shah

et al. 2013

ACS Chem. Neurosci.

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In this Article, we have demonstrated the in vivo efficacy of D-512 and D-440 in a 6-OHDA-induced unilaterally lesioned rat model experiment, a Parkinson's disease animal model. D-512 is a novel highly potent D2/D3 agonist, and D-440 is a novel highly selective D3 agonist. We evaluated the neuroprotective properties of D-512 and D-440 in the dopaminergic MN9D cells. Cotreatment of these two drugs with 6-OHDA and MPP+ significantly attenuated and reversed 6-OHDA-and MPP+-induced toxicity in a dosedependent manner in the dopaminergic MN9D cells. The inhibition of caspase 3/7 and lipid peroxidation activities along with the restoration of tyrosine hydroxylase levels by D-512 in 6-OHDA-treated cells may partially explain the mechanism of its neuroprotective property. Furthermore, studies were carried out to elucidate the time-dependent changes in the pERK1/2 and pAkt, two kinases implicated in cell survival and apoptosis, levels upon treatment with 6-OHDA in presence of D-512. The neuroprotective property exhibited by these drugs was independent of their dopamine-agonist activity, which is consistent with our multifunctional drug-development approach that is focused on the generation of disease-modifying symptomatic-treatment agents for Parkinson's disease.

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Section: ■ Discussionmentioning

confidence: 99%

D-512 and D-440 as Novel Multifunctional Dopamine Agonists: Characterization of Neuroprotection Properties and Evaluation of In Vivo Efficacy in a Parkinson’s Disease Animal Model

Santra

Shah

et al. 2013

ACS Chem. Neurosci.

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“…Compared with 6-hydroxydopamine, the compound now used for this purpose, DSP 4 has the advantage of readily passing the bloodbrain barrier and can accordingly be injected parenterally. Furthermore, it seems to be more selective than 6-hydroxydopamine, which also affects dopamine neurones (Ungerstedt, 1968). However, before DSP 4 can be used as a pharmacological tool its action on central and peripheral monoaminergic receptor mechanisms has to be evaluated.…”

Section: Discussionmentioning

confidence: 99%

LONG‐TERM EFFECTS OF N‐2‐CHLOROETHYL‐N‐ETHYL‐2‐BROMOBENZYLAMINE HYDROCHLORIDE ON NORADRENERGIC NEURONES IN THE RAT BRAIN AND HEART

Ross

1976

British J Pharmacology

272

106

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I N-2-Chloroethyl-N-ethyl-2-bromobenzylamine hydrochloride (DSP 4) 50 mg/kg intraperitoneally, produced a long-term decrease in the capacity of brain homogenates to accumulate noradrenaline with significant effect 8 months after the injection. It had no effect on the noradrenaline uptake in homogenates from the striatum (dopamine neurones) and on the uptake of 5-hydroxytryptamine (5-HT) in various brain regions. 2 In vitro DSP 4 inhibited the noradrenaline uptake in a cortical homogenate with an IC50 value of 2 gM but was more than ten times less active on the dopamine uptake in a striatal homogenate and the 5-HT uptake in a cortical homogenate. 3 DSP 4 (50 mg/kg i.p.) inhibited the uptake of noradrenaline in the rat heart atrium in vitro but this action was terminated within 2 weeks. 4 DSP 4 (50 mg/kg i.p.) caused a decrease in the dopamine-,B-hydroxylase (DBH) activity in the rat brain and heart. The onset of this effect was slow; in heart a lag period of 2-4 days was noted. In brain the DBH-activity in cerebral cortex was much more decreased than that in hypothalamus which was only slightly affected. A significant effect was still found 8 months after the injection. The noradrenaline concentration in the brain was greatly decreased for at least two weeks, whereas noradrenaline in heart was only temporarily reduced. S The long-term effects of DSP 4 on the noradrenaline accumulation, the DBH activity and noradrenaline concentration in the rat brain were antagonized by desipramine (10 mg/kg i.p.). 6 It is suggested that DSP 4 primarily attacks the membranal noradrenaline uptake sites forming a covalent bond and that the nerve terminals, as a result of this binding, degenerate.

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“…Although icv 6-OHDA results in a depletion of noradrenaline and dopamine from rat brain (Ungerstedt, 1968;Uretsky & Iversen, 1969;, it has been suggested (Simmonds & Uretsky, 1970) that 6-OHDA may also release endogenous dopamine in an active form in the brain which causes the observed hypothermia. If this is so, it supports the suggestion that the hypothermia produced by icv ouabain also primarily involves a dopaminergic mechanism, particularly since depressant doses of icv ouabain produce an elevation of whole-brain dopamine levels with no effect on noradrenaline .…”

Section: Discussionmentioning

confidence: 99%

Pharmacological properties of centrally‐administered agents which interfere with neurotransmitter function: a comparison with the central depressant effects of ouabain

Doggett

Spencer

1973

British J Pharmacology

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Summary1. Centrally administered sodium diethyldithiocarbamate (DDC) produced hypothermia, central nervous depression and potentiation of the antinociceptive effect of morphine. These effects resemble those seen with centrally administered ouabain. Furthermore, the interactions of (+)-amphetamine, desmethylimipramine and nialamide with DDC and ouabain were similar. 2. 6-Hydroxydopamine by the same route also produced central nervous depressant effects including hypothermia, decreased locomotor activity and catalepsy but not ptosis. 3. Both ouabain and chlorpromazine produced similar effects on behaviour and body temperature including selective abolition of a conditioned avoidance response.4. Although centrally administered tetrabenazine produced ptosis, decreased locomotor activity and catalepsy, it had no significant effect on body temperature. However, the hypothermia produced by peripherally administered reserpine was reversed by centrally administered dibutyryl cyclic 3',5'-adenosine monophosphate. 5. Centrally administered cocaine and desmethylimipramine produced no depressant effects but an increased excitability and responsiveness were apparent in both cases. 6. Although the observed behavioural depression and hypothermia can occur independently both seem to involve an interference with dopaminergic systems.

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6-hydroxy-dopamine induced degeneration of central monoamine neurons

Cited by 2,076 publications

References 14 publications

D-512 and D-440 as Novel Multifunctional Dopamine Agonists: Characterization of Neuroprotection Properties and Evaluation of In Vivo Efficacy in a Parkinson’s Disease Animal Model

D-512 and D-440 as Novel Multifunctional Dopamine Agonists: Characterization of Neuroprotection Properties and Evaluation of In Vivo Efficacy in a Parkinson’s Disease Animal Model

LONG‐TERM EFFECTS OF N‐2‐CHLOROETHYL‐N‐ETHYL‐2‐BROMOBENZYLAMINE HYDROCHLORIDE ON NORADRENERGIC NEURONES IN THE RAT BRAIN AND HEART

Pharmacological properties of centrally‐administered agents which interfere with neurotransmitter function: a comparison with the central depressant effects of ouabain

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