Delayed O-methylation of L-DOPA in MB-COMT-deficient mice after oral administration of L-DOPA and carbidopa

1.Catechol-O-methyltransferase (COMT) is involved in the O-methylation of l-DOPA, dopamine, and other catechols. The enzyme is expressed in two isoforms: soluble (S-COMT), which resides in the cytoplasm, and membrane-bound (MB-COMT), which is anchored to intracellular membranes. 2.To obtain specific information on the functions of COMT isoforms, we studied how a complete MB-COMT deficiency affects the total COMT activity in the body, peripheral l-DOPA levels, and metabolism after l-DOPA (10mg kg(-1)) plus carbidopa (30mg kg(-1)) administration by gastric tube in wild-type (WT) and MB-COMT-deficient mice. l-DOPA and 3-O-methyl-l-DOPA (3-OMD) levels were assayed in plasma, duodenum, and liver. 3.We showed that the selective lack of MB-COMT did not alter the total COMT activity, COMT enzyme kinetics, l-DOPA levels, or the total O-methylation of l-DOPA but delayed production of 3-OMD in plasma and peripheral tissues.Peer reviewe

PENGARUH GERMINASI DAN ELISITASI TERHADAP PERUBAHAN KANDUNGAN L-DOPA PADA KACANG Vicia faba

Vicia faba adalah legum yang kaya akan nutrisi, protein, karbohidrat dan levo dihydroxy phenylalanine (L-dopa). L-dopa adalah asam amino non protein yang telah digunakan untuk mengobati gangguan saraf seperti penyakit Parkinson. Tujuan penelitian ini adalah untuk mengetahui pengaruh dari germinasi/perkecambahan dan elisitasi terhadap kandungan L-dopa pada V. faba. Metode yang digunakan dalam penelitian ini yaitu dilakukan dengan model systematic review. Berdasarkan penelusuran yang dilakukan terdapat 5 artikel dengan data yang sesuai untuk kemudian dianalisis dan ditarik kesimpulannya. Berdasarkan hasil penelitian review yang telah dilakukan, diperoleh hasil bahwa kandungan L-dopa tertinggi terdapat pada V. faba yang digerminasi satu hari dan menurun seiring dengan bertambahnya waktu germinasi, dengan penurunan kadar L-dopa sebesar 33%-63% setelah delapan hari germinasi. Pengaruh penambahan berbagai jenis elisitor pada saat pengecambahan V. faba, bervariasi dan tergantung pada jenis elisitor. Pada penambahan elisitor berbahan dasar asam amino, termasuk di dalamnya adalah protein ikan hidrolisat (FPH), laktoferin (LF), azetedine-2-carboxylate (A2C), prolin, dan kombinasi A2C-prolin, kadar L-dopa pada V. faba mengalami penurunan setelah delapan hari elisitasi. Namun demikian, penambahan elisitor FPH meningkatkan kandungan L-dopa pada hari kedua elisitasi. Bahkan dibandingkan terhadap V. faba yang digerminasi 2 hari, kandungan L-dopa pada V. faba yang dielisitasi FPH selama 2 hari lebih tinggi 100%. Kandungan L-dopa dengan pengaruh elisitor A2C, prolin, dan kombinasi A2C-prolin menunjukkan kandungan L-dopa tertinggi pada hari pertama, dan menurun seiring waktu perkecambahan. Pada penggunaan elisitor UV, pemaparan sinar UV selama 15 jam juga dapat merangsang sintesis L-Dopa pada awal germinasi. Namun kadar L-dopa pada V. faba juga mengalami penurunan setelah delapan hari elisitasi dengan sinar UV. Tren yang sama diperoleh pada saat menggunakan elisitor berbahan dasar fenolik dan karbohidrat. Penggunaan ekstrak oregano (OE) sebagai elisitor berbahan dasar senyawa fenolik menunjukkan peningkatan kandungan L-Dopa sebesar 20% pada hari pertama. Sementara itu penggunaan ekstrak gellan gum (GG) sebagai elisitor berbahan dasar karbohidrat menunjukkan peningkatan kandungan L-Dopa sebesar 7,2% pada hari pertama. Kandungan L-Dopa dalam V. faba juga dapat ditingkatkan dengan memberikan perlakuan awal dengan menggunakan microwave, dengan peningkatan sebesar 59% dibandingkan kontrol

Modulation of the 5-HT3 Receptor as a Novel Anti-Dyskinetic Target in Parkinson’s Disease

La L-3,4-dihydroxyphénylalanine (L-DOPA) est le traitement le plus efficace de la maladie de Parkinson. Cependant, avec une administration chronique de L-DOPA, les patients développent des complications motrices telles que les dyskinésies. Des études antérieures ont montré que le blocage des récepteurs type 3 de la sérotonine (5-HT3) réduit les niveaux de dopamine dans les ganglions de la base, suggérant qu'il pourrait atténuer la libération de dopamine qui caractérise l'état dyskinétique. Ici, nous avons étudié les effets de l’ondansétron, un antagoniste hautement sélectif du récepteur 5-HT3 à diminuer et à prévenir le développement des dyskinésies induites par L-DOPA chez le rat lésé a la 6-hydroxydopamine. Dans la première expérience, les rats sensibilisés avec L-DOPA pour induire des mouvements involontaires anormaux (AIMs), ont reçu L-DOPA en combinaison avec l'ondansétron ou un véhicule. Dans la seconde expérience, les doses efficaces d'ondansétron ont été administrées simultanément avec L-DOPA pendant 22 jours, et la sévérité des dyskinésies a été évaluée. Après 3 jours d’élimination, L-DOPA a été administré en aigu et la sévérité des dyskinésies évaluée. Nous avons trouvé que l'ondansétron 0,0001 mg/kg en combinaison avec L-DOPA, a significativement diminué la sévérité des dyskinésies par rapport à L-DOPA seul. Ondansétron 0,0001 mg/kg, administré en même temps que L-DOPA, a retardé le développement des dyskinésies. L'action anti-dyskinétique de l'ondansétron n'a pas compromis le bénéfice thérapeutique conféré par la L-DOPA. Ces résultats suggèrent que l'antagonisme des récepteurs 5-HT3 est une stratégie thérapeutique potentiellement nouvelle et efficace pour soulager la sévérité et prévenir le développement des dyskinésies.L-3,4-dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson’s disease However, with chronic administration of L-DOPA, patients develop motor complications such as dyskinesia. Previous studies have shown that 5-HT3 receptor blockade reduces dopamine levels within the basal ganglia, suggesting that it could mitigate the aberrant dopamine release that characterises the dyskinetic state. Here, we investigated the effects of the highly-selective 5-HT3 antagonist ondansetron at diminishing the expression of established, and preventing the development of L-DOPA-induced dyskinesia in the 6-hydroxydopamine-lesioned rat. In the first set of experiments, rats were primed with L-DOPA to induce abnormal involuntary movements (AIMs), after which L-DOPA was administered, in combination with ondansetron or vehicle. The effect of ondansetron on L-DOPA anti-parkinsonian action was subsequently determined by the cylinder test. In the second set of experiments, rats were administered effective doses of ondansetron, started concurrently with L-DOPA for 22 days, during which dyskinesia severity was monitored. After a 3-day washout period, an acute challenge of L-DOPA was administered and AIMs severity was assessed. We found that acute challenges of ondansetron 0.0001 mg/kg in combination with L-DOPA, significantly diminished the severity of AIMs compared to L-DOPA alone. Ondansetron 0.0001 mg/kg, when started concurrently with L-DOPA, attenuated the priming process leading to the development of dyskinesia. The anti-dyskinetic action of ondansetron did not compromise the therapeutic benefit conferred by L-DOPA. These results suggest that 5-HT3 receptor antagonism is a potentially new and effective therapeutic strategy to alleviate the severity, and prevent the development of dyskinesia

Pretreatment Effects on the Uptake/Retention Kinetics of L-Dopa in Harding-Passey Melanoma

Malignant melanoma cells possess a unique biochemical pathway that converts L-3,4-dihydroxyphenylalanine (L-dopa) to the biopigment melanin. Selective cytotoxic incorporation of exogenous L-dopa into melanoma cells in vivo may provide a means of designing specific chemotherapeutic agents useful in the treatment of this disease. Using the Harding-Passey murine melanotic tumor model, a preferential uptake of [3H]L-dopa by the tumor was characterized. Following pretreatment of the tumor-bearing mice with nonradioactive L-dopa, a significant enhancement (p < 0.01) of [3H]L-dopa incorporation and retention into melanoma for a period of 24h was observed, when compared with the concomitant tissue distribution and clearance of radioactivity in the control animals. This finding suggests that by initial pretreatment of melanoma with nonradioactive L-dopa, the subsequent selective accumulation of [3H]L-dopa in tumor may provide a useful tool in testing new modalities of therapy in malignant melanoma

Imbalanced Dopaminergic Transmission Mediated by Serotonergic Neurons in L-DOPA-Induced Dyskinesia

L-DOPA-induced dyskinesias (LIDs) are one of the main motor side effects of L-DOPA therapy in Parkinson's disease. The review will consider the biochemical evidence indicating that the serotonergic neurons are involved in the dopaminergic effects of L-DOPA in the brain. The consequences are an ectopic and aberrant release of dopamine that follows the serotonergic innervation of the brain. After mid- to long-term treatment with L-DOPA, the pattern of L-DOPA-induced dopamine release is modified. In several brain regions, its effect is dramatically reduced while, in the striatum, its effect is quite preserved. LIDs could appear when the dopaminergic effects of L-DOPA fall in brain areas such as the cortex, enhancing the subcortical impact of dopamine and promoting aberrant motor responses. The consideration of the serotonergic system in the core mechanism of action of L-DOPA opens an important reserve of possible strategies to limit LIDs

L-Dopa and the Albino Riddle: Content of L-Dopa in the Developing Retina of Pigmented and Albino Mice

Background: The absence or deficiency of melanin as in albinos, has detrimental effects on retinal development that include aberrant axonal projections from eye to brain and impaired vision. In pigmented retinal pigment epithelium (RPE), dihydroxyphenalanine (L-Dopa), an intermediate in the synthetic path for melanin, has been hypothesized to regulate the tempo of neurogenesis. The time course of expression of retinal L-Dopa, whether it is harbored exclusively in the RPE, the extent of deficiency in albinos compared to isogenic controls, and whether L-Dopa can be restored if exogenously delivered to the albino have been unknown. Methodology/Principal Findings: L-Dopa and catecholamines including dopamine extracted from retinas of pigmented (C57BL/6J) and congenic albino (C57BL/6J-tyrc2j) mice, were measured throughout development beginning at E10.5 and at maturity. L-Dopa, but not dopamine nor any other catecholamine, appears in pigmented retina as soon as tyrosinase is expressed in RPE at E10.5. In pigmented retina, L-Dopa content increases throughout pre- and postnatal development until the end of the first postnatal month after which it declines sharply. This time course reflects the onset and completion of retinal development. L-Dopa is absent from embryonic albino retina and is greatly reduced in postnatal albino retina compared to pigmented retina. Dopamine is undetectable in both albino and pigmented retinas until after the postnatal expression of the neuronal enzyme tyrosine hydroxylase. If provided to pregnant albino mothers, L-Dopa accumulates in the RPE of the fetuses. Conclusions: L-Dopa in pigmented RPE is most abundant during development after which content declines. This L-Dopa is not converted to dopamine. L-Dopa is absent or at low levels in albino retina and can be restored to the RPE by administration in utero. These findings further implicate L-Dopa as a factor in the RPE that could influence development, and demonstrate that administration of L-Dopa could be a means to rescue developmental abnormalities characteristic of albinos

Dopamine Transporter Binding Is Unaffected by L-DOPA Administration in Normal and MPTP-Treated Monkeys

BACKGROUND: Radiotracer imaging of the presynaptic nigrostriatal dopaminergic system is used to assess disease progression in Parkinson's disease (PD) and may provide a useful adjunct to clinical assessment during therapeutic trials of potential neuroprotective agents. Several clinical trials comparing dopamine agonists to L-DOPA or early vs. late L-DOPA have revealed differences between clinical assessment and imaging of the presynaptic dopaminergic system, hence questioning the comparability of these measures as neuroprotection outcome variables. Thus, results of these studies may have been affected by factors other than the primary biological process investigated. METHODOLOGY/PRINCIPAL FINDINGS: We tested the possibility that L-DOPA might interfere with DAT binding. Post-mortem DAT binding was conducted in normal and MPTP-treated macaque monkeys that were administered L-DOPA, acutely or chronically. In parallel, DAT SPECT was conducted in MPTP-treated animals that were administered chronic L-DOPA. [99mTc]TRODAT-1 SPECT binding was similarly reduced in all MPTP monkeys regardless of L-DOPA treatment. L-DOPA had no significant effect on post-mortem DAT binding either in saline or in MPTP-lesioned animals. CONCLUSIONS/SIGNIFICANCE: These data indicate that L-DOPA does not induce modifications of DAT expression detectable by SPECT of by DAT binding autoradiography, suggesting that differences between clinical assessment and radiotracer imaging in clinical trials may not be specifically related to L-DOPA treatment

Altered Resting State Cortico-Striatal Connectivity in Mild to Moderate Stage Parkinson's Disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by dopamine depletion in the striatum. One consistent pathophysiological hallmark of PD is an increase in spontaneous oscillatory activity in the basal ganglia thalamocortical networks. We evaluated these effects using resting state functional connectivity MRI in mild to moderate stage Parkinson's patients on and off l-DOPA and age-matched controls using six different striatal seed regions. We observed an overall increase in the strength of cortico-striatal functional connectivity in PD patients off l-DOPA compared to controls. This enhanced connectivity was down-regulated by l-DOPA as shown by an overall decrease in connectivity strength, particularly within motor cortical regions. We also performed a frequency content analysis of the BOLD signal time course extracted from the six striatal seed regions. PD off l-DOPA exhibited increased power in the frequency band 0.02–0.05 Hz compared to controls and to PD on l-DOPA. The l-DOPA associated decrease in the power of this frequency range modulated the l-DOPA associated decrease in connectivity strength between striatal seeds and the thalamus. In addition, the l-DOPA associated decrease in power in this frequency band correlated with the l-DOPA associated improvement in cognitive performance. Our results demonstrate that PD and l-DOPA modulate striatal resting state BOLD signal oscillations and cortico-striatal network coherence

Striatal Proteomic Analysis Suggests that First L-Dopa Dose Equates to Chronic Exposure

L-3,4-dihydroxypheylalanine (L-dopa)-induced dyskinesia represent a debilitating complication of therapy for Parkinson's disease (PD) that result from a progressive sensitization through repeated L-dopa exposures. The MPTP macaque model was used to study the proteome in dopamine-depleted striatum with and without subsequent acute and chronic L-dopa treatment using two-dimensional difference in-gel electrophoresis (2D-DIGE) and mass spectrometry. The present data suggest that the dopamine-depleted striatum is so sensitive to de novo L-dopa treatment that the first ever administration alone would be able (i) to induce rapid post-translational modification-based proteomic changes that are specific to this first exposure and (ii), possibly, lead to irreversible protein level changes that would be not further modified by chronic L-dopa treatment. The apparent equivalence between first and chronic L-dopa administration suggests that priming would be the direct consequence of dopamine loss, the first L-dopa administrations only exacerbating the sensitization process but not inducing it