摘要:

AbstractNeurons in the substantia nigra may be vulnerable to oxidant stress because (a) the metabolism of dopamine generates peroxides, which, in the presence of iron, can lead to the formation of the highly reactive hydroxyl free radical; and (b) neuromelanin within nigral neurons can bind metals such as iron and aluminum and thereby promote the site‐specific formation of free radicals. Postmortem studies show increased iron, decreased glutathione, and increased lipid peroxidation in the substantia nigra of patients with Parkinson's disease (PD). Recent studies also report iron and aluminum accumulation within neuromelanin granules of patients with PD. These findings suggest that the substantia nigra in the patient with PD is in a state of oxidant stress and that antioxidant therapy might protect residual dopamine neurons and slow the natural progression of PD. Selective inhibitors of monoamine oxidase type B (MAO‐B) have been chosen for study because of their capacity to interfere with the oxidative metabolism of dopamine and so diminish the likelihood that free radicals will be formed. Initial studies demonstrate that the MAO‐B inhibitorL‐deprenyl (selegiline) delays the development of disability in otherwise untreated patients with early Parkinson's disease. Although the mechanism responsible for these observationsremains unclear, these results are consistent with the possibility that L‐deprenyl provides neuroprotectiv

ISSN:0885-3185    

DOI:10.1002/mds.870080503

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractDopamine and 2‐phenylethylamine levels in striatal tissue are known to be increased after administration of selegiline (L‐deprenyl), but it is still difficult to explain why this treatment induces longevity or dopaminergic neuroprotection in Parkinson's disease. In the absence of significant polyamine or diamine oxidase activities in human brain, polyamines and histamine are detoxified byN‐acetylation and methylation, respectively. Methylhistamine as well asN‐acetylated polyamine derivatives are selective substrates for monoamine oxidase type B (MAO‐B). Theoretically at least, MAO‐B inhibition by selegiline could result in the increase in the levels of polyamines and theirN‐acetyl derivatives. This could have significance for the action of selegiline in Parkinson's disease, as overactive corticostriatal glutaminergic function has been implicated in the degeneration of nigrostriatal dopamine neurons, and polyamines are potent modulators of the excitotoxic NMDA (N‐methyl‐D‐aspartate)‐gluta

ISSN:0885-3185    

DOI:10.1002/mds.870080504

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractRecent clinical studies suggest that selegiline (L‐deprenyl) is useful in retarding the progress of Parkinson's disease, an effect that may be related to its inhibition of monoamine oxidase type B (MAO‐B). Selegiline is also reported to prevent the toxic effects of the noradrenergic neurotoxin,N‐(2‐chloroethyl)‐N‐ethyl‐2‐bromobenzylamine (DSP‐4). This article reviews recent studies on the role of MAO‐B and its inhibition in this neuroprotective action of selegiline. Male C57Bl/6 mice were given DSP‐4 (50 mg/kg) 1 h, 24 h, or 4 days after the administration of selegiline (10 mg/kg) or the selective MAO‐B inhibitor MDL 72974 (1.25 mg/kg) and then killed 1 week later for the assay of norepinephrine in hippocampus. The MAO‐B‐inhibiting effects of selegiline or MDL 72974 were also determined after these same intervals. Selegiline and MDL 72974 produced comparable degrees of enzyme inhibition 1 h (>95%), 24 h(>90%), or 4 days (>70%) after their administration. Given 1 h before, selegline totally bloked the norepinephrinedepleting effects of DSP‐4, but this protection declined sharply when 24 h or 4 days was allowed to elapse between selegiline and DSP‐4 administration. MDL 72974 failed to protect at any time point. In vitro, no activity was observed when DSP‐4 was used as a substrate for MAO. All of these findings suggest that the ability of selegiline to protect against DSP‐4‐induced neuronal degeneration does

ISSN:0885-3185    

DOI:10.1002/mds.870080505

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractSelegiline [(–)‐deprenyl] has been reported to slow the progression of disabling deficits in Parkinson's disease (PD) and cognitive decline in Alzheimer disease (AD). The apparent slowing has been proposed to be based on either symptomatic improvement due to increased dopaminergic neurotransmission or alternately on protection of neurons from damage caused by toxic oxidative radicals. Both mechanisms are hypothesized to result from the inhibition of monoamine oxidase type B (MAO‐B) activity. Our experiments in two animal models have shown that selegiline has a second, previously unsuspected action. That is, selegiline can rescue neurons after they have sustained lethal damage and the rescue is independent of MAO‐B inhibition. It was previously shown that the coadministration of selegiline with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) could protect dopaminergic substantia nigra neurons (dSNns) from damage by blocking con version of MPTP to its active radicalN‐methyl‐4‐phenylpyridinium (MPP+) by inhibiting MAO‐B. In the first model, we treated C57BL mice with MPTP but delayed selegiline treatment for 72 h after the MPTP treatment to allow for complete conversion of MPTP to MPP+and for maximal dSNn damage by MPP+The delayed selegiline treatment rescued ∼69% of the dSNns that had not died by the time the treatment began but were found to die with saline treatment. Selegiline doses that were too small to cause inhibition of MAO‐B substrate oxidation rescued the MPTP‐damaged dSNns. The second model was based on previous work showing that immature (14‐day‐ old) rat facial motoneurons die after axotomy because of a loss of trophic support from the muscle they innervate. Selegiline treatment increased the number of motoneurons surviving axotomy from 24 to 52%, showing that selegiline can rescue neurons by partially compensating for the loss of target‐derived trophic support. This “trophic‐like” action of selegiline might account for the reported slowing of the progression of PD and AD and suggests that selegiline therapy may be of value with acute nervous system d

ISSN:0885-3185    

DOI:10.1002/mds.870080506

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractNeuronal loss in the substantia nigra of patients with Parkinson's disease (PD) does not occur evenly throughout the nucleus: the ventrolateral part of the substantia nigra degenerates more severely, whereas the medial part is relatively preserved. This pattern of nigral neuronal loss is compatible with the uneven loss of dopamine in the striatum (the putamen more affected than the caudate nucleus). The predominant loss of ventrolateral nigrostriatal projections in PD, leading to substantial loss of dopamine especially in the putamen, is thought to contribute to the motor symptoms of the patients. On the other hand, the more medial nigral projections may be involved in the cognitive symptoms of patients. Selegiline (L‐deprenyl) has been shown to delay the need to initiate levodopa therapy in early PD, and selegiline has also been suggested to increase the survival of PD patients. These observations have led to the proposal of selegiline's neuron‐saving effect in PD. There is some pathological evidence supporting the better survival of nigral neurons in PD patients treated with selegiline as compared with those without such treatment. Further studies are, however, needed to elucidate this question more clea

ISSN:0885-3185    

DOI:10.1002/mds.870080507

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractThe French Selegiline Multicenter Trial was carried out in 1990 to investigate whether the disability of de novo patients with parkinsonism could be improved during the first 3 months by monotherapy with selegiline (10mg/day). A double‐blind, randomized, placebo‐controlled clinical trial was conducted over 3 months with 93 patients from 13 centers. Symptomatology was assessed on various disease rating scales, including Hoehn and Yahr, Hamilton Depression Rating Scale, Unified Parkinson's Disease rating scale, and Schwab and England scores, as well as self‐assessment. Biological and clinical parameters were measured for tolerability, and efficacy was investigated with special reference to the point at which therapy withL‐dopa had to be started. Selegiline was significantly superior to placebo on the various motor rating scores, and depressive scores were significantly improved at the end of 3 months. Adverse effects were rare and minor. Therefore, selegiline could be the therapy of choice for the treatment of de novo parkinsonian p

ISSN:0885-3185    

DOI:10.1002/mds.870080508

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractSelegiline (L‐deprenyl) has been recommended as an antiparkinsonian drug to be used as an adjunct to therapy withL‐dopa, if and whenL‐dopa starts to lose its effect. However, initial selegiline monotherapy followed byL‐dopa may be both effective and safe. A double‐blind, placebo‐controlled trial was carried out in previously untreated patients with Parkinson's disease randomized to receive selegiline (10 mg/day; 27 patients) or placebo (25 patients) untilL‐dopa treatment became imperative. Three rating scales were used for assessment. The study design continues to be double‐blind even afterL‐dopa is introduced.L‐Dopa was needed after 545 ± 90 days in the selegiline group. This was significantly later (p= 0.03) than after placebo (372 ± 28 days). Disability was less severe in the selegiline group, and there were no serious adverse effects. A nearly twofold dose ofL‐dopa was needed in the placebo group to achieve a sufficient therapeutic effect during longterm treatment. These results show that selegiline is safe and effective as monotherapy in early parkinsonism. It delays the need forL‐dopa treatment and reduces the amount of dailyL‐dopa required. This could be explained by either a symptomatic effect or neuroprotective efficacy or, more li

ISSN:0885-3185    

DOI:10.1002/mds.870080509

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

ISSN:0885-3185    

DOI:10.1002/mds.870080502

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY