dynorphins and Parkinson-Disease--Secondary

In Parkinson's disease (PD), bradykinesia, or slowness of movement, only appears after a large striatal dopamine depletion. Compensatory mechanisms probably play a role in this delayed appearance of symptoms.. Our hypothesis is that the striatal direct and indirect pathways participate in these compensatory mechanisms.. We used the unilateral 6-hydroxydopamine (6-OHDA) rat model of PD and control animals. Four weeks after the lesion, the spontaneous locomotor activity of the rats was measured and then the animals were killed and their brain extracted. We quantified the mRNA expression of markers of the striatal direct and indirect pathways as well as the nigral expression of dopamine transporter (DAT) and tyrosine hydroxylase (TH) mRNA. We also carried out an immunohistochemistry for the striatal TH protein expression.. As expected, the unilateral 6-OHDA rats presented a tendency to an ipsilateral head turning and a low locomotor velocity. In 6-OHDA rats only, we observed a significant and positive correlation between locomotor velocity and both D1-class dopamine receptor (D1R) (direct pathway) and enkephalin (ENK) (indirect pathway) mRNA in the lesioned striatum, as well as between D1R and ENK mRNA.. Our results demonstrate a strong relationship between both direct and indirect pathways and spontaneous locomotor activity in the parkinsonian rat model. We suggest a synergy between both pathways which could play a role in compensatory mechanisms and may contribute to the delayed appearance of bradykinesia in PD.

Topics: Animals; Dopamine Plasma Membrane Transport Proteins; Dynorphins; Enkephalins; Female; Gene Expression; Glutamate Decarboxylase; Hydroxydopamines; Immunohistochemistry; In Situ Hybridization; Motor Activity; Neostriatum; Neural Pathways; Parkinson Disease, Secondary; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; RNA, Messenger; Signal Transduction; Tyrosine 3-Monooxygenase

We investigated the effect of early vs. late initiation of levodopa treatment on dyskinetic movements, rotational behavior and molecular markers in hemiparkinsonian rats. Male Sprague-Dawley rats received a unilateral 6-hydroxydopamine (6-OHDA) administration in the nigrostriatal pathway. Rats were divided into three groups treated with: (i) levodopa (6 mg/kg) twice daily for 22 days starting at 4 weeks after 6-OHDA (Early group); (ii) levodopa at the same dose, regimen and duration but starting at 12 weeks after 6-OHDA (Late group), and (iii) saline starting at 4 weeks after 6-OHDA and continuing until the Late group finished treatment. Dyskinesias were quantified on days 1 and 22 of levodopa treatment. Striatal expression of preproenkephalin and preprodynorphin mRNAs, subthalamic cytochrome oxidase mRNA, and glutamate decarboxylase 67 mRNA in the pars reticulata of the substantia nigra was measured by in-situ hybridization. After 22 days of levodopa treatment, the percentage of rats showing dyskinesia was lower in the Early group than in the Late group (60% vs. 100%, respectively). No significant differences in total dyskinesia score were observed between both groups with the exception of the orolingual dyskinesias that were significantly less frequent in the Late group (P < 0.01). No significant differences were observed in the molecular markers between the Early and Late groups. Prompt initiation of levodopa treatment might be able to delay some of the basal ganglia molecular and circuitry changes underlying the development of dyskinesia but, once developed, they are behaviorally and molecularly similar to those appearing after late initiation of levodopa.

Topics: Animals; Corpus Striatum; Dopamine Plasma Membrane Transport Proteins; Dynorphins; Dyskinesias; Electron Transport Complex IV; Enkephalins; Glutamate Decarboxylase; Immunohistochemistry; In Situ Hybridization; Levodopa; Male; Neurons; Oxidopamine; Parkinson Disease, Secondary; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Substantia Nigra; Subthalamic Nucleus

Antagonism of adenosine A2A receptor function has been proposed as an effective therapy in the treatment of Parkinson's disease. Thus, the study of new adenosine receptor antagonists is of great importance for the potential use of these drugs in clinical practice. The present study evaluated effects of the new preferential adenosine A2A receptor antagonist 2-butyl-9-methyl-8-(2H-1,2,3-triazol-2-yl)-9H-purin-6-ylamine (ST1535) in unilaterally 6-hydroxydopamine lesioned rats. Acute ST1535 dose-dependently potentiated contralateral turning behaviour induced by a threshold dose of l-3,4-dihydroxyphenylalanine (L-DOPA) (3 mg/kg i.p.), a classical test for antiparkinson drug screening. Subchronic (18 days, twice a day) ST1535 (20 mg/kg i.p.)+L-DOPA (3 mg/kg i.p.) did not induce sensitization to turning behaviour or abnormal involuntary movements during the course of treatment, indicating a low dyskinetic potential of the drug. Moreover, while subchronic administration of a fully effective dose of L-DOPA (6 mg/kg i.p.) significantly increased GABA synthesizing enzyme glutamic acid decardoxylase (GAD67), dynorphin and enkephalin mRNA levels in the lesioned striatum, subchronic ST1535 (20 mg/kg i.p.)+L-DOPA (3 mg/kg i.p.) did not modify any of these markers, although it induced a similar number of contralateral rotations at the beginning of treatment. Finally, acute administration of ST1535 (20 mg/kg i.p.) proved capable of reducing jaw tremors in tacrine model of Parkinson's disease tremor. Results showed that ST1535, in association with a low dose of L-DOPA, displayed antiparkinsonian activity similar to that produced by a full dose of L-DOPA without exacerbating abnormal motor side effects. Moreover, in agreement to other well characterized adenosine A2A receptor antagonists, ST1535 features antitremorigenic effects.

Topics: Adenine; Adenosine A2 Receptor Antagonists; Adrenergic Agents; Animals; Antiparkinson Agents; Behavior, Animal; Corpus Striatum; Dynorphins; Enkephalins; Glutamate Decarboxylase; Isoenzymes; Levodopa; Male; Oxidopamine; Parkinson Disease, Secondary; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tacrine; Tremor; Triazoles

In Parkinson's disease (PD), the striatal dopamine depletion and the following overactivation of the indirect pathway of the basal ganglia leads to very early disinhibition of the subthalamic nucleus (STN) that may contribute to the progression of PD by glutamatergic overstimulation of the dopaminergic neurons in the substantia nigra. Adenosine A2A antagonism has been demonstrated to attenuate the overactivity of the striatopallidal pathway. To investigate whether neuroprotection exerted by the A2A antagonist 8-(3-chlorostyryl)caffeine (CSC) correlates with a diminution of the striatopallidal pathway activity, we have examined the changes in the mRNA encoding for enkephalin, dynorphin, and adenosine A2A receptors by in situ hybridization induced by subacute systemic pretreatment with CSC in rats with striatal 6-hydroxydopamine(6-OHDA) administration. Animals received CSC for 7 days until 30 min before 6-OHDA intrastriatal administration. Vehicle-treated group received a solution of dimethyl sulfoxide. CSC pretreatment partially attenuated the decrease in nigral tyrosine hydroxylase immunoreactivity induced by 6-OHDA, whereas no modification of the increase in preproenkephalin mRNA expression in the dorsolateral striatum was observed. The neuroprotective effect of the adenosine A2A antagonist CSC in striatal 6-OHDA-lesioned rats does not result from a normalization of the increase in striatal PPE mRNA expression in the DL striatum, suggesting that other different mechanisms may be involved.

Topics: Adenosine A2 Receptor Antagonists; Animals; Caffeine; Cell Count; Dynorphins; Enkephalins; Globus Pallidus; Immunohistochemistry; In Situ Hybridization; Male; Microinjections; Neostriatum; Neural Pathways; Neuroprotective Agents; Oxidopamine; Parkinson Disease, Secondary; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A; RNA, Messenger; Stereotyped Behavior; Substantia Nigra; Sympatholytics; Tyrosine 3-Monooxygenase

To investigate the role of A(2A) adenosine receptors in adaptive responses to chronic intermittent dopamine receptor stimulation, we compared the behavioral sensitization elicited by repeated l-DOPA treatment in hemiparkinsonian wild-type (WT) and A(2A) adenosine receptor knock-out (A(2A) KO) mice. Although the unilateral nigrostriatal lesion produced by intrastriatal injection of 6-hydroxydopamine was indistinguishable between WT and A(2A) KO mice, they developed strikingly different patterns of behavioral sensitization after daily treatment with low doses of l-DOPA for 3 weeks. WT mice initially displayed modest contralateral rotational responses and then developed progressively greater responses that reached a maximum within 1 week and persisted for the duration of the treatment. In contrast, any rotational behavioral sensitization in A(2A) KO mice was transient and completely reversed within 2 weeks. Similarly, the time to reach the peak rotation was progressively shortened in WT mice but remained unchanged in A(2A) KO mice. Furthermore, daily l-DOPA treatment produced gradually sensitized grooming in WT mice but failed to induce any sensitized grooming in A(2A) KO mice. Finally, repeated l-DOPA treatment reversed the 6-OHDA-induced reduction of striatal dynorphin mRNA in WT but not A(2A) KO mice, raising the possibility that the A(2A) receptor may contribute to l-DOPA-induced behavioral sensitization by facilitating adaptations within the dynorphin-expressing striatonigral pathway. Together these results demonstrate that the A(2A) receptor plays a critical role in the development and particularly the persistence of behavioral sensitization to repeated l-DOPA treatment. Furthermore, they raise the possibility that the maladaptive dyskinetic responses to chronic l-DOPA treatment in Parkinson's disease may be attenuated by A(2A) receptor inactivation.

Topics: 3,4-Dihydroxyphenylacetic Acid; Adaptation, Physiological; Animals; Autoradiography; Behavior, Animal; Corpus Striatum; Dopamine; Dopamine Plasma Membrane Transport Proteins; Drug Administration Schedule; Dynorphins; Female; Levodopa; Male; Membrane Glycoproteins; Membrane Transport Proteins; Mice; Mice, Knockout; Motor Activity; Nerve Tissue Proteins; Oxidopamine; Parkinson Disease, Secondary; Receptor, Adenosine A2A; Receptors, Purinergic P1; RNA, Messenger; Substantia Nigra