Dose-related effects of continuous levodopa infusion in rats with unilateral lesions of the substantia nigra

Preclinical studies in rats have demonstrated markedly different effects of intermittent and continuous levodopa administration on many biochemical and functional parameters yet the dose regimens employed have not been fully evaluated. In this study, rats with unilateral 6-hydroxydopamine nigral lesions were administered levodopa (0–1200 mg/kg/day) and benserazide (25 mg/kg/day) subcutaneously via osmotic minipump and studied 20–22 h later for rotational behavior, striatal dopamine concentration, and regional cerebral glucose utilization (RCGU). Levodopa infusion at 100 mg/kg/day resulted in minimal rotation and minimal striatal dopamine replacement but did increase RCGU in the subthalamic nucleus and decrease RCGU in the lateral habenula, consistent with a selective inhibition of the striatopallidal GABAergic (indirect striatal output) pathway. Levodopa infusion at 100 mg/kg/day did not significantly increase RCGU in the entopeduncular nucleus (EP) and substantia nigra pars reticulata (SNr), as does the acute injection of levodopa (25–50 mg/kg), indicating that this levodopa dose elicits only part of the spectrum of metabolic effects elicited by acute levodopa injection. Higher doses of levodopa (400–1200 mg/kg/day) resulted in moderate rates of rotation, dose-dependent increases in striatal dopamine, and increased RCGU in the EP and SNr, consistent with activation of the striatonigral GABAergic (direct striatal output) pathway. In the EP and SNr, the two major output nuclei of the basal ganglia, levodopa infusion at 800 and 1200 mg/kg/day reproduced the metabolic effects elicited by acute injection of levodopa. These results demonstrate, for the first time, dose-dependent effects of levodopa on distinct populations of striatal output neurons which may be relevant to the pathogenesis of levodopa-induced dyskinesias in Parkinson's disease. The minimal dopamine replacement and partial functional effects elicited by levodopa infusion at 100 mg/kg/day indicate the need for caution in the interpretation of prior studies of continuous levodopa infusion which employed this dose.     

Coadministration of entacapone with levodopa attenuates the severity of dyskinesias in hemiparkinsonian rats.

Levodopa-induced dyskinesias (LIDs) have been associated with a sequence of events that includes pulsatile stimulation of dopamine receptors. The degree of nigrostriatal degeneration, the half-life of dopaminomimetic agents, and the dose of levodopa used to treat parkinsonian symptoms are factors directly correlated with the development of motor complications in Parkinson's disease patients. Long-acting agents producing continuous dopaminergic stimulation are less likely to prime for dyskinesia than short-acting drugs that produce pulsatile stimulation of dopamine receptors. Inhibition of the enzyme catechol-O-methyl transferase (COMT) by entacapone extends the half-life of levodopa and minimizes variability in plasma levodopa levels. The aim of the present study was to characterize the effect of the early administration of the COMT inhibitor entacapone in the recently described model of LIDs in rats with a nigrostriatal lesion induced by 6-hydroxydopamine (6-OHDA). Male Sprague-Dawley rats received a unilateral 6-OHDA administration in the nigrostriatal pathway. Animals were treated either with levodopa (6 mg/kg, twice at day, i.p.) plus entacapone (30 mg/kg per day, i.p.) or levodopa (6 mg/kg, twice at day, i.p.) plus vehicle for 22 consecutive days. Early administration of entacapone, in association with levodopa, induces a decrease in the severity of dyskinesia and delays their onset in hemiparkinsonian rats. All dyskinesia subtypes evaluated, such as axial, limb, and orofacial dyskinesias, have shown similar reductions. These results suggest that entacapone, by extending levodopa elimination half-life, might reduce its propensity to induce motor complications.     

Nicotine reduces established levodopa‐induced dyskinesias in a monkey model of Parkinson's disease

Although 3,4‐dihydroxyphenylalanine (levodopa) is the gold‐standard treatment for Parkinson's disease, it can lead to disabling dyskinesias. Previous work demonstrated that nicotine reduces levodopa‐induced dyskinesias (LIDs) in several parkinsonian animal models. The goal of this study was to determine whether the duration of nicotine administration affects its ability to reduce LIDs in levodopa‐primed and levadopa‐naíve monkeys and also to test whether tolerance develops to the beneficial effects of nicotine. Monkeys were injected with MPTP (1.9‐2.0 mg/kg subcutaneously) over 3 to 5 months until parkinsonism developed. Nicotine (300 μg/mL) was administered in drinking water (over 4–6 months) to levodopa‐primed or levodopa‐naíve monkeys, with levodopa/carbidopa (10/2.5 mg/kg) gavaged twice daily. One set of MPTP‐lesioned monkeys (n = 23) was first gavaged with levodopa and subsequently received nicotine 4 weeks later, when dyskinesias plateaued, or 8 weeks later, when dyskinesias were established. A 60% to 70% decrease in LIDs was observed after several weeks of nicotine treatment in both groups. A second set of monkeys (n = 26) received nicotine 8 or 2 weeks before levodopa. In the 8‐week nicotine pretreatment group, there was an immediate reduction in LIDs, which plateaued at 60% to 70%. In the 2‐week nicotine pretreatment group, there were initial small decreases in LIDs, which plateaued at 60% to 70% several weeks later. Thus, nicotine pretreatment and nicotine post‐treatment were similarly efficacious in reducing LIDs. The beneficial effect of nicotine persisted throughout the study (17–23 weeks). Nicotine did not worsen parkinsonism. These data suggest that nicotine treatment has potential as a successful antidyskinetic therapy for patients with Parkinson's disease. © 2013 International Parkinson and Movement Disorder Society     

Blockade of A2A receptors plus l-DOPA after nigrostriatal lesion results in GAD67 mRNA changes different from l-DOPA alone in the rat globus pallidus and substantia nigra reticulata

Studies in animal models of Parkinson's disease (PD) suggest the potential utility of adenosine A(2A) antagonists in the treatment of this disease. In the present study, unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats received chronic intermittent treatment with the adenosine A(2A) antagonist SCH58261 (5 mg/kg) plus l-DOPA (3 mg/kg) or l-DOPA (6 mg/kg) alone, at doses producing the same intensity of contralateral turning on first administration. Three days after discontinuation of treatments, GABA synthesizing enzyme glutamic acid decarboxylase (GAD67) mRNA was evaluated at cellular level in the globus pallidus (GP) and substantia nigra pars reticulata (SNr) by in situ hybridization. 6-OHDA lesion significantly increased GAD67 mRNA levels in both the GP and SNr ipsilateral to the lesion. Chronic l-DOPA (6 mg/kg), in contrast to SCH58261 plus l-DOPA (3 mg/kg), produced a sensitized contralateral turning indicative of dyskinetic potential and further increased GAD67 mRNA in the GP. In the SNr, a significant decrease in GAD67 mRNA was observed after either treatments. However, while l-DOPA (6 mg/kg) decreased SNr GAD67 mRNA below the intact side, SCH58261 plus l-DOPA (3 mg/kg) brought GAD67 mRNA to the same level of the intact SNr. l-DOPA (3 mg/kg) or SCH58261 (5 mg/kg) alone failed to modify GAD67 mRNA. Results suggest that an increase in GAD67 mRNA in GP and a decrease in SNr might underlie dyskinetic movements induced by chronic l-DOPA. In contrast, the lack of GAD67 mRNA changes in the GP and a less marked inhibition of SNr might correlate with the absence of dyskinetic potential observed after SCH58261 plus l-DOPA.     

Postural changes after lesions of the substantia nigra pars reticulata in hemiparkinsonian monkeys

Current neurosurgical strategies target overactive brain regions including the subthalamic nucleus, globus pallidus and thalamus to control various symptoms of Parkinson's disease. Subthalamotomy improves akinesia and can induce postural deficits in both parkinsonian humans and animals, pallidotomy improves limb dyskinesia and more variably, distal bradykinesia whilst thalamotomy improves tremor. Because the SNr also becomes overactive in PD and there are few surgical studies in parkinsonian primates, we therefore evaluated the effects of lesioning the SNr in hemiparkinsonian marmosets to establish the effects on symptomatology. Nine monkeys received unilateral 6-hydroxydopamine (6-OHDA) lesions. Seven weeks later, four received kainic acid lesions of the SNr. Behavioural tests were performed prior to 6-OHDA surgery and then fortnightly for 14 weeks. Unilateral 6-OHDA lesions induced ipsilateral postural bias, ipsilateral rotation after amphetamine injection and bradykinesia. Whilst, SNr lesions significantly altered the direction of head position and amphetamine-induced rotation relative to 6-OHDA lesions, there was no improvement in 6-OHDA-induced reaching deficits or sensorimotor neglect. Unbiased quantitation of the nigral lesions showed on average 88% loss of dopaminergic neurons after 6-OHDA lesions and 77% loss of non-dopaminergic neurons after SNr lesions. Our results demonstrate that the SNr is important in body orientation changes in parkinsonism.     

Selective D1 and D2 dopamine agonists differentially alter basal ganglia glucose utilization in rats with unilateral 6-hydroxydopamine substantia nigra lesions

The relative roles of D1 and D2 dopamine receptor stimulation in mediating the antiparkinsonian effects of dopaminergic drugs remain unclear. To determine the functional metabolic consequences of selective dopamine receptor stimulation, we used 2-deoxyglucose (2-DG) autoradiography to examine the effects of the D1 agonist SKF-38393 and the D2 agonist LY-171555 on regional cerebral glucose utilization (RCGU) in rats with unilateral 6-hydroxydopamine (6-OHDA) substantia nigra lesions. SKF-38393 (0.5-25.0 mg/kg) and LY-171555 (0.01-5.0 mg/kg) produced indistinguishable behavioral responses, including vigorous contralateral rotation. Treatment with each drug similarly increased glucose utilization, dose-dependently, in the parafascicular thalamus, subthalamic nucleus, deep layers of the superior colliculus, and lateral midbrain reticular formation ipsilateral to the nigral lesion; glucose utilization was decreased in the ipsilateral lateral habenula. By contrast, the D1 and D2 agonists differentially altered glucose utilization in the entopeduncular nucleus (EP) and the substantia nigra pars reticulata (SNr). SKF-38393, 5.0 and 25.0 mg/kg, increased glucose utilization 127 and 275%, respectively, in the pars reticulata ipsilateral to the lesion. LY-171555, 1.0 and 5.0 mg/kg, caused maximal contralateral turning, yet did not alter glucose utilization in the ipsilateral SNr. The glucose utilization response of the ipsilateral EP paralleled that of the SNr demonstrating large increases following administration of SKF-38393 and minimal change following the use of LY-171555. The results demonstrate that the selective D1 agonist reproduces the marked glucose utilization increases (2-3-fold above control values) in the EP and SNr that were previously observed using L-DOPA and apomorphine in this model, whereas the selective D2 agonist does not.(ABSTRACT TRUNCATED AT 250 WORDS)     

Therapies for dopaminergic-induced dyskinesias in Parkinson disease

Existing and emerging strategies for managing L-dopa-induced dyskinesias (LIDs) in patients with Parkinson disease have involved either delaying the introduction of L-dopa therapy, treatment with an antidyskinetic agent, using a therapy or delivery system that can provide continuous dopaminergic stimulation, or using novel agents that target receptors implicated in the mechanisms underlying LIDs. Treatment with dopamine agonists such as pramipexole or ropinirole allows levodopa to be delayed, but once levodopa is added to the drug regimen the usual course of onset of dyskinesias is observed. Amantadine, an N-methyl-D-aspartate antagonist, is so far the only approved compound with evidence of providing a sustained antidyskinetic benefit in the absence of unacceptable side effects. These findings support the hypothesis of glutamate overactivity in the development of dyskinesias. More continuous delivery of dopaminergic medication, such as through intraintestinal or subcutaneous routes, is promising but invasive and associated with injection site reactions. As a result of molecular research and elucidation of the role of a variety of neurotransmitters in the mechanism of LIDs, new compounds have been identified, including those that modulate the direct and indirect striatal output pathways; some of these new agents are in the early stages of development or undergoing proof-of-concept evaluation as antidyskinetic agents.     

Correlation of apomorphine- and amphetamine-induced turning with nigrostriatal dopamine content in unilateral 6-hydroxydopamine lesioned rats

In the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease, controversy exists concerning the use of apomorphine- ord-amphetamine-induced rotations as reliable indicators of nigrostriatal dopamine depletion. Our objective was to evaluate which, if either, drug-induced behavior is more predictive of the extent of nigrostriatal dopamine depletion. Fischer 344 and Sprague-Dawley rats were unilaterally injected with 9μg/4μl/4 min 6-hydroxydopamine into the medial forebrain bundle. The animals were behaviorally tested with apomorphine (0.05 mg/kg, s.c.) andd-amphetamine (5.0 mg/kg, s.c.). Following testing, the brains were removed and the right and left striata, substantia nigra and ventral tegmental area were dissected free and quickly frozen at −70°C for analysis of catecholamine content by high performance liquid chromatography coupled with electrochemical detection. Our results indicate that an animal which has greater than a 90% depletion of dopamine in the striatum might not rotate substantially on apomorphine, without a concomitant depletion of 50% of the DA content in the corresponding substantia nigra. No correlations were seen involving depletions of the ventral tegmental area and the extent of the lesions to the striatum. Submaximally lesioned (75–90% depleted) rats were found to rotate ond-amphetamine but not on apomorphine. In addition, control rats that did not receive lesions were often seen to rotate extensively ond-amphetamine. We therefore conclude that maximal lesions of the striatum and substantia nigra are required to generate rotations demonstrable with low dose apomorphine but not withd-amphetamine. Apomorphine, rather thand-amphetamine, is thus a better predictor of maximal lesions of the striatum produced by 6-OHDA.     

Increased slow oscillatory activity in substantia nigra pars reticulata triggers abnormal involuntary movements in the 6-OHDA-lesioned rat in the presence of excessive extracellular striatal dopamine

Since electrophysiological correlates of L-dopa-induced dyskinesia (LID) are almost unknown, changes of striatal dopamine (DA) transmission and electrophysiological activity of the substantia nigra pars reticulata (SNr) were recorded before and after acute L-dopa administration in sham-operated and 6-hydroxydopamine (6-OHDA)-lesioned rats that were previously treated with vehicle or L-dopa for 10 days. Abnormal involuntary movements occurred only in the L-dopa-primed 6-OHDA-lesioned rats that showed after acute l-dopa administration a decrease in firing rate, the highest local field potential power in the theta/alpha band, a consequent oscillatory activity in the same frequency band at the single neuron level and an excessive increase in striatal DA release associated with the lowest level of DA metabolism. These results suggest that increased synchronised afferent activity may drive SNr oscillations in the same frequency band and is associated with abnormal involuntary movements, further suggesting the potential use of desynchronising drugs for managing LID in Parkinson's disease.     

Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson's disease

In an attempt to define clinically relevant models of akinesia and dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats, we have examined the effects of drugs with high (L-DOPA) vs. low (bromocriptine) dyskinesiogenic potential in Parkinson's disease on three types of motor performance, namely: (i) abnormal involuntary movements (AIMs) (ii) rotational behaviour, and (iii) spontaneous forelimb use (cylinder test). Rats with unilateral 6-OHDA lesions received single daily i.p. injections of L-DOPA or bromocriptine at therapeutic doses. During 3 weeks of treatment, L-DOPA but not bromocriptine induced increasingly severe AIMs affecting the limb, trunk and orofacial region. Rotational behaviour was induced to a much higher extent by bromocriptine than L-DOPA. In the cylinder test, the two drugs initially improved the performance of the parkinsonian limb to a similar extent. However, L-DOPA-treated animals showed declining levels of performance in this test because the drug-induced AIMs interfered with physiological limb use, and gradually replaced all normal motor activities. L-DOPA-induced axial, limb and orolingual AIM scores were significantly reduced by the acute administration of compounds that have antidyskinetic efficacy in parkinsonian patients and/or nonhuman primates (-91%, yohimbine 10 mg/kg; -19%, naloxone 4-8 mg/kg; -37%, 5-methoxy 5-N,N-dimethyl-tryptamine 2 mg/kg; -30%, clozapine 8 mg/kg; -50%, amantadine 40 mg/kg). L-DOPA-induced rotation was, however, not affected. The present results demonstrate that 6-OHDA-lesioned rats do exhibit motor deficits that share essential functional similarities with parkinsonian akinesia or dyskinesia. Such deficits can be quantified using novel and relatively simple testing procedures, whereas rotometry cannot discriminate between dyskinetic and antiakinetic effects of antiparkinsonian treatments.     

Differential expression of Fos and Zif268 in the nigrostriatal system after methamphetamine administration in a rat model of Parkinson's disease

The goal of this study was to examine the topological specificity of methamphetamine-induced activation of the immediate-early gene proteins, Fos and Zif268, in the nigrostriatal system in a unilateral 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease with or without intrastriatal grafts of fetal ventral mesencephalon. Methamphetamine (3 mg/kg, i.p.) induced Fos-like immunoreactivity (FLI) dominantly in the striatum and the globus pallidus (GP) on the intact side as well as in the substantia nigra pars reticulata (SNr) on the lesioned side in the 6-OHDA rats. Lower levels of methamphetamine-induced FLI in the striatum and GP on the lesioned side were restored by intrastriatal grafts which could completely suppress the methamphetamine-induced rotation. In the striatum, a similar tendency could be observed between Fos and Zif268 immunoreactivity following methamphetamine. However, sparse immunoreactivity of Zif268 could be detected in the GP and SNr on both sides in the 6-OHDA rats. Intrastriatal grafts had little influence on Zif268 expression in these two regions. The differential expression of Fos and Zif268 was observed among the three regions of the nigrostriatal system following methamphetamine in the 6-OHDA rats. This may suggest that Fos and Zif268 therefore possess gene-specific and region-specific functions in the basal ganglia nuclei.     

Methamphetamine induces Fos expression in the striatum and the substantia nigra pars reticulata in a rat model of Parkinson''s disease

In rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion in the nigrostriatal pathway, methamphetamine (3 mg/kg, i.p.) induced Fos-like immunoreactivity (FLI) not only in the striatum on the intact side but also in the substantia nigra pars reticulata (SNr) on the lesioned side. The methamphetamine-induced hyperexpression of FLI in the SNr on the lesioned side was suppressed by pretreatment with either dopamine D₁ receptor antagonist SCH-23390 (0.5 mg/kg, i.p.), D₂ receptor antagonist raclopride (2 mg/kg, i.p.) or N-methyl- -aspartate receptor antagonist MK-801 (1 mg/kg, i.p.), which was concomitant with inhibition of the methamphetamine-induced rotational behavior of each antagonist. However, the hyperexpression of FLI in the SNr was not suppressed by intrastriatal grafts of fetal ventral mesencephalon which could suppress the methamphetamine-induced rotation completely. These results indicate that opposite hemispheric asymmetries in FLI are induced by methamphetamine in the striatum and the SNr in the 6-OHDA rats. It is suggested that the FLIs in the two discrete sites are activated independently by different mechanisms, and furthermore, different neuronal pathways are involved in the methamphetamine-induced rotation and Fos expression in the SNr of 6-OHDA rats.     

Behavioral sensitization to different dopamine agonists in a parkinsonian rodent model of drug-induced dyskinesias

Repeated treatment with dopamine (DA) receptor agonists strongly potentiates contralateral turning behavior due to selective stimulation of D1 or D2-class receptors in 6-hydroxydopamine (6-OHDA)-lesioned rats. This phenomenon, referred to as sensitization, is believed to be related to the motor response complications (dyskinesias, on-off states) that occur during chronic administration of levodopa in Parkinson's disease patients. In recent years a new method for the evaluation of abnormal involuntary movements (AIMs) secondary to dopaminergic stimulation in 6-OHDA-lesioned rats was described. These AIMs resemble dyskinesias as seen in parkinsonian patients under levodopa therapy. Our objective was to evaluate the effects of repeated treatment with different regimes of DA agonists on turning behavior and on an AIMs scale in 6-OHDA lesioned rats, with the aim of discriminating between drugs with different dyskinesia-inducing potential. In addition, we explored the effects of a previous exposure to a DA agonist (priming) on the behavioral response to the subsequent administration of a DA agonist with the same or different pharmacologic profile. Our results show that in apomorphine-treated rats, rotational behavior and AIMs run a parallel course of enhancement, while in those receiving quinpirole there is a dissociation, suggesting that they could be mediated by different mechanisms. The finding of a significant priming effect on subsequent testing of 6-OHDA lesioned rats should be borne in mind as the use of these pharmacological tests in the screening of well lesioned animals could lead to an erroneous interpretation of further results on dyskinesias and rotational behavior.     

Paradoxical reinforcing properties of apomorphine: Effects of nucleus accumbens and area postrema lesions

Apomorphine (0.01–10.0 mg/kg, subcutaneously) paradoxically produced both dose-dependent aversive and positive reinforcing effects, as measured in conditioned taste aversion and place preference paradigms, respectively. The conditioned taste aversions produced by apomorphine were not modified in rats with bilateral 6-hydroxydopamine (6-OHDA) lesions of the nucleus accumbens (producing 92% depletion of dopamine in the nucleus accumbens) nor in rats with thermal lesions of the area postrema. Both types of lesions were behaviorally verified as effective in other paradigms; the 6-OHDA lesions potentiated the facilitatory effects of apomorphine on locomotor activity in photocell cages, and the area postrema lesions attenuated the conditioned taste aversions to a novel flavor paired with scopolamine methylnitrate (1.0 mg/kg, intraperitoneally). However, 6-OHDA lesions of the nucleus accumbens did clearly potentiate the conditioned place preferences induced by apomorphine. These results suggest that both the positive reinforcing and locomotor effects of apomorphine may partially result from activation of post-synaptic dopamine receptors in the nucleus accumbens. Moreover, the dissociation of apomorphine's aversive and positive reinforcing properties revealed by the 6-OHDA lesions may provide the first step in attempts to pinpoint the different brain sites of action where apomorphine produces its opposite motivational effects.     

Normalization of GABAA receptor specific binding in the substantia nigra reticulata and the prevention of L-dopa-induced dyskinesias in MPTP parkinsonian monkeys

L-Dopa therapy in Parkinson's disease (PD) is counfounded by the development of involuntary movements such as L-Dopa-induced dyskinesias (LIDs). In this study GABA(A) receptor autoradiography was assessed using [(3)H]flunitrazepam binding to the benzodiazepine site of the GABA(A) receptor and [(35)S]t-butylbicyclophosphorothionate (TBPS) binding to the chloride channel of GABA(A) receptors in the substantia nigra reticulata (SNr) and subthalamic nucleus (STN). L-Dopa-treated parkinsonian monkeys experiencing LIDs were compared to animals in which LIDs was prevented by adjunct treatments with CI-1041, a selective antagonist of the NR1A/2B subtype of NMDA receptor, or low doses of the dopamine D2 receptor agonist, cabergoline. Our results demonstrated a decrease of GABA(A) receptor specific binding in the posterior part of the SNr in dyskinetic monkeys compared to nondyskinetic animals, while no modulation has been observed in the STN. These results provide evidence for the first time that pharmacological treatments preventing LIDs in nonhuman primate model of PD are associated with normalization of GABA(A) receptor-mediated signalling in the SNr.     

Protective effect of caffeine against neurodegeneration in a model of Parkinson's disease in rat: behavioral and histochemical evidence

Epidemiological studies have consistently demonstrated an inverse association between coffee consumption and Parkinson's disease (PD). This study was designed to investigate the beneficial effect of caffeine at a dose comparable to that of human exposure in a model of PD. For this purpose, unilateral intrastriatal 6-hydroxydopamine (6-OHDA)-lesioned rats were pretreated with caffeine (20 mg/kg; i.p.) 1 h before surgery and treated twice a day (10 mg/kg) for 1 month. Apomorphine-induced rotations and number of Nissl-stained neurons of substantia nigra pars compacta (SNC) were counted. The results demonstrated that caffeine administration for 1 month could attenuate the rotational behavior in lesioned rats and protect the neurons of SNC against 6-OHDA toxicity.     

Intranigral injection of the H3 agonist immepip and systemic apomorphine elicit ipsilateral turning behaviour in naive rats, but reduce contralateral turning in hemiparkinsonian rats

There is evidence that histamine H3 receptors co-localise with dopamine D1 receptors on the terminals of striato-nigral neurones. In this work we studied the effect of the local activation of H3 receptors present in substantia nigra pars reticulata (SNr) on turning behaviour following apomorphine administration to either naive or hemiparkinsonian rats. In naive rats the intranigral (SNr) injection of the H3 receptor agonist immepip (3.2 or 32 ng/1 microl) resulted in ipsilateral turning following systemic apomorphine (0.5 mg/kg, subcutaneous). The effect of immepip was related to the dose and prevented by the H3 antagonist thioperamide (5 mg/kg, intraperitoneal). Conversely, in rats with 6-hydroxydopamine (6-OHDA) lesions to either substantia nigra pars compacta or the medial forebrain bundle (mfb), apomorphine-induced contralateral turning was reduced by intranigral immepip, an effect prevented by systemic thioperamide. Our data show that H3 receptors present in SNr regulate the synaptic output of the basal ganglia, most likely by reducing GABA release from striato-nigral terminals. These results may be relevant for the understanding of the role of histamine and H3 receptors in the control of motor behaviour both in normal and pathophysiological conditions, such as Parkinson's disease in which histaminergic innervation and histamine levels in substantia nigra have been shown to increase.     

Effect of monoamine oxidase A and B and of catechol-O-methyltransferase inhibition on L-DOPA-induced circling behavior

Summary The effect of enzyme-inhibiting adjuvants on L-DOPA + benserazide-induced contralateral turning in unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats was studied. Both the number of turns and the duration of turning were examined. Inhibition of MAO-A with 10mg/kg Ro 41–1049 increased both parameters; inhibition of COMT with 10mg/kg Ro 40–7592 had a similar effect. In contrast, inhibition of MAO-B with 10mg/kg Ro 19–6327 did not change turning behavior. A further potentiation of turning behavior was observed after the combined administration of both the MAO-A and COMT inhibitor. MAO-A inhibition in conjunction with MAO-B inhibition prolonged the duration of L-DOPA-induced turning but had no effect on the number of turns. However, in conjunction with COMT inhibition, 10mg/kg of the MAO-B inhibitor, Ro 19–6327, significantly affected both the number and duration of turning behavior. An even further potentiation of turning behavior was observed after the combined administration of all three enzyme-inhibitors.Deceased     

Oral pelargonidin exerts dose-dependent neuroprotection in 6-hydroxydopamine rat model of hemi-parkinsonism

Parkinson's disease (PD) is a neuropathological and debilitating disorder involving the degeneration of mesencephalic dopaminergic neurons. Neuroprotective effect of pelargonidin (Pel) has already been reported, therefore, this study examined whether Pel administration would attenuate behavioural and structural abnormalities and markers of oxidative stress in an experimental model of PD in rat. For this purpose, unilateral intrastriatal 6-hydroxydopamine (6-OHDA, 12.5 μg/5 μl of saline-ascorbate)-lesioned rats were pre-treated p.o. with Pel (10 and/or 20 mg/kg). Pel administration dose-dependently attenuated the rotational behavior in lesioned rats and protected the neurons of SNC against 6-OHDA toxicity. In addition, pre-treatment with Pel (20 mg/kg) significantly decreased the 6-OHDA-induced thiobarbituric acid reactive substances (TBARS) formation, indicative of a neuroprotection against lipid peroxidation. Furthermore, the increase of nitrite levels induced by 6-OHDA, indicate the nitric oxide formation and free radicals production and the decrease of antioxidant defense enzyme superoxide dismutase (SOD) was non-significantly prevented by Pel (20 mg/kg). In summary, Pel administration has a dose-dependent neuroprotective effect against 6-OHDA toxicity, partly through attenuating oxidative stress. Our findings suggest that pelargonidin could provide benefits, along with other therapies, in neurodegenerative disorders including PD.