Effect of a synthetic norepinephrine precursor, l-threo-3,4-dihydroxyphenylserine on the total norepinephrine concentration in the cerebrospinal fluid of parkinsonian patients

Tohgi, Hideo; Abe, Takashi; Takahashi, Satoshi; Takahashi, Jun; Ueno, M.; Nozaki, Yuichi

doi:10.1016/0304-3940(90)90409-3

Cited by 22 publications

(14 citation statements)

References 8 publications

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“…DOPS can serve as a precursor of peripheral NA in cases of dopamine-B-hydroxylase deficiency (Biaggioni and Robertson, 1987;Man in 't Veld et al, 1987). In a clinical study in PD patients with symptoms of freezing, CSF levels of NA were increased after oral administration of DOPS (Tohgi et al, 1990). However, CSF NA may, at least partly, have been derived from peripheral sources (Sternberg et al, 1981;Siever, 1987).…”

Section: Discussionmentioning

confidence: 95%

“…These symptoms have been attributed, at least in part, to a deficiency of noradrenaline (NA) in the brains of patients in advanced stages of PD (Narabayashi, 1984). Treatment with L-threo-3,4-dihydroxyphenylserine (DOPS), a synthetic precursor of NA, ameliorates freezing, dysarthria, all day life activity and mood (Narabayashi et al, 1986(Narabayashi et al, , 1987Ogawa et al, 1985;Teelken et al, 1989;Yoshida et al, 1989;Tohgi et al, 1990). However, little is known about the mechanisms underlying the beneficial effect of DOPS.…”

Section: Introductionmentioning

confidence: 95%

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Attenuation of haloperidol-induced catalepsy by noradrenaline and L-threo-DOPS

Verhagenkamerbeek

Hazemeijer

Korf

et al. 1993

J Neural Transm Gen Sect

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In addition to impaired dopaminergic neurotransmission a dysfunctional noradrenergic system has been demonstrated in Parkinson's disease. L-threo-3,4-dihydroxyphenylserine (DOPS), a synthetic precursor of noradrenaline (NA), appears to be effective in the treatment of some akinetic symptoms in parkinsonian patients. In the present study the possible effect of DOPS was studied in rats, in which catalepsy was induced with haloperidol as a model for parkinsonian akinesia. Intravenous infusion of NA (1.5 and 15 micrograms/kg) or DOPS (2 and 4 mg/kg) in male Wistar rats (240-290 g) significantly decreased catalepsy. The effect of DOPS was abolished by pretreatment with the peripheral decarboxylase inhibitor benserazide (2 mg/kg). Pretreatment with Ro 40-7592, a catechol-O-methyltransferase inhibitor, potentiated and prolonged the anticataleptic effect of DOPS. The findings suggest a peripheral site of NA mediated anticataleptic action. Therapy with DOPS may be successful only without a peripheral decarboxylase inhibitor. Moreover, the therapeutic effect of DOPS may be potentiated by COMT inhibition.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 95%

Attenuation of haloperidol-induced catalepsy by noradrenaline and L-threo-DOPS

Verhagenkamerbeek

Hazemeijer

Korf

et al. 1993

J Neural Transm Gen Sect

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“…The rate of decrease was reportedly less conspicuous in cortical MHPG levels than in NE levels (Riederer et al, 1977) suggesting compensatory hyperactivity of the remaining noradrenergic neurons. Administration of L-threo-3,4-dihydroxyphenylserine (L-threodops) increased the total NE concentrations in the CSF dose-dependently (Tohgi et al, 1990b), and also the extracellular NE levels in the striatum of normal rats (Brannan et al, 1990). The freezing phenomena have been alleviated by administration of L-threodops in some patients (Narabayashi et al, 1981(Narabayashi et al, , 1987, particularly in patients at mild to moderate stages, but not by administration of DLthreodops, instead of L-threodops, in a patient at an advanced stage (Quinn et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

Monoamine metabolism in the cerebrospinal fluid in Parkinson's disease: relationship to clinical symptoms and subsequent therapeutic outcomes

Tohgi

Abe

Takahashi

et al. 1993

J Neural Transm Gen Sect

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We correlated monoamine concentrations in the cerebrospinal fluid from de novo (untreated) patients with Parkinson's disease with their clinical symptoms and therapeutic outcome after two years of L-dopa with/without other anti-parkinson medication. A significant correlation was found between the severity of some parkinsonian symptoms and the reduction in particular monoamines: Hoehn and Yahr's stage with dopamine, norepinephrine, and homovanillic acid: rigidity with dopamine; akinesia with dopamine and norepinephrine; freezing of gait with norepinephrine; and dementia with dopamine and homovanillic acid. Tremor had no correlations with the concentrations of the monoamines measured. Patients with dementia had a significantly increased level of epinephrine concentrations. Insufficient therapeutic responses of individual symptoms were associated with significantly decreased concentrations of particular monoamines before treatment: Hoehn and Yahr's stage with norepinephrine and epinephrine; akinesia with homovanillic acid and 5-hydroxyindoleacetic acid; and freezing of gait with dopamine, norepinephrine, homovanillic acid, and 5-hydroxyindoleacetic acid. These results suggest a significant correlation between the reduction in particular monoamines and the severity of some parkinsonian symptoms and their subsequent responses to L-dopa.

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“…In rats, L-DOPS has only about 1/4 the ability of L-DOPA to traverse the blood-brain barrier (48), and the amount of increase of central NE by L-DOPS is actually less than that from L-DOPA. In humans, CSF levels of NE do increase, especially in patients treated concurrently with carbidopa (103,104).…”

Section: Clinical Pharmacokinetics and Metabolic Fate Of L-dopsmentioning

confidence: 99%

L‐Dihydroxyphenylserine (L‐DOPS): A Norepinephrine Prodrug

Goldstein

2006

Cardiovascular Drug Reviews

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L-threo-3,4-dihydroxyphenylserine (L-DOPS, droxydopa) is a synthetic catecholamino acid. When taken orally, L-DOPS is converted to the sympathetic neurotransmitter, norepinephrine (NE), via decarboxylation catalyzed by L-aromatic-amino-acid decarboxylase (LAAAD). Plasma L-DOPS levels peak at about 3 h, followed by a monoexponential decline with a half-time of 2 to 3 h. Plasma levels of NE and of its main neuronal metabolite, dihydroxyphenylglycol (DHPG) peak approximately concurrently but at much lower concentrations. The relatively long half-time for disappearance of L-DOPS from plasma, compared to that of NE, explains their very different attained plasma concentrations. In patients with neurogenic orthostatic hypotension, L-DOPS increases blood pressure and ameliorates orthostatic intolerance. Inhibition of LAAAD, such as by treatment with carbidopa, which does not penetrate the blood-brain barrier, prevents the blood pressure effects of the drug, indicating that L-DOPS increases blood pressure by augmenting NE production outside the brain. Patients with pure autonomic failure (which usually entails loss of sympathetic noradrenergic nerves), and patients with multiple system atrophy (in which noradrenergic innervation remains intact) have similar plasma NE responses to L-DOPS. This suggests mainly non-neuronal production of NE from L-DOPS. L-DOPS is very effective in treatment of deficiency of dopamine-beta-hydroxylase (DBH), the enzyme required for conversion of dopamine to NE in sympathetic nerves. L-DOPS holds promise for treating other much more common conditions involving decreased DBH activity or NE deficiency, such as a variety of syndromes associated with neurogenic orthostatic hypotension.

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Effect of a synthetic norepinephrine precursor, l-threo-3,4-dihydroxyphenylserine on the total norepinephrine concentration in the cerebrospinal fluid of parkinsonian patients

Cited by 22 publications

References 8 publications

Attenuation of haloperidol-induced catalepsy by noradrenaline and L-threo-DOPS

Attenuation of haloperidol-induced catalepsy by noradrenaline and L-threo-DOPS

Monoamine metabolism in the cerebrospinal fluid in Parkinson's disease: relationship to clinical symptoms and subsequent therapeutic outcomes

L‐Dihydroxyphenylserine (L‐DOPS): A Norepinephrine Prodrug

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