Therapeutic Effect Of Levodopa Research Articles

Rho kinase inhibitor fasudil reduces l-DOPA-induced dyskinesia in a rat model of Parkinson's disease.

Rho kinase (ROCK) activation is involved in neuroinflammatory processes leading to progression of neurodegenerative diseases such as Parkinson's disease. Furthermore, ROCK plays a major role in angiogenesis. Neuroinflammation and angiogenesis are mechanisms involved in developing l-DOPA-induced dyskinesias (LID). However, it is not known whether ROCK plays a role in LID and whether ROCK inhibitors may be useful against LID. In rats, we performed short- and long-term dopaminergic lesions using 6-hydroxydopamine and developed a LID model. Effects of dopaminergic lesions and LID on the RhoA/ROCK levels were studied by western blot, real-time PCR analyses and ROCK activity assays in the substantia nigra and striatum. The effects of the ROCK inhibitor fasudil on LID were particularly investigated. Short-term 6-hydroxydopamine lesions increased nigrostriatal RhoA/ROCK expression, apparently related to the active neuroinflammatory process. However, long-term dopaminergic denervation (completed and stabilized lesions) led to a decrease in RhoA/ROCK levels. Rats with LID showed a significant increase of RhoA and ROCK expression. The development of LID was reduced by the ROCK inhibitor fasudil (10 and 40 mg·kg-1 ), without interfering with the therapeutic effect of l-DOPA. Interestingly, treatment of 40 mg·kg-1 of fasudil also induced a significant reduction of dyskinesia in rats with previously established LID. The present results suggest that ROCK is involved in the pathophysiology of LID and that ROCK inhibitors such as fasudil may be a novel target for preventing or treating LID. Furthermore, previous studies have revealed neuroprotective effects of ROCK inhibitors.

L-DOPA reverses the impairment of Dentate Gyrus LTD in experimental parkinsonism via β-adrenergic receptors

Parkinson's disease (PD) patients exhibit motor and non-motor symptoms that severely affect quality of life. Cognitive alterations in PD subjects have been related to both structural and functional hippocampal changes. Here we investigated the effects of the 6-hydroxydopamine (6-OHDA) lesion in the Medial Forebrain Bundle (MFB) on the hippocampus focusing on the Dentate Gyrus (DG). In vivo microdialysis measurements revealed that the 6-OHDA injection disrupts both dopaminergic and noradrenergic transmission in rat DG. In vitro electrophysiological recordings showed that these neurochemical alterations were accompanied by impairment of long-term depression (LTD) at medial perforant path/DG synapses. Furthermore, this alteration was reversed by l-DOPA treatment. Notably, the therapeutic effect of l-DOPA on LTD was blocked by the antagonism of β-noradrenergic receptors, but not by dopamine D1 or D2 receptor antagonists. Thus, while the dopaminergic transmission does not seem to be implicated in this therapeutic effect of l-DOPA, the noradrenergic system plays a central role in the synaptic dysfunction of the DG in experimental PD. Our work provides new evidence on the role of catecholamines in DG synaptic plasticity and sheds light on the possible synaptic mechanisms underlying cognitive deficits in PD. Furthermore, our results indicate that l-DOPA exerts a therapeutic effect on the parkinsonian brain through different, coexistent, mechanisms.

Inhibition of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) signaling in the striatum reverts motor symptoms associated with l -dopa–induced dyskinesia

L-dopa-induced dyskinesia (LID) is a common debilitating complication of dopamine replacement therapy in Parkinson's disease. Recent evidence suggests that LID may be linked causally to a hyperactivation of the Ras-ERK signaling cascade in the basal ganglia. We set out to determine whether specific targeting of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1), a brain-specific activator of the Ras-ERK pathway, may provide a therapy for LID. On the rodent abnormal involuntary movements scale, Ras-GRF1-deficient mice were significantly resistant to the development of dyskinesia during chronic L-dopa treatment. Furthermore, in a nonhuman primate model of LID, lentiviral vectors expressing dominant negative forms of Ras-GRF1 caused a dramatic reversion of dyskinesia severity leaving intact the therapeutic effect of L-dopa. These data reveal the central role of Ras-GRF1 in governing striatal adaptations to dopamine replacement therapy and validate a viable treatment for LID based on intracellular signaling modulation.

Dopamine‐dependent motor learning: Insight into levodopa's long‐duration response

Dopamine (DA) is critical for motor performance, motor learning, and corticostriatal plasticity. The relationship between motor performance and learning, and the role of DA in the mediation of them, however, remain unclear. To examine this question, we took advantage of PITx3-deficient mice (aphakia mice), in which DA in the dorsal striatum is reduced by 90%. PITx3-deficient mice do not display obvious motor deficits in their home cage, but are impaired in motor tasks that require new motor skills. We used the accelerating rotarod as a motor learning task. We show that the deficiency in motor skill learning in PITx3(-/-) is dramatic and can be rescued with levodopa treatment. In addition, cessation of levodopa treatment after acquisition of the motor skill does not result in an immediate drop in performance. Instead, there is a gradual decline of performance that lasts for a few days, which is not related to levodopa pharmacokinetics. We show that this gradual decline is dependent on the retesting experience. This observation resembles the long-duration response to levodopa therapy in its slow buildup of improvement after the initiation of therapy and gradual degradation. We hypothesize that motor learning may play a significant, underappreciated role in the symptomatology of Parkinson disease as well as in the therapeutic effects of levodopa. We suggest that the important, yet enigmatic long-duration response to chronic levodopa treatment is a manifestation of rescued motor learning.

Current and Future Therapeutic Strategies for Parkinsons Disease

The heterogeneity of symptoms and disease progression observed in synucleinopathies, of which Parkinson's disease (PD) is the most common representative, poses large problems for its treatment and for the discovery of novel therapeutics. The molecular basis for pathology is currently unclear, both in familial and in sporadic cases. While the therapeutic effects of L-DOPA and dopamine receptor agonists are still the gold standards for symptomatic treatment in PD, the development of neuroprotective and/or neurorestorative treatments for these disorders faces significant challenges due to the poor knowledge of the putative targets involved. Recent experimental evidence strongly suggests a central role for neurotoxic alpha-synuclein oligomeric species in neurodegeneration. The events leading to protein oligomerization, as well as the oligomeric species themselves, are likely amenable to modulation by small molecules, which are beginning to emerge in high throughput compound screens in a variety of model organisms. The therapeutic potential of small molecule modulators of oligomer formation demands further exploration and validation in cellular and animal disease models in order to accelerate human drug development.

Susceptibility genes for restless legs syndrome are not associated with Parkinson disease

Restless legs syndrome (RLS) is a neurologic condition characterized by a distressing urge to move the legs, usually accompanied by an uncomfortable sensation described as a crawling, muscle ache, or tension. It is usually brought on by rest, worse in the evening or night and partially or totally relieved by movement. RLS is a common disorder with a prevalence of 1.2–15% depending on the population.1 Although the pathophysiology of RLS remains largely unknown, the worsening of symptoms later in the day and the therapeutic effects of levodopa and dopamine agonists support a hypothesis for dysfunction in the dopamine system.2 Parkinson disease (PD) is associated with progressive dopaminergic neuronal loss, for which dopamine agonists are typically prescribed as the first course of treatment. PD is characterized by bradykinesia, resting tremor, muscle rigidity, and postural instability3; it affects >1% of the population aged >55 years and is the most common cause of parkinsonism.4 Although still controversial, several studies have indicated a higher prevalence of RLS in …

Drug Targeting of α-Synuclein Oligomerization in Synucleinopathies

The heterogeneity of symptoms and disease progression observed in synucleinopathies, of which Parkinson's disease (PD) is the most common representative, poses large problems for the discovery of novel therapeutics. The molecular basis for pathology is currently unclear, both in familial and in sporadic cases. While the therapeutic effects of L-DOPA and dopamine receptor agonists constitute good options for symptomatic treatment in PD, the development of neuroprotective and/or neurorestorative treatments for PD and other synucleinopathies faces significant challenges due to the poor knowledge of the putative targets. Recent experimental evidence strongly suggests a central role for neurotoxic α-synuclein oligomeric species in neurodegeneration. The events leading to protein oligomerization, as well as the oligomeric species themselves, are likely amenable to modulation by small molecules, which are beginning to emerge in high throughput compound screens in a variety of model organisms. The therapeutic potential of small molecule modulators of oligomer formation demands further exploration and validation in cellular and animal disease models in order to accelerate human drug development.

Clinical Observation on Acupuncture Treatment of Parkinson’s Syndrome

Objective: To explore if the therapeutic effect can be enhanced, the dose of levodopa-like medications can be decreased and the complications can be reduced by acupuncture treatment in the patients with Parkinson’s disease (PD) who took levodopa-like medications for a long time.Methods: thirty cases of the patients, most of whom were noticed with the decreased therapeutic effect and drug-induced complications, were treated by puncturing Shuigou (GV 26) and Baihui (GV 20), by reduction of Madopa dose, and the patients’ conditions and complications were evaluated six months later.Results: After treatments for six months, the physiological functions were improved and the dose of Madopa was reduced and the total effective rate was 66.7%.Conclusion: After acupuncture treatments in PD patients, the therapeutic effects of levodopa were enhanced, with its dose and complications reduced.

Análise acústica da prosódia em mulheres com doença de Parkinson: efeito da Levodopa

Untreated Parkinson's disease (PD) patients display speech abnormalities characterized by narrow range of fundamental frequency (Fo) variation and higher amplitude. The role of dopaminergic systems in the pathogenesis of these changes as well as the therapeutic effect of L-dopa have not been clearly determined. The aim of this study is to assess the effect of L-dopa on the prosodic features of the speech of female PD patients. We have studied 8 PD female patients (63.5 +/- 6.8 years). The PD patients (H-Y stage 2, seven subjects; stage 2.5, four patients; stage 1, one patient) were examined when off and on. The fundamental frequency, intensity and duration of five affirmative sentences were analysed with the software WinPitch 1.8 (Philippe Martin). The analysed Fo parameters were: usual Fo (Fo us), maximal Fo (Fo max), minimal Fo (Fo min), Fo max of the prenuclear tonic (Fo max PNT), Fo min of the prenuclear tonic (Fo min PNT), Fo max of the nuclear tonic (Fo max NT), Fo min of the nuclear tonic (Fo min TN), velocity of melodic variation of the PNT (VPNT), velocity of melodic variation of the NT (VNT), amplitude of melodic variation of the PNT (APNT), and amplitude of melodic variation of the NT (ANT). Duration of the statement (D), duration of the PNT (DPNT), duration of the NT (DNT) and number of syllables per second (NSS) were the duration parameters investigated. The following intensity variables were studied: mean intensity (MI), maximal intensity (I max), minimal intensity (I min), intensity of the PNT (IPNT) and intensity of the NT (INT). Differences were statistically significant if p<0.05. When on, PD patients had significantly higher Fo max PNT (201.9 +/- 27.5 Hz), higher APNT (22.1 +/- 18.7 Hz), and smaller MI (32 +/- 6.2 dB) in comparison with off period (respectively: 168.5 +/- 83.5 Hz, 20.4 +/- 12.1 Hz, 32.7 +/- 5.6 dB). Our findings show that L-dopa replacement therapy slightly improves the Fo range and the intensity of speech of Brazilian female PD patients. These results suggest that non-dopaminergic systems are probably involved in the pathogenesis of prosody changes in PD. They also indicate that therapies other than dopaminergic agents are warranted to treat speech abnormalities in PD.

L-DOPA-derived extracellular dopamine in the striatum with dopaminergic denervation: role of serotonergic neurons in l-DOPA metabolism

In order to determine the state of dopamine (DA) derived from exogenously administered l-3,4-dihydroxyphenylalanine (l-DOPA) in the striatum of Parkinson's disease, we have applied an in vivo brain microdialysis method to rats with dopaminergic denervation with 6-hydroxydopamine (6-OHDA), the rat model of Parkinson's disease, and measured extracellular DA levels in the striatum after l-DOPA administration. We obtained the following results: (1) Inhibitory effect of the potent D2 agonist quinpirole on l-DOPA-derived extracellular DA was not detected in the denervated striatum; (2) reserpine pretreatment greatly reduced l-DOPA-derived extracellular DA; (3) additional serotonergic denervation to rats with dopaminergic denervation induced a significant reduction in l-DOPA-derived extracellular DA; and (4) activation of 5-hydroxytryptamine (serotonin) (5-HT)1A receptors attenuated an increase in l-DOPA-derived extracellular DA. These results suggest that the conversion of exogenous l-DOPA to DA and the storage and release of converted DA occur in serotonergic nerve terminals when dopaminergic neurons are denervated. It is possible that serotonergic neurons play a critical role in the therapeutic effect of l-DOPA in Parkinson's disease.

Interactions between drugs and vitamins at advanced age.

Drug consumption increases at advanced age due to increased morbidity. At the same time the state of repletion is reduced for several vitamins. Physiological and kinetic alterations in the elderly are reviewed in order to analyse possible interrelations between these two phenomena. At high age the status of all vitamins is compromised by reduced food intake. Decreased active intestinal transport and an increased propensity for atrophic gastritis may reduce the absorption of vitamins A, B1, folate and B12. Decreased exposure to sunlight and reduced cutaneous synthesis impair the vitamin D status. Studies on the state of vitamin repletion in hospital patients indicate a specific response of vitamins A, B1, B6 and C to drug administration at advanced age. Reduced food intake in the elderly is further compromised by drugs that impair appetite and absorption. Anticonvulsives and other drugs that induce hepatic microsomal enzymes accelerate vitamin D metabolism and aggravate post-menopausal osteoporosis. Acid inhibiting agents increase achlorhydria and reduce vitamin B12 absorption. Renal clearance of acidic drugs such as acetylsalicylic acid and barbituric acid, which is impaired at high age, is further reduced by high doses of vitamin C. Vitamin B6 reduces the therapeutic effect of L-dopa. When recognised, the negative effects of drug-vitamin interactions can be compensated by adequate vitamin supplementation and by adaptation of drug dosing.

Perspectives in the treatment of Parkinson's disease: COMT inhibitors open up new treatment strategies.

Catechol O-methyltransferase (COMT) inhibition has been proposed as a means to increase levodopa bioavailability in patients with Parkinson's disease, which may be useful in reducing the total dose of levodopa, diminishing its frequency of administration and, more importantly, improving fluctuations in the response to each individual dose of levodopa, which usually develop after chronic treatment. Entacapone is a potent, selective peripheral catechol O-methyltransferase inhibitor which effectively inhibits the O-methylation of levodopa, thus increasing its central bioavailability and potentiating its behavioral effects. In clinical trials in patients with Parkinson's disease, entacapone has prolonged and improved the therapeutic effect of levodopa combined with a dopa decarboxylase inhibitor. The new drug has increased the "on" time duration, decreased the "off" time duration and has reduced the total dose requirements of levodopa. Entacapone has shown optimal tolerability at the currently recommended doses, with the added benefit of a lower required dose of levodopa. This, in turn, improves the tolerability of levodopa and thus the overall tolerability of the treatment of advanced Parkinson's disease.

Clinical Potential of Catechol-O-Methyltransferase (COMT) Inhibitors as Adjuvants in Parkinsonʼs Disease

A series of new and selective catechol-O-methyltransferase (COMT) inhibitors have been developed. Entacapone, nitecapone and to1capone are nitrocatechol- type agents that are potent COMT inhibitors in vitro and are active in vivo after oral administration. CGP 28014 is a pyridine derivative that is active only in vivo.In animal studies, these compounds inhibit effectively the O-methylation of levodopa, thus improving its bioavailability and brain penetration, and potentiating its behavioural effects. Entacapone and nitecapone have mainly peripheral effects, whereas to1capone and CGP 280 14 inhibit O-methylation also in the brain. In human volunteers, entacapone, nitecapone and tolcapone inhibit dose-dependently COMT activity of erythrocytes. COMT inhibitors also decrease the levels of COMT-dependent metabolites of adrenaline (epinephrine) and noradrenaline (norepinephrine) in plasma.Entacapone, to1capone and CGP 28014 improve the bioavailability of levodopa and inhibit the formation of 3-0-methyldopa in human volunteers. In initial clinical studies in patients with Parkinson's disease, both entacapone and tolcapone potentiated and prolonged the therapeutic effects of levodopa.

Levodopa, with or without selegiline, and bromocriptine similarly reduced disability in patients with Parkinson disease

Source Citation Parkinson's Disease Research Group in the United Kingdom. Comparisons of therapeutic effects of levodopa, levodopa and selegiline, and bromocriptine in patients with early, mild Par...

The effects of L-DOPA on regional cerebral blood flow and oxygen metabolism in patients with Parkinson's disease.

Studies performed on 18 patients with Parkinson's disease and 6 control subjects have shown that acute administration of L-DOPA in clinically effective doses gives rise to a diffuse increase in regional cerebral blood flow without accompanying stimulation of regional oxygen utilization. The data suggest that this rise in rCBF is caused by vasodilatation due to a direct action of the drug on the cerebral blood vessels. The effect of L-DOPA on rCBF did not correlate with the degree of clinical improvement seen in each patient after treatment. The therapeutic effect of L-DOPA in the brain was not reflected in any change of regional cerebral oxygen utilization as measured by our technique. We suggest that the pharmacological actions of L-DOPA in the brain take place on at least two different levels.

Antagonism of KW-5338 (domperidone) against emesis and depression of intestinal motility induced by L-DOPA.

KW-5338 (domperidone), a new dopamine antagonist, is considered to be an agent to cross the blood-brain barrier with difficulty. The antagonistic activities of KW-5338 against L-DOPA were investigated, KW-5338 showed a strong anti-emetic action against L-DOPA induced emesis in beagle dogs (ED50=0.056 mg/kg (p.o.)) and restored the L-DOPA induced depression of intestinal motility to some extent, while it did not antagonize anti-tremorine activities of L-DOPA and trihexyphenidyl in mice. These results suggest that KW-5338 prevents side effects of L-DOPA such as nausea, vomiting and constipation, without reduction in therapeutic effects of L-DOPA in Parkinson's disease.

Plasma DOPA and growth hormone in parkinsonism: oscillations in symptoms.

In 19 patients with Parkinson disease, we studied the relationship of the therapeutic effect of levodopa, or dyskinesia, to the plasma content of DOPA and growth hormone (GH). Those with stable responses to levodopa, individually or as a group, showed stable and lower plasma DOPA levels than those with unstable symptomatic responses. These results show that stable and oscillating clinical responses in Parkinson disease parallel plasma DOPA levels, suggesting that there are different mechanisms in peripheral levodopa metabolism and that extracerebral mechanisms are important in regulating the availability of levodopa to the brain. Plasma GH did not differ in the two groups, suggesting that the secretion of GH is independent of the effects of levodopa in parkinsonism.

THE EFFECT OF CHLORPROMAZINE ON CATECHOLAMINE CONTENTS IN RAT BRAINS

The effect of chlorpromazine on the contents of dopamine in rat's brains has been studied in order to clarify the cause of the chlorpromazine-induced Parkinsonism. A significant reduction of the contents of dopamine and also noradrenaline in rat's brains was noted one hour after a single i. p. injection of chlorpromazine. The significance of this result was discussed in connection with the therapeutic effect of L-dopa on the pharmacological Parkinsonism.

Psychic Effects in Patients Treated With Levodopa

To the Editor.— The letter of Drs. Tobias and Merlis ( 211 :1857,1970) reported their experience of the aggravation of psychiatric symptoms following the administration of levodopa to schizophrenic patients suffering from drug-induced parkinsonism, and the appearance of psychiatric symptoms in patients with Parkinson's disease. The production of psychotic and other mental symptoms in nonschizophrenic patients has been reported by others. 1-3 Bunney and coworkers 4 reported an apparent antidepressant action of levodopa but other authors have reported the appearance of severe depression in some patients. 3,5 A number of drugs and foods are reputed to antagonize the therapeutic effects of levodopa. They include monoamine oxidase inhibitors and psychic energizers, reserpine, phenothiazines, antiemetics, tranquillizers, and alpha methyldopa, 6 cheese, chocolate, and red wine, 7 butyrophenones, and pyridoxine. 8 Because of the lack of information on psychic features given in most articles, and because the warnings against certain other drugs appears to be