8-(3-chlorostyryl)caffeine and Parkinsonian-Disorders

A(2A) adenosine receptor antagonists have been proposed as a new therapy of PD. Since oxidative stress plays an important role in the pathogenesis of PD, we studied the effect of the selective A(2A) adenosine receptor antagonists 8-(-3-chlorostyryl)caffeine (CSC) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) on hydroxyl radical generation, and glutamate (GLU) and dopamine (DA) extracellular level using a microdialysis in the striatum of 6-OHDA-treated rats. CSC (1 mg/kg) and ZM 241385 (3 mg/kg) given repeatedly for 14 days decreased the production of hydroxyl radical and extracellular GLU level, both enhanced by prior 6-OHDA treatment in dialysates from the rat striatum. CSC and ZM 241385 did not affect DA and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) extracellular levels in the striatum of 6-OHDA-treated rats. L-DOPA (6 mg/kg) given twice daily for two weeks in the presence of benserazide (3 mg/kg) decreased striatal hydroxyl radical and glutamate extracellular level in 6-OHDA-treated rats. At the same time, L-DOPA slightly but significantly increased the extracellular levels of DOPAC and HVA. A combined repeated administration of L-DOPA and CSC or ZM 241385 did not change the effect of L-DOPA on hydroxyl radical production and glutamate extracellular level in spite of an enhancement of extracellular DA level by CSC and elevation of extracellular level of DOPAC and HVA by ZM 241385. The data suggest that the 6-OHDA-induced damage of nigrostriatal DA-terminals is related to oxidative stress and excessive release of glutamate. Administration of L-DOPA in combination with CSC or ZM 241385, by restoring striatal DA-glutamate balance, suppressed 6-OHDA-induced overproduction of hydroxyl radical.

Topics: 3,4-Dihydroxyphenylacetic Acid; Adenosine A2 Receptor Antagonists; Animals; Benserazide; Caffeine; Dopamine; Glutamic Acid; Hydroxyl Radical; Levodopa; Male; Microdialysis; Neostriatum; Oxidopamine; Parkinsonian Disorders; Rats; Rats, Wistar; Receptor, Adenosine A2A; Triazines; Triazoles

l-DOPA remains the gold-standard treatment for Parkinson's disease (PD). However, the emergence of l-DOPA-induced dyskinesia (LID) and motor fluctuations represents a major clinical problem in PD. The selective localization of adenosine A(2A) receptors to the basal ganglia and specifically to the indirect output pathway appear to be crucial both in the pathogenesis of PD and in the development of LID. In this study, we investigated the effects of a 3-week treatment with l-DOPA (50mg/kg/day+benserazide 12.5mg/kg/day, twice daily, i.p.) alone or combined with adenosine A(2A) receptor antagonist 8-(3-Chlorostyryl)caffeine (CSC) (5mg/kg/day, twice daily), on the rotational motor response duration, abnormal involuntary movements (AIM) and the associated striatal expression of adenosine A(2A) receptor in rats with a nigrostriatal lesion. CSC treatment ameliorated the shortening of the rotational motor response duration, partly attenuated dyskinesia and reduced striatal expression of adenosine A(2A) receptor induced by l-DOPA. Electron microscopy technique results showed that the postsynapse density depth was much thicker, synapse cleft width was narrower and the ratio of perforated synapses significantly increased in the l-DOPA-treated rats, while systemic coadministration of CSC with l-DOPA attenuated the overactivity of corticostriatal synaptic ultrastructure and function induced by l-DOPA. In conclusion, CSC by means of its dual action as A(2A) receptor antagonist and MAO-B inhibitor ameliorated the changed behavior, expression of adenosine A(2A) receptor and postsynaptic effects, observed in the 6-OHDA-lesioned rats, pointing out to its potential benefit for the treatment of LID.

Topics: Adenosine A2 Receptor Antagonists; Animals; Blotting, Western; Brain; Caffeine; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Levodopa; Male; Microscopy, Electron, Transmission; Parkinsonian Disorders; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A; Synapses

The molecular mechanisms involved in the reversion of levodopa-induced motor fluctuations by the adenosine A2A antagonist 8-(3-chlorostryryl) caffeine (CSC) were investigated in rats with a 6-hydroxydopamine (6-OHDA)-induced lesion and compared with the ones achieved by the kappa-opioid agonist, U50,488. Animals were treated with levodopa (50 mg/kg/day) for 22 days and for one additional week with levodopa + CSC (5 mg/kg/day), levodopa + U50,488 (1 mg/kg/day), or levodopa + vehicle. The reversion of the decrease in the duration of levodopa-induced rotations by CSC, but not by U50,488, was maintained until the end of the treatment and was associated with a further increase in levodopa-induced preprodynorphin mRNA in the lesioned striatum, being higher in the ventromedial striatum. The increase in striatal preprodynorphin expression, particularly in the ventromedial striatum, may be related to the reversion of levodopa-induced motor fluctuations in the CSC-treated animals, suggesting a role of the direct striatal output pathway activity in the ventromedial striatum in the pathophysiology of motor fluctuations.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Adenosine; Adrenergic Agents; Animals; Caffeine; Corpus Striatum; Dynorphins; Dyskinesias; Enkephalins; Immunohistochemistry; In Situ Hybridization; Levodopa; Male; Oxidopamine; Parkinsonian Disorders; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; RNA, Messenger

To evaluate the possible involvement of adenosine A(2A) receptor-mediated mechanisms in levodopa-induced motor fluctuations, we investigated the effects of CSC (8-(3-chlorostryryl) caffeine), a selective adenosine A(2A) receptor antagonist, on levodopa-induced motor alterations in rats with unilateral 6-OHDA lesion. Acute and chronic administration of CSC was studied to evaluate the possible reversion or prevention of these levodopa effects. In a first set of experiments, rats were treated with levodopa (25 mg/kg with benserazide, twice daily, i.p.) for 22 days and on day 23 CSC (5 mg/kg, i.p.) was administered immediately before levodopa. In a second set of experiments, rats were treated daily for 22 days with levodopa and CSC (5 mg/kg/day, i.p.). The duration of the rotational behavior induced by chronic levodopa decreased after 22 days (P < 0.05). Acute administration of CSC on day 23 reversed levodopa-induced shortening in motor response duration (P < 0.01). Chronic CSC administration did not prevent the shortening in response duration induced by levodopa. Our results demonstrate that the adenosine A(2A) receptor antagonist CSC reverses but does not prevent levodopa-induced motor alterations in parkinsonian rats. These results suggest a role for adenosine A(2A) receptor-mediated mechanisms in the pathophysiology of levodopa-induced motor response complications. These findings suggest that the antagonism of adenosine A(2A) receptors might confer clinical benefit to parkinsonian patients under levodopa therapy suffering from motor complication syndrome.

Topics: Animals; Caffeine; Levodopa; Male; Motor Activity; Parkinsonian Disorders; Purinergic P1 Receptor Antagonists; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A; Receptors, Purinergic P1