Dyskinesia and motor fluctuations affect up to 90% of patients with Parkinson's disease (PD) within ten years of L-DOPA pharmacotherapy, and represent a major challenge to a successful clinical ...management of this disorder. There are currently two main treatment options for these complications, namely, deep brain electrical stimulation or continuous infusion of dopaminergic agents. The latter is achieved using either subcutaneous apomorphine infusion or enteric L-DOPA delivery. Some patients also benefit from the antidyskinetic effect of amantadine as an adjunct to L-DOPA treatment. Ongoing research in animal models of PD aims at discovering additional, novel treatment options that can either prevent or reverse dyskinesia and motor fluctuations. Alternative methods of continuous L-DOPA delivery (including gene therapy), and pharmacological agents that target nondopaminergic receptor systems are currently under intense experimental scrutiny. Because clinical response profiles show large individual variation in PD, an increased number of treatment options for dyskinesia and motor fluctuations will eventually allow for antiparkinsonian and antidyskinetic therapies to be tailor-made to the needs of different patients and/or PD subtypes.
Several demographic and selective events occurred during the domestication of wheat from the allotetraploid wild emmer (Triticum turgidum ssp. dicoccoides). Cultivated wheat has since been affected ...by other historical events. We analyzed nucleotide diversity at 21 loci in a sample of 101 individuals representing 4 taxa corresponding to representative steps in the recent evolution of wheat (wild, domesticated, cultivated durum, and bread wheats) to unravel the evolutionary history of cultivated wheats and to quantify its impact on genetic diversity. Sequence relationships are consistent with a single domestication event and identify 2 genetically different groups of bread wheat. The wild group is not highly polymorphic, with only 212 polymorphic sites among the 21,720 bp sequenced, and, during domestication, diversity was further reduced in cultivated forms-by 69% in bread wheat and 84% in durum wheat-with considerable differences between loci, some retaining no polymorphism at all. Coalescent simulations were performed and compared with our data to estimate the intensity of the bottlenecks associated with domestication and subsequent selection. Based on our 21-locus analysis, the average intensity of domestication bottleneck was estimated at about 3-giving a population size for the domesticated form about one third that of wild dicoccoides. The most severe bottleneck, with an intensity of about 6, occurred in the evolution of durum wheat. We investigated whether some of the genes departed from the empirical distribution of most loci, suggesting that they might have been selected during domestication or breeding. We detected a departure from the null model of demographic bottleneck for the hypothetical gene HgA. However, the atypical pattern of polymorphism at this locus might reveal selection on the linked locus Gsp1A, which may affect grain softness-an important trait for end-use quality in wheat.
We explored possible differences in the peripheral and central pharmacokinetics of l‐DOPA as a basis for individual variation in the liability to dyskinesia. Unilaterally, 6‐hydroxydopamine (6‐OHDA) ...lesioned rats were treated chronically with l‐DOPA for an induction and monitoring of abnormal involuntary movements (AIMs). Comparisons between dyskinetic and non‐dyskinetic cases were then carried out with regard to plasma and striatal l‐DOPA concentrations, tissue levels of dopamine (DA), DA metabolites, and serotonin. After a single intraperitoneal injection of l‐DOPA, plasma l‐DOPA concentrations did not differ between dyskinetic and non‐dyskinetic animals, whereas peak levels of l‐DOPA in the striatal extracellular fluid were about fivefold larger in the former compared with the latter group. Interestingly, the time course of the AIMs paralleled the surge in striatal l‐DOPA levels. Intrastriatal infusion of l‐DOPA by reverse dialysis concentration dependently induced AIMs in all 6‐OHDA lesioned rats, regardless of a previous priming for dyskinesia. Steady‐state levels of DA and its metabolites in striatal and cortical tissue did not differ between dyskinetic and non‐dyskinetic animals, indicating that the observed difference in motor response to l‐DOPA did not depend on the extent of lesion‐induced DA depletion. These results show that an elevation of l‐DOPA levels in the striatal extracellular fluid is necessary and sufficient for the occurrence of dyskinesia. Individual differences in the central bioavailability of l‐DOPA may provide a clue to the varying susceptibility to dyskinesia in Parkinson's disease.
Dyskinesia (abnormal involuntary movements) is a common complication of
l-DOPA pharmacotherapy in Parkinson's disease, and is thought to depend on abnormal cell signaling in the basal ganglia. ...Dopamine (DA) denervated mice can exhibit behavioral and cellular signs of dyskinesia when they are treated with
l-DOPA, but the clinical relevance of this animal model remains to be established. In this study, we have examined the pharmacological profile of
l-DOPA-induced abnormal involuntary movements (AIMs) in the mouse. C57BL/6 mice sustained unilateral injections of 6-hydroxydopamine (6-OHDA) in the striatum. The animals were treated chronically with daily doses of
l-DOPA that were sufficient to ameliorate akinetic features without inducing overt signs of dyskinesia upon their first administration. In parallel, other groups of mice were treated with antiparkinsonian agents that do not induce dyskinesia when administered de novo, that is, the D2/D3 agonist ropinirole, and the adenosine A2a antagonist KW-6002.
During 3 weeks of treatment,
l-DOPA-treated mice developed AIMs affecting the head, trunk and forelimb on the side contralateral to the lesion. These movements were not expressed by animals treated with ropinirole or KW-6002 at doses that improved forelimb akinesia. The severity of
l-DOPA-induced rodent AIMs was significantly reduced by the acute administration of compounds that have been shown to alleviate
l-DOPA-induced dyskinesia both in parkinsonian patients and in rat and monkey models of Parkinson's disease (amantadine, −47%; buspirone, −46%; riluzole, −33%). The present data indicate that the mouse AIMs are indeed a functional equivalent of
l-DOPA-induced dyskinesia.
l-DOPA-induced dyskinesia is a major complication of
l-DOPA pharmacotherapy in Parkinson's disease, and is thought to depend on abnormal cell signaling in the basal ganglia. In this study, we have ...addressed the possibility to model
l-DOPA-induced dyskinesia in the mouse at both the behavioral and the molecular level. C57BL/6 mice sustained unilateral injections of 6-hydroxydopamine (6-OHDA) either in the medial forebrain bundle (MFB) or in the sensorimotor part of the striatum. Both types of lesion produced a similar degree of forelimb akinesia on the contralateral side of the body. The lowest dose of
l-DOPA that could significantly relieve this akinetic deficit (i.e., 6 mg/kg) did not differ between MFB and intrastriatal lesions. The
l-DOPA threshold dose for the induction of dyskinesia did however differ between the two lesion types. A daily dose of 6 mg/kg
l-DOPA caused MFB lesioned mice to develop abnormal movements affecting orofacial, trunk, and forelimb muscles on the side contralateral to the lesion, whereas a daily dose of 18 mg/kg was required to produce comparable dyskinetic effects in the intrastriatally lesioned animals. The development of abnormal movements was accompanied by a striatal induction of ΔFosB-like proteins and prodynorphin mRNA, that is, molecular markers that are associated with
l-DOPA-induced dyskinesia in both rats and nonhuman primates. We conclude that 6-OHDA lesioned mice exhibit behavioral and cellular features of akinesia and
l-DOPA-induced dyskinesia that are similar to those previously characterized in rats. The mouse model of
l-DOPA-induced dyskinesia will provide a useful tool to study the molecular determinants of this movement disorder in transgenic mice strains.
We show that intranigral lipopolysaccharide (LPS) injection, which provokes specific degeneration of DA neurons, induced caspase-3 activation in the rat ventral mesencephalon, which was mostly ...associated with glial cells. In contrast, nigral DA neurons exhibited AIF nuclear translocation in response to LPS. A significant decrease of the Bcl-2/Bax ratio in nigral tissue after LPS injection was observed. We next developed an in vitro co-culture system with the microglial BV2 and the DA neuronal MN9D murine cell lines. The silencing of caspase-3 or AIF by small interfering RNAs exclusively in the DA MN9D cells demonstrated the key role of AIF in the LPS-induced death of DA cells. In vivo chemical inhibition of caspases and poly(ADP-ribose)polymerase-1, an upstream regulator of AIF release and calpain, proved the central role of the AIF-dependent pathway in LPS-induced nigral DA cell death. We also observed nuclear translocation of AIF in the ventral mesencephalon of Parkinson's disease subjects.
We have examined the ability of KW‐6002, an adenosine A2a antagonist, to modulate the dyskinetic effects of l‐DOPA in 6‐hydroxydopamine‐lesioned rats. In animals rendered dyskinetic by a previous ...course of l‐DOPA treatment, KW‐6002 did not elicit any abnormal involuntary movements on its own, but failed to reduce the severity of dyskinesia when coadministered with l‐DOPA. A second experiment was undertaken in order to study the effects of KW‐6002 in l‐DOPA‐naive rats. Thirty‐five animals were allotted to four groups to receive a 21‐day treatment with: (i) KW‐6002 (10 mg/kg/day); (ii) l‐DOPA (6 mg/kg/day) i.p.; (iii) KW‐6002 plus l‐DOPA (same doses as above) or (iv) vehicle. Chronic treatment with KW‐6002‐only produced a significant relief of motor disability in the rotarod test in the absence of any abnormal involuntary movements. Combined treatment with l‐DOPA and KW‐6002 improved rotarod performance to a significantly higher degree than did each of the two drugs alone. However, this combined treatment induced dyskinesia to about the same degree as did l‐DOPA alone. In situ hybridization histochemistry showed that KW‐6002 treatment alone caused an approximately 20% reduction in the striatal levels of preproenkephalin mRNA, whereas neither the coadministration of KW‐6002 and l‐DOPA nor l‐DOPA alone significantly altered the expression of this transcript in the dopamine‐denervated striatum. Either alone or in combination with l‐DOPA, KW‐6002 did not have any modulatory effect on prodynorphin mRNA expression or FosB/ΔFosB‐like immunoreactivity in the dopamine‐denervated striatum.
These results show that monotreatment with an adenosine A2a receptor antagonist can relieve motor disability without inducing behavioural and cellular signs of dyskinesia in rats with 6‐hydroxydopamine lesions. Cotreatment with KW‐6002 and l‐DOPA potentiates the therapeutic effect but not the dyskinesiogenic potential of the latter drug.
The crucial role of dopamine (DA) in movement control is illustrated by the spectrum of motor disorders caused by either a deficiency or a hyperactivity of dopaminergic transmission in the basal ...ganglia. The degeneration of nigrostriatal DA neurons in Parkinson's disease causes poverty and slowness of movement. These symptoms are greatly improved by pharmacological DA replacement with l -3,4-dihydroxy-phenylalanine ( l -DOPA), which however causes excessive involuntary movements in a majority of patients. l -DOPA-induced dyskinesia (abnormal involuntary movements) provides a topic of investigation at the interface between clinical and basic neuroscience. In this article, we review recent studies in rodent models, which have uncovered two principal alterations at the basis of the movement disorder, namely, an abnormal pre-synaptic handling of exogenous l -DOPA, and a hyper-reactive post-synaptic response to DA. Dysregulated nigrostriatal DA transmission causes secondary alterations in a variety of non-dopaminergic transmitter systems, the manipulation of which modulates dyskinesia through mechanisms that are presently unclear. Further research on l -DOPA-induced dyskinesia will contribute to a deeper understanding of the functional interplay between neurotransmitters and neuromodulators in the motor circuits of the basal ganglia.
Changes in platelet count (PLT) are very important during pregnancy. Many platelet disorders occur during pregnancy and a reduction in PLT is the most common hemostasis abnormality identified, and ...this has important implications for mother and foetus. Many of these disorders share clinical and laboratory features, making accurate diagnosis difficult. The aim of this study was to establish reference intervals of platelet parameters for some of the more important pathologies associated to pregnancy (pre‐eclampsia, gestational diabetes, autoimmune disorders, viral infections) using the automated hematology analyzer Sysmex XE‐2100 and to evaluate the difference between healthy and pathological pregnancy. We enrolled in our study 100 pregnant women in the third trimester of pregnancy. The parameters analyzed included PLT, platelet distribution width, and mean platelet volume (MPV). We found statistically significant difference in PLT in pre‐eclampsia, autoimmune disorders, and viral infections. Our results demonstrated also a statistically significant difference in MPV in pre‐eclampsia and gestational diabetes. Our results allow the clinicians to detect hematologic change by simple complete blood count useful for the management of the pathological pregnancies. In conclusion, the overall picture of platelet disorders is extremely variegated, leading to numerous diagnostic and therapeutic problems whose solutions require close collaboration between clinicians and laboratory specialists.
In some patients, graft-induced dyskinesia develops following intrastriatal transplantation of embryonic neural tissue for the treatment of Parkinson's disease. The mechanisms underlying these ...involuntary movements need to be clarified before this approach to clinical cell therapy can be developed further. We previously found that rats with 6-OHDA lesions, primed with L-DOPA treatment and that have subsequently undergone intrastriatal graft surgery exhibit involuntary movements when subjected to amphetamine. This model of amphetamine-induced AIMs reflects a pattern of post-graft behaviours that in the absence of robust spontaneous GID in the rat is the closest approximation that we currently have available. We now show that they are associated with the chronic administration of L-DOPA prior to the transplantation surgery. We also demonstrate that neither changes in c-fos nor FosB/ΔFosB expression in the lateral striatum are associated with the expression of these behaviours. Taken together, these data reveal that the severity of abnormal movements elicited by amphetamine in grafted animals may relate to previous L-DOPA exposure and dyskinesia development, but they develop through mechanisms that are independent of FosB/ΔFosB upregulation.
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