8-(3-chlorostyryl)caffeine and Parkinson-Disease--Secondary

8-(3-chlorostryryl) caffeine (CSC), a selective adenosine A(2A) receptor antagonist, has been reported to inhibit the levodopa-induced motor fluctuation in Parkinson's disease. However, the underlying mechanism of its action remains largely unknown. In our study, we investigated the signaling pathway by which CSC inhibited levodopa-induced motor fluctuation in rats with a 6-hydroxydopamine (6-OHDA)-induced lesion. We treated 6-OHDA-lesioned rats with levodopa (50 mg/kg/day, twice daily) for 22 days, followed by levodopa+CSC (5 mg/kg/day, twice daily) or levodopa+vehicle for 7 days. The sham-lesioned and 6-OHDA-lesioned rats treated with saline for 29 days served as sham and lesion control groups. We found that the treatment of CSC reversed the shortening of the rotational motor response duration induced by levodopa administration and the effect was maintained until the end of the treatment. The chronic levodopa treatment upregulated the adenosine A(2A) receptor expression and modified downstream signaling pathway including decreasing the phosphorylation of DARPP-32 at Thr75 site and increasing the phosphorylation of ERK1/2 in the lesioned striatum. However, the following CSC treatment attenuated the levodopa-induced adenosine A(2A) receptor upregulation and abolished the aberrant phosphorylation of DARPP-32 at Thr75 site and that of ERK1/2. Our results indicate that the inhibitory effect of CSC on levodopa-induced motor fluctuation may be associated with the inhibition of Adenosine A(2A) Receptor and downstream DARPP-32 and ERK1/2 signaling pathway.

Topics: Adenosine A2 Receptor Agonists; Animals; Antiparkinson Agents; Caffeine; Corpus Striatum; Dopamine and cAMP-Regulated Phosphoprotein 32; Levodopa; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Motor Activity; Movement; Oxidopamine; Parkinson Disease, Secondary; Phosphorylation; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A; Signal Transduction; Up-Regulation

While dopamine replacement remains the standard pharmacotherapy for Parkinson's disease, chronic L-dopa treatment is associated with development of debilitating motor fluctuations such as L-dopa-induced dyskinesia (LID). In this study we evaluated the effects of the partial dopamine D(2) agonist terguride on the development of LID in hemiparkinsonian mice (unilaterally lesioned with 6-hydroxydopamine). First, consistent with the partial agonist property, terguride had 1000-fold higher potency than dopamine, yet producing one-third level of maximal activation of dopamine, as assayed by [(35)S]GTPgammaS binding. Furthermore, in the absence and presence of dopamine in vitro, terguride increased and decreased striatal [(35)S]GTPgammaS binding, respectively. Next, we found that co-administration of terguride (at 0.1 and 0.5mg/kg, i.p.) with L-dopa (1.8 mg/kg) daily for 14 days, significantly attenuated the development and expression of L-dopa-induced rotational sensitization. Furthermore, the cross-challenge paradigm revealed that chronic L-dopa treatment (but not terguride) sensitized locomotor response to the dopamine D(1) agonist SKF 81297 while chronic treatment with terguride (but not L-dopa) produced sensitized locomotor responses to the adenosine A(2A) antagonist 8-(3-chlorostyryl)caffeine (CSC). Importantly, the co-administration of terguride with L-dopa did not show locomotor sensitization to either SFK 81297 or CSC upon challenge. Together, these results suggest that co-administration of partial dopamine D(2) agonists with L-dopa may prophylactically attenuate L-dopa-induced abnormal behavioral responses such as LID.

Topics: Adenosine A2 Receptor Antagonists; Animals; Antiparkinson Agents; Benzazepines; Caffeine; Corpus Striatum; Dopamine Agonists; Drug Therapy, Combination; Guanosine 5'-O-(3-Thiotriphosphate); Levodopa; Lisuride; Male; Mice; Mice, Inbred C57BL; Motor Activity; Oxidopamine; Parkinson Disease, Secondary; Random Allocation; Receptors, Dopamine D1; Receptors, Dopamine D2; Sulfur Radioisotopes

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