Levodopa and 3-O-Methyldopa in Cerebrospinal Fluid After Levodopa-Carbidopa Association

Benetello, P.; Furlanut, Mario; Fortunato, Mariella G.; Pea, Federico; Baraldo, Massimo

doi:10.1006/phrs.1997.0145

Cited by 28 publications

(16 citation statements)

References 16 publications

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“…It is known that COMT inhibition may decrease 3-O-methyldopa occurrence and thus may improve levodopa transport over the blood brain barrier. However, the long half plasma life of 3-O-methyldopa facilitates its accumulation similar to homocysteine (Benetello et al 1997;Kuoppamaki et al 2009). In view of the SEM error bars however, we cannot exclude that the small sample size or the precision of measurement effect was also responsible to the missing significant effect of EN supplementation on 3-O-methyldopa metabolism.…”

Section: Discussionmentioning

confidence: 97%

Inhibition of catechol-O-methyltransferase modifies acute homocysteine rise during repeated levodopa application in patients with Parkinson’s disease

Müller

Woitalla

Muhlack

2011

Naunyn-Schmiedeberg's Arch Pharmacol

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Elevation of plasma total homocysteine concentrations were observed in levodopa/dopa decarboxylase inhibitor (DDI)-treated patients with Parkinson's disease (PD). Degradation of levodopa to 3-O-methyldopa via the enzyme catechol-O-methyltransferase (COMT) is a methyl group demanding reaction. It generates homocysteine from the methyl group donor methionine. But there are inconsistent outcomes, as most investigators determined homocysteine after an overnight washout of levodopa. They did not consider the acute effects of levodopa/DDI intake in relation with COMT inhibition on homocysteine bioavailability. The purpose of this study is to measure levels of homocysteine, levodopa, and its metabolite 3-O-methyldopa in plasma after reiterated oral levodopa/DDI administration with and without the COMT-inhibitor entacapone (EN). Sixteen PD patients received 100 mg levodopa/carbidopa three times on day 1 and with EN on day 2 under standardized conditions. Homocysteine concentrations increased on day 1 and generally over the whole interval. No significant ascent of homocysteine appeared on day 2 only. Levodopa bioavailability was higher on day 2 due to the COMT inhibition. No change of 3-O-methyldopa appeared between both days. The correlation coefficients between homocysteine, levodopa, and 3-O-methyldopa were higher on day 1 than on day 2. Rise of homocysteine does not only depend on the oral levodopa dose, but also on the acute intake of levodopa/DDI with or without COMT inhibition. Measurements of homocysteine should consider acute repeated levodopa/DDI applications, as homocysteine and metabolically related 3-O-methyldopa accumulate due to their long plasma half-life in contrast to short-living levodopa.

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Section: Discussionmentioning

confidence: 97%

Inhibition of catechol-O-methyltransferase modifies acute homocysteine rise during repeated levodopa application in patients with Parkinson’s disease

Müller

Woitalla

Muhlack

2011

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Therefore, the present study suggested that 3-OMD which penetrated into brain decreased locomotor activity. 3-OMD is competitive substrate at the site of transporter against L-DOPA through the bloodbrain barrier 8) and 3-OMD is considered to reduce clinical effect of L-DOPA. Consequently, it was suggested that 3-OMD produced motor fluctuation in PD patients receiving L-DOPA therapy.…”

Section: Discussionmentioning

confidence: 99%

“…7) 3-OMD inhibits distribution of L-DOPA into the brain, since 3-OMD competes with L-DOPA at the blood-brain barrier transporter system. 8) In addition, 3-OMD might inhibit DA release because DA efflux from striatal tissue slices was significantly reduced after L-DOPA superfusion with 3-OMD. 9) Some studies reported that 3-OMD blood level in PD patients with motor complications, such as dyskinesia and wearing-off, is higher than that of patients without motor fluctuations.…”

Section: 3)mentioning

confidence: 99%

Effects of 3-<i>O</i>-Methyldopa, <small>L</small>-3,4-Dihydroxyphenylalanine Metabolite, on Locomotor Activity and Dopamine Turnover in Rats

Onzawa

Kimura

Uzuhashi

et al. 2012

Biological & Pharmaceutical Bulletin

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It has been well known that 3-O-methyldopa (3-OMD) is a metabolite of L-3,4-dihydroxyphenylalanine (L-DOPA) formed by catechol O-methyltransferase (COMT), and 3-OMD blood level often reaches higher than physiological level in Parkinson's disease (PD) patients receiving long term L-DOPA therapy. However, the physiological role of 3-OMD has not been well understood. Therefore, in order to clarify the effects of 3-OMD on physiological function, we examined the behavioral alteration in rats based on locomotor activity, and measured dopamine (DA) and its metabolites levels in rats at the same time after 3-OMD subchronic administration. The study results showed that repeated administrations of 3-OMD increased its blood and the striatum tissue levels in those rats, and decreased locomotor activity in a dose dependent manner. Although 3-OMD subchronic administration showed no significant change in DA level in the striatum, DA metabolite levels, such as 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), and homovanillic acid (HVA) were significantly decreased. After 3-OMD washout period (7 d), locomotor activity and DA turnover in those rats returned to normal levels. Furthermore, locomotor activity and DA turnover decreased by 3-OMD administration were recovered to normal level by acute L-DOPA administration. These results suggested that 3-OMD affect to locomotor activity via DA neuron system. In conclusion, 3-OMD itself may have a disadvantage in PD patients receiving L-DOPA therapy.Key words 3-O-methyldopa; L-3,4-dihydroxyphenylalanine; locomotor activity; dopamine turnover; rat Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons in the substantia nigra region of the basal ganglia, which results in movement-related symptoms. Current treatment for PD includes dopamine replacement therapy in the form of L-3,4-dihydroxyphenylalanine (L-DOPA), a precursor to dopamine (DA) in its synthesis pathway that has been the gold standard of care for decades. More recently, DA receptor agonists, such as pramipexole, pergolide, and ropinirole, have become more commonly prescribed for the treatment of PD. Approximately 50% of PD patients, when treated with L-DOPA for more than 5 years, experience motor fluctuations such as the "wearing-off" phenomenon or the "no-on" phenomenon. 1) L-DOPA is commonly administered with aromatic amino acid decarboxylase (AADC) inhibitor, such as carbidopa or benserazide. 3-O-methyldopa (3-OMD) is a major metabolite of L-DOPA. 3-OMD is formed by catechol O-methyltransferase (COMT) in many organs including blood, peripheral tissues and brain.2) 3-OMD easily accumulates in several tissues (liver, kidney, brain, blood) because 3-OMD has much longer half-life (approximately 15 h) than L-DOPA. 2,3)It is reported that L-DOPA upregulates the expression and activity of COMT. 4) Therefore, blood level of 3-OMD is continually high and 3-OMD accumulates in PD patients receiving long term L-DOPA therapy.5) COMT inhibitor, such as entacapone, increases the area under ...

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“…To gain insight into these underlying mechanisms, we measured participants' restingstate fMRI activity following extinction training on day 1, asking whether spontaneous activity in a dopaminergic-midbrain seed region (43) would correlate with spontaneous activity in the vmPFC. The 10-min scan was placed 45 min after drug administration when L-dopa should reach its maximum concentration in plasma and already well elevated levels in the brain (18,44). L-dopa participants showed a significantly higher midbrain-vmPFC coupling than placebo participants (Fig.…”

Section: Significancementioning

confidence: 99%

Single dose of l -dopa makes extinction memories context-independent and prevents the return of fear

Haaker

Gaburro

Sah

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

147

164

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Traumatic events can engender persistent excessive fear responses to trauma reminders that may return even after successful treatment. Extinction, the laboratory analog of behavior therapy, does not erase conditioned fear memories but generates competing, fearinhibitory "extinction memories" that, however, are tied to the context in which extinction occurred. Accordingly, a dominance of fear over extinction memory expression-and, thus, return of fear-is often observed if extinguished fear stimuli are encountered outside the extinction (therapy) context. We show that postextinction administration of the dopamine precursor L-dopa makes extinction memories context-independent, thus strongly reducing the return of fear in both mice and humans. Reduced fear is accompanied by decreased amygdala and enhanced ventromedial prefrontal cortex activation in both species. In humans, ventromedial prefrontal cortex activity is predicted by enhanced resting-state functional coupling of the area with the dopaminergic midbrain during the postextinction consolidation phase. Our data suggest that dopamine-dependent boosting of extinction memory consolidation is a promising avenue to improving anxiety therapy.fear conditioning | psychotherapy | reinstatement | renewal | resilience

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Levodopa and 3-O-Methyldopa in Cerebrospinal Fluid After Levodopa-Carbidopa Association

Cited by 28 publications

References 16 publications

Inhibition of catechol-O-methyltransferase modifies acute homocysteine rise during repeated levodopa application in patients with Parkinson’s disease

Inhibition of catechol-O-methyltransferase modifies acute homocysteine rise during repeated levodopa application in patients with Parkinson’s disease

Effects of 3-<i>O</i>-Methyldopa, <small>L</small>-3,4-Dihydroxyphenylalanine Metabolite, on Locomotor Activity and Dopamine Turnover in Rats

Single dose of l -dopa makes extinction memories context-independent and prevents the return of fear

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