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PubMed2002

Regulation of apical transporter of L-DOPA in human intestinal Caco-2 cells.

The present study examined the nature of the apical inward L-3,4-dihydroxyphenylalanine (L-DOPA) transporter in human intestinal epithelial Caco-2 cells, and whether protein kinases modulate the activity of this transporter. The apical inward transfer of L-DOPA was promoted through an energy-dependent and sodium-insensitive transporter (Km=33 microM; Vmax=2932 pmol/mg protein/6 min). This transporter was insensitive to N-(methylamino)-isobutyric acid, but competitively inhibited by 2-aminobicyclo(2,2,1)-heptane-2-carboxylic acid (BCH; IC50=83 microM). The organic cation inhibitor decynium 24 failed to affect the accumulation of L-DOPA, whereas the organic anion inhibitor 4,4'-diisothiocynatostilbene-2,2'-disulphonic acid (DIDS) competitively inhibited L-DOPA uptake (IC50=83 microM). However, the apical-to-basal and basal-to-apical transepithelial transport and the cell accumulation of [3H]-PAH was close to that of [14C]-sorbitol and insensitive to DIDS (300 microM). Modulators of protein kinase A (PKA) [cyclic adenosine monophosphate (cAMP), forskolin, H-89 and cholera toxin], protein kinase G (PKG) [cyclic guanosine monophosphate (GMP), zaprinast, LY 83583 and sodium nitroprusside] and protein kinase C (PKC) (phorbol 12,13-dibutirate and chelerythrine) failed to affect the accumulation of L-DOPA. The Ca2+/calmodulin inhibitors calmidazolium and trifluoperazine inhibited L-DOPA uptake (IC50s of 53 and 252 microM, respectively), but the rise of intracellular Ca2+ by A23187 (1 microM) and thapsigargin (1 microM) played no role on L-DOPA uptake. It is concluded that Caco-2 cells take up L-DOPA over the apical cell border through the sodium-independent and pH-sensitive L-type amino acid transporter.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2000

Alterations in preproenkephalin and adenosine-2a receptor mRNA, but not preprotachykinin mRNA correlate with occurrence of dyskinesia in normal monkeys chronically treated with L-DOPA.

Chronic treatment with L-DOPA induces dyskinesia in patients with Parkinson's disease (PD) and 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-treated monkeys, but is not thought to do so in normal humans or primates. However, we have shown that chronic oral high dose L-DOPA administration, with the peripheral decarboxylase inhibitor, carbidopa and with or without the peripherally acting catechol-O-methyl transferase (COMT) inhibitor, entacapone, to normal macaque monkeys for 13 weeks induced dyskinesia in a proportion of animals. In the present study, in situ hybridization histochemistry was used to investigate the effect of chronic L-DOPA administration on the activity of the direct and indirect striatal output pathways by measuring striatal preprotachykinin (PPT), preproenkephalin-A (PPE-A) and adenosine-2a (A2a) receptor gene expression in these monkeys. Overall there was no significant difference in striatal PPT, PPE-A and A2a receptor mRNA levels between normal animals and all L-DOPA (plus carbidopa and/or entacapone)-treated animals irrespective of whether or not dyskinesia occurred. However, when the level of PPE-A and A2a receptor mRNA was analysed in eight monkeys displaying marked dyskinesias as a result of L-DOPA (plus carbidopa with or without entacapone) treatment, there was a significant increase in PPE-A and A2a receptor mRNA message levels in the striatum compared with animals receiving identical treatment, but displaying few or no involuntary movements, and compared with normal controls. There was no difference in striatal PPT mRNA levels in monkeys exhibiting severe dyskinesia compared with those showing little or no dyskinesia after L-DOPA treatment or to normal controls. These results suggest that prolonged L-DOPA treatment alone has no consistent effect on either the direct or indirect pathways, as judged by striatal PPT, PPE-A or A2a receptor mRNA levels in normal monkeys. However, in monkeys exhibiting marked dyskinesia resulting from chronic L-DOPA treatment, abnormal activity is detected in the indirect striato-pallidal output pathway, as judged by striatal PPE-A and A2a receptor mRNA levels, indicating an imbalance between the direct and indirect striatal pathway which may explain the emergence of dyskinesia in these animals.

Animals↗
PubMed2001

GDNF reverses priming for dyskinesia in MPTP-treated, L-DOPA-primed common marmosets.

Parkinson's disease (PD) is associated with a progressive loss of dopamine neurons in the substantia nigra and degeneration of dopaminergic terminals in the striatum. Although L-DOPA treatment provides the most effective symptomatic relief for PD it does not prevent the progression of the disease, and its long-term use is associated with the onset of dyskinesia. In rodent and primate studies, glial cell line-derived neurotrophic factor (GDNF) may prevent 6-OHDA- or MPTP-induced nigral degeneration and so may be beneficial in the treatment of PD. In this study, we investigate the effects of GDNF on the expression of dyskinesia in L-DOPA-primed MPTP-treated common marmosets, exhibiting dyskinesia. GDNF or saline was administered by two intraventricular injections, 4 weeks apart, to MPTP-treated, L-DOPA-treated common marmosets primed to exhibit dyskinesia. Prior to GDNF or saline administration, all animals displayed marked dyskinesia when treated with L-DOPA. GDNF administration produced a significant improvement in motor disability and, following the second injection of GDNF, a significant improvement in the locomotor activity was observed. Following the administration of L-DOPA there was a greater reversal of disability and a reduction in the intensity of L-DOPA-induced dyskinesia in GDNF-treated animals compared to saline-treated controls. However, there was no significant difference in L-DOPA's ability to increase locomotor activity between GDNF-treated and saline-treated animals. GDNF treatment caused a significant increase in the number of tyrosine hydroxylase-positive neurons in the substantia nigra, but no change in [(3)H]mazindol binding to dopamine terminals was found in the striatum of GDNF-treated animals compared to saline-treated controls. In GDNF-treated animals a small but significant reduction in enkephalin mRNA was observed in the caudate nucleus but not in the putamen or the nucleus accumbens. Substance P mRNA expression was equally reduced in the caudate nucleus and the putamen of the GDNF-treated animals but not in the nucleus accumbens. Intraventricular administration of GDNF improved MPTP-induced disability and reversed dopamine cell loss in the substantia nigra. GDNF also diminished L-DOPA-induced dyskinesia, which may relate to its ability to partly restore nigral dopaminergic transmission or to modify the activity of striatal output pathways.

Animals↗
PubMed1996

L-DOPA up-regulates glutathione and protects mesencephalic cultures against oxidative stress.

Incubation with L-DOPA induced a rise in GSH level in cultures of fetal rat mesencephalon, mouse neuroblastoma (Neuro-2A), human neuroblastoma (SK-N-MC), pig kidney epithelial cells (LLC-PK1), and glia from newborn rat brain, but not C6 glioma cells or neuronal cultures (no glia) from the mesencephalon. The pure neuronal cultures were destroyed by incubation with L-DOPA; added ascorbic acid or superoxide dismutase protected the cells. Washout of L-DOPA after 48 h amplified the rise in GSH content in mixed cultures (neurons plus glia). Examination of structure-activity relationships for elevating GSH levels in responsive cell types revealed that autooxidizable compounds (alpha-methyl-DOPA, dopamine, apomorphine, catechol, and hydroquinone) behaved similarly to L-DOPA, whereas structural analogues that cannot undergo autooxidation (3-O-methyl-DOPA, tyrosine, 2,4-dihydroxyphenylalanine, and resorcinol) failed to elevate GSH levels. Therefore, up-regulation of GSH appears to be a response to a mild oxidative stress. When mixed mesencephalic cultures were exposed to a strong oxidant stress by incubation with tert-butyl hydroperoxide, a loss in viability was seen. Cultures pretreated with L-DOPA or hydroquinone were protected from loss of viability. However, when cultures were pretreated with both L-DOPA and ascorbate, which prevents the rise in GSH level, protection was lost, in accord with the failure to up-regulate GSH. These results show that the up-regulation of cellular GSH evoked by autooxidizable agents is associated with significant protection of cells. Glia play an essential role in the response of mesencephalic cell cultures. An ability to up-regulate GSH may serve a protective role in vivo.

Animals↗
PubMed1996

Regulation of L-DOPA biosynthesis by site-specific phosphorylation of tyrosine hydroxylase in AtT-20 cells expressing wild-type and serine 40-substituted enzyme.

De novo L-DOPA biosynthesis was studied in stably transfected AtT-20 cells expressing wild-type- or [Leu40]-recombinant tyrosine hydroxylase (rTH). Basal rates of DOPA accumulation were much higher by cells expressing rTH in which Leu was substituted for Ser4O (S40L-rTH) than by those expressing wild-type rTH (WT-rTH). Treatment of WT-rTH cells with forskolin produced an increase in DOPA accumulation and a concomitant increase in WT-rTH phospho-Ser40 content, whereas DOPA production by cells expressing S40L-rTH was entirely unaffected by forskolin. After forskolin treatment of 32Pi-prelabeled cells, WT-rTH was phosphorylated at Ser8, Ser19, Ser31, and Ser40, whereas 32P incorporation into S40L-rTH was restricted to Ser8, Ser19, and Ser31. Relatively prolonged treatment of AtT-20 cells expressing WT-rTH with either a depolarizing agent (elevated potassium) or a phosphatase inhibitor (okadaic acid) increased DOPA production and increased the phosphorylation state of Ser40; but, unlike forskolin, these treatments also increased DOPA production by cells expressing S40L-rTH. Thus, the present studies demonstrate that Ser40 phosphorylation mediates forskolin-induced increases in DOPA biosynthesis directly but that mechanisms other than Ser40 phosphorylation can mediate the increases in DOPA biosynthesis produced either by depolarization or by protein phosphatase inhibition.

Animals↗
PubMed1990

Prolactin release and milk removal induced by suckling and milking in lactating ewes is prevented by L-dopa treatment.

The effect of L-DOPA on milk removal and on prolactin release during suckling or milking was studied in lactating ewes. Various doses of L-DOPA (25, 50, 100 and 200 mg per animal) were injected iv 30 min before the suckling or milking period. Control ewes were injected with 0.9% NaCl solution only. Milking induced a significant long-lasting release of prolactin. An inhibition of milk removal was obtained with the dose of 200 mg of L-DOPA. An inhibition of prolactin secretion was observed related to the dose of drug administered. The inhibitory effect of 200 mg of L-DOPA on the secretion of prolactin after milking lasted for about 120 min, and thereafter a significant increase in serum prolactin level occurred. This increase in serum prolactin was not due to a "rebound" effect of L-DOPA, since the milking stimulus had to be present to induce the delayed increase in prolactin. Doses of 25 or 50 mg of L-DOPA prevented the surge of prolactin observed immediately after milking, but a long-lasting release of prolactin was obtained thereafter. The inhibitory effect of L-DOPA on prolactin release could be overridden by the suckling or milking stimuli according to the dose administered. The suckling stimulus was more effective than milking in overriding the inhibitory effect of the low dose of L-DOPA. The results indicate that milk removal and prolactin release induced by milking or suckling in lactating ewes is inhibited by an increase in monoamines at the hypothalamic-hypophyseal level.

Animals↗
PubMed1971

Decrease in liver aromatic L-amino-acid decarboxylase produced by chronic administration of L-dopa.

L-Dopa, an intermediate in the biosynthesis of catecholamines, is now widely used in the treatment of parkinsonism. A number of clinical observations suggested that L-dopa may induce changes in its own metabolism during the course of therapy. In the present study, it was found that when L-dopa was administered to rats, the activity of liver aromatic L-amino-acid decarboxylase, the enzyme which catalyzes the conversion of dopa to dopamine, was reduced by as much as 50%. There were no corresponding changes in enzyme activity in heart, adrenals, kidneys, and brain. Decarboxylase activity in the liver continued to decrease for at least 5 days after the last dose of L-dopa. The reduction of enzyme activity in the liver occurred when L-dopa was administered either subcutaneously or orally at doses comparable to those used clinically. In vitro and in vivo experiments indicated that this action of L-dopa is not due to some effect on the cofactor, pyridoxal phosphate. Immunological evidence was obtained that enzyme protein is reduced in the same proportion as enzyme activity. By a reduction of decarboxylase activity in liver without any affect on the enzyme in brain, more L-dopa should be made available to the brain for decarboxylation to dopamine. These findings may explain the clinical observations that the therapeutic efficacy of the drug increases with continued administration.

Administration, Oral↗
PubMed1980

Maintenance by L-DOPA treatment of estrous cycles and LH response to estrogen in aging female rats.

Nineteen, non-cycling female rats, 13-15 months of age, were fed 125 mg L-DOPA/15 g feed daily, and nineteen control rats of the same age were provided feed without L-DOPA. Sixteen of the L-DOPA fed rats each demonstrated 1-7 (average = 3) vaginal estrous cycles during the 75-day period of treatment, whereas no cycles were observed in the untreated controls. All animals were then ovariectomized and the post-castration rise in LH was monitored. Four weeks after ovariectomy, serum LH levels in the L-DOPA treated old female rats were significantly higher than in the non-treated old female rats. A single injection of 20 micrograms of estradiol benzoate (EB) significantly lowered serum LH in the L-DOPA treated rats, but no effect was observed in the non-treated controls. A second injection of EB three days later produced a significantly greater LH surge in the old rats given L-DOPA than in the non-L-DOPA treated controls. These results indicate that prolonged L-DOPA administration can partially prevent the decline in function of the hypothalamo-pituitary-ovarian system in aging female rats.

Aging↗
PubMed2004

The fate of perfluoro-tagged metabolites of L-DOPA in mice brains.

A novel compound for use in magnetic resonance (MR) imaging was created by covalently bonding multiple 19F atom tags to L-DOPA. Tagging L-DOPA permits bypassing the rate-limiting factor in the biosynthesis of dopamine (DA), the conversion of tyrosine into L-DOPA. The next step in the biosynthetic pathway, the removal of the carboxyl group on the molecule by the enzyme L-aromatic acid decarboxylase (AADC), happens rapidly after L-DOPA is taken up into neurons. In order to be useful as a tool in MR imaging, the novel compound and/ or its perfluoro-tagged metabolites must accumulate in vesicles in dopaminergic neurons. We administered L-DOPA with a nine 19F atom tag (250 mg/kg) to mice pups, waited 1.5 or 3 hr, and used high pressure liquid chromatography (HPLC) to examine neural tissue samples for tagged L-DOPA and tagged DA. The isomer of L-DOPA with the tag bonded at the 5 position yielded the highest conversion to tagged DA at 1.5 hr after an i.p. injection. This study provides the first direct evidence that L-DOPA, tagged with nine fluorine atoms, is taken up into mammalian brain dopaminergic neurons where it is converted to perfluro-tagged DA. The use of these tagged compounds may make it feasible to investigate the uptake and conversion of important neurotransmitter in vivo with fluorine imaging.

Animals↗
PubMed1991

D1/D2 dopamine receptor stimulation by L-dopa. A [14C]-2-deoxyglucose autoradiographic study.

In rats with unilateral 6-hydroxydopamine substantia nigra lesions, the effects of selective D1 and D2 dopamine receptor antagonists on L-DOPA-induced rotation and regional cerebral glucose utilization (RCGU) changes were examined. Contralateral rotation induced by L-DOPA (25 mg/kg) was effectively blocked by D1 (SCH 23390, 1.0 mg/kg) and D2 (eticlopride, 2.0 mg/kg) antagonists, in combination, but not by either antagonist alone. This suggests that in the dopamine-depleted rat, L-DOPA administration results in the stimulation of both D1 and D2 receptor systems, each capable of independently eliciting a full motor response, L-DOPA altered RCGU in the following brain regions ipsilateral to the lesion: entopeduncular nucleus (EP, + 105%), substantia nigra pars reticulata (SNr, + 121%), subthalamic nucleus (STN, + 32%), deep layers of the superior colliculus (DLSC, + 35%), and lateral habenula nucleus (LHN, -52%). The effects in the EP and SNr were blocked completely by D1 antagonist pretreatment but only partially attenuated by D2 antagonist pretreatment, indicating the critical dependence of these changes on D1 stimulation. In contrast, combined D1 and D2 antagonist pretreatment, but neither drug alone, blocked the L-DOPA-induced increases in the STN and DLSC. The effects of L-DOPA in the LHN were attenuated by either SCH 23390 or eticlopride, and blocked completely by the antagonist combination. These results provide evidence that dopamine formed following the decarboxylation of L-DOPA stimulates both D1 and D2 receptors in vivo and that stimulation of each receptor contributes uniquely to its physiological effects. Neural mechanisms of action of L-DOPA are discussed in the context of these findings.

Animals↗
PubMed1998

Variability in spatiotemporal gait characteristics over the course of the L-dopa cycle in people with advanced Parkinson disease .

BACKGROUND AND PURPOSE: Understanding the nature and extent of fluctuations in spatial and temporal variables of gait (eg, speed, stride length [SL], stride time [ST]) over the course of the levodopa (L-dopa) cycle of individuals with advanced Parkinson disease (PD) is important in order to assess patients and examine the effectiveness of interventions. The purpose of this study was to determine whether gait variables are sufficiently stable to be used as outcome measures in a clinical trial involving patients with advanced PD. SUBJECTS: Five volunteers (3 male, 2 female; mean age=67.8 years; Hoehn and Yahr stages 3-4) with idiopathic PD of a mean duration of 15.0 years participated. METHODS: Gait speed, SL, and ST were measured as the subjects walked 7.2 m at self-selected speeds. To evaluate the full "on-off" sequence of the L-dopa response, this analysis was repeated 11 times, at intervals of 10% of the L-dopa cycle. Each subject was analyzed on 3 separate days, with approximately 1 month between tests. Two-way repeated-measures analyses of covariance, with 2 within-subject factors (percentage of L-dopa cycle and day) and 1 covariate (height), were applied, and coefficients of variation were calculated to determine the extent of change in speed, SL, and ST over the L-dopa cycle and over the 3 days. RESULTS: The subjects' overall mean gait speed was 70.39 cm/s, representing 55.4% of the age-related normative values. There were no effects of percentage of the L-dopa cycle or day or of the interaction of percentage of the L-dopa cycle and day on speed, SL, and ST. The coefficients of variation for speed and SL were consistently higher than the normative values, ranging from 13.5% to 23.8% and from 13.9% to 23.3% at 20% of the L-dopa cycle, respectively. CONCLUSION AND DISCUSSION: When interpreting spatiotemporal measurements of gait of patients with advanced PD, fluctuations can be extensive and may not follow a predictable pattern.

Aged↗
PubMedDate not supplied

Intravenous l-DOPA plus carbidopa in depressed patients: average evoked response, learning, and behavioral changes.

The peripheral decarboxylase inhibitor carbidopa (L-alphamethyl-dopa-hydrazine) allowed safe intravenous administration of L-DOPA in amounts sufficient to alter cortical average evoked response (AER) and learning function in 13 depressed patients. The apparently rapid conversion of L-DOPA to dopamine, as reported from studies in animals, is consistent with the 20-30 min onset of effects seen in our study. Unipolar and bipolar depressed patients responded differently to the alterations in brain biogenic amines and also to the nonspecific stress of the experiment. Intravenous L-DOPA given acutely had effects on the AER that were similar to those documented with oral dopa given chronically--an augmentation of amplitude--intensity slopes in unipolar patients and a relative reduction of slopes in bipolar patients. In contrast, intravenous L-DOPA did not enhance verbal learning as did chronic oral treatment, but rather was associated with reduced learning compared with placebo infusions. Different neurochemical changes following L-DOPA given in single intravenous doses may be responsible for the different learning and behavioral changes form those found previously with oral dopa administered chronically.

Administration, Oral↗
PubMed1986

Does short-term fasting desensitize human somatotrophs to oral L-dopa stimulation?

To investigate whether short-term fasting influences hormone release from human somatotrophs and lactotrophs, two oral L-dopa tests, using 0.5 g L-dopa, were carried out in seven normal subjects. The first test was performed after an overnight fast (8 h), the second after an additional 48 h of total food withdrawal. Basal blood glucose declined by 21 +/- 2% (mean +/- SEM) between the two tests (P less than 0.001). Free T3 in serum (FT3) fell by 32 +/- 4% (P less than 0.001). GH responsiveness to L-dopa--as reflected by the GH incremental area (ng/ml X min)--decreased from 588 +/- 162 to 24 +/- 240 (P less than 0.02). The latter response area did not even differ significantly from zero. Food deprivation failed to affect the lactotrophs, inasmuch as similar PRL decremental areas (ng/ml X min) were obtained in response to L-dopa before (704 +/- 165) and after (686 +/- 128) the prolonged fast. In order to prevent blood glucose from falling significantly during the period of food deprivation eight additional normal subjects were given 9 small oral doses of glucose (each dose 0.5 g/kg) at regular intervals between the two L-dopa tests. This resulted in similar FT3 concentrations before and after the prolonged fast. Furthermore, glucose supplementation restored normal GH responsiveness to L-dopa, as evidenced by similar GH incremental areas before and after the glucose fast. These results imply that short-term fasting desensitizes human somatotrophs to exogenous L-dopa. The finding that the decreased GH responsiveness returns to normal if a decline in FT3 is prevented by oral glucose supplementation, suggests that changes in FT3 might contribute to the abolished GH responsiveness to L-dopa in fasting.

Adult↗
PubMed1989

Plasma dihydroxyphenylalanine (DOPA) is independent of sympathetic activity in humans.

To clarify the origin of plasma DOPA (3,4-Dihydroxyphenylalanine), the relationship between plasma DOPA and acute or chronic changes in sympathetic activity has been studied. Plasma DOPA and noradrenaline (NA) concentrations were measured by reverse-phase high-performance liquid chromatography with electrochemical detection. Administration of clonidine to healthy men decreased plasma NE markedly compared to no drug. Plasma DOPA decreased slightly but significantly with time, but values were identical after clonidine compared to no drug. Baseline plasma NE concentrations were significantly reduced in diabetic patients with autonomic neuropathy compared to diabetics without neuropathy, whereas baseline plasma DOPA concentrations were similar in the three groups investigated: 6.55 (5.03-7.26, median [interquartile range], n = 8) nmol l-1 in diabetics with neuropathy, 7.41 (5.79-7.97, n = 8) nmol l-1 in diabetics without neuropathy, and 6.85 (5.58-7.36, n = 8) nmol l-1 in controls. No relationship was obtained between baseline values of plasma NE and plasma DOPA. Plasma DOPA did not change in the upright position, whereas plasma NE increased significantly. Our results indicate that plasma DOPA is not related to sympathetic activity and may be of non-neuronal origin.

Adult↗
PubMed1995

Altered basal release and depressor effect of L-DOPA in the nucleus tractus solitarii of spontaneously hypertensive rats.

1. L-DOPA as a probable neurotransmitter of baroreceptor afferents functions as a tonic to mediate cardiodepressor control in the nucleus tractus solitarii (NTS). We attempted to clarify further whether a transmitter-like L-DOPA system is altered in NTS of adult spontaneously hypertensive rats (SHR). 2. By microdialysis of left NTS area, the basal L-DOPA release was lower in SHR than in Wistar-Kyoto (WKY) rats. This release was partially inhibited by tetrodotoxin (TTX, 1 mu mol/L) to a similar degree in both strains. TTX-sensitive L-DOPA release was lower in SHR than in WKY. 3. L-DOPA (10-300 ng) and L-glutamate (3-100 ng) microinjected into left NTS produced dose-dependent hypotension and bradycardia. No difference of responses to L-glutamate was seen in either strain. However, depressor but not bradycardic responses to L-DOPA at higher doses were slightly greater in SHR than in WKY. 4. In caudal dorsomedial medulla including NTS, tyrosine hydroxylase activity was increased in SHR compared to WKY, while there was no difference in either strain of L-aromatic amino acid decarboxylase activity. 5. Impaired tonic neuronal activity to release L-DOPA in NTS may be involved in the maintenance of hypertension in SHR. An increase in sensitivity of a recognition site for L-DOPA seems to occur as a compensatory mechanism for impairment of the neuronal activity.

Animals↗
PubMed1995

Altered basal release and pressor effect of L-DOPA in the rostral ventrolateral medulla of spontaneously hypertensive rats.

1. Transmitter-like L-DOPA functions as a tonic to produce postsynaptic cardiopressor responses in the rostral ventrolateral medulla (RVLM) of rats. We attempted to clarify whether a transmitter-like L-DOPA system is altered in the RVLM of spontaneously hypertensive rats (SHR) to maintain the hypertension. 2. By microdialysis of left RVLM area, the basal L-DOPA release was higher in SHR than in Wistar-Kyoto (WKY) rats. This release was partially inhibited by tetrodotoxin (TTX, 1 mu mol/L) to a similar degree in both strains. TTX-sensitive L-DOPA release was higher in SHR than in WKY. 3. L-DOPA (10-600 ng) and L-glutamate (10-300 ng) microinjected into left RVLM produced dose-dependent hypertension and tachycardia. Pressor but not tachycardiac responses to L-DOPA at lower doses were slightly greater in SHR than in WKY, whereas no difference to L-glutamate was observed in either strain. 4. In RVLM regions, there was no difference of tyrosine hydroxylase activity in SHR or WKY; however, L-aromatic amino acid decarboxylase activity was lower in SHR than in WKY. 5. Enhanced presynaptic neuronal L-DOPA release, including a decrease in decarboxylation and sensitization of postsynaptic pressor sites to L-DOPA in RVLM, may be involved in the maintenance of hypertension in SHR.

Animals↗
PubMed2005

Adeno-associated virus-mediated gene transfer of human aromatic L-amino acid decarboxylase protects mixed striatal primary cultures from L-DOPA toxicity.

Although L-DOPA is the drug of choice for Parkinson's disease, prolonged L-DOPA therapy results in decreased drug effectiveness and the appearance of motor complications. This may be due in part to the progressive loss of the enzyme, aromatic L-amino acid decarboxylase (AADC). We have developed an adeno-associated virus vector (AAV-hAADC) that contains human AADC cDNA under the control of the cytomegalovirus promoter. Infusion of this vector into the striatum of parkinsonian rats and monkeys improves L-DOPA responsiveness by improving AADC-mediated conversion of L-DOPA to dopamine. This is now the basis of a proposed therapy for advanced Parkinson's disease. A key concern has been that over-production of dopamine in striatal neurons could cause dopamine toxicity. To investigate this possibility in a controlled system, mixed striatal primary rat neuronal cultures were prepared. Exposure of cultures to high concentrations of L-DOPA induced the following changes: cell death in nigral and striatal neurons, aggregation of neurofilaments and focal axonal swellings, abnormal expression of DARPP-32, and activation of astroglia and microglial cells. Transduction of cultures with AAV-hAADC resulted in efficient and sustained neuronal expression of the AADC protein and prevented all the L-DOPA-induced toxicities. The protective effects were due primarily to AADC-dependent conversion of L-DOPA to dopamine and an increase in induction of vesicular monoamine transporter resulting in dopamine storage in cultured cells. These results suggest a neuroprotective role for AADC gene transfer against L-DOPA toxicity.

Animals↗
PubMed1979

Reversal of DOPA-induced arousal in reserpine-treated rabbits and mice by histidine.

1 The behavioural effects induced by histidine were studied in two species. In rabbits, sedation was assessed by the presence of blepharospasm, loss of righting reflex, and loss of response to painful stimuli. In mice, sedation and arousal were assessed by changes in the locomotor activity, exploratory activity, and minimal electroshock seizure threshold.2 The administration of histidine to normal rabbits or mice, in doses of 800 mg/kg and 1000 mg/kg respectively, had no apparent effect on behaviour. Moreover, it did not affect the behavioural excitation induced by L-DOPA (100 mg/kg i.v. in rabbits and 750 mg/kg i.p. in mice) in these animals.3 The administration of histidine with or after L-DOPA in reserpine-treated rabbits (2.5 mg/kg i.v.) or mice (5 mg/kg, i.p.) produced sedation. This sedative effect was dose-dependent.4 The sedative effects induced by histidine after DOPA-induced arousal in reserpine-treated rabbits and mice were prevented by prior injection of the histamine H(1)-receptor blockers, chlorpheniramine (2.5 mg/kg) or diphenhydramine (5 mg/kg).5 Imipramine (7 to 10 mg/kg, i.v.)-induced arousal in reserpine-treated rabbits was also reversed by histidine infusion.6 The infusion of 5-hydroxytryptophan (100 mg/kg, i.v.) with L-DOPA, or of arginine (450 mg/kg, i.v.) with or after L-DOPA, or of histamine (100 mug/kg), i.v.) after L-DOPA, did not affect the DOPA-induced arousal in reserpine-treated rabbits.7 These findings indicate that histamine, formed centrally from exogenous histidine, and released in increased amounts at the synapses in reserpine-treated animals, possesses a central sedative effect. This effect may be sufficient to antagonize the behavioural excitation induced by high levels of catecholamines in the brain of these animals when aroused by L-DOPA administration.8 It is concluded that in addition to the other monoamines, histamine may also be implicated in the regulation of brain excitability.

Animals↗