ABSTRACT
Serotonin transporter blockade with selective serotonin reuptake inhibitors (SSRIs) was recently shown to counteract L-DOPA-induced dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats. However, this effect has never been described in Parkinson's disease (PD) patients, despite that they often receive SSRIs for the treatment of depression. In the present study, we investigated the efficacy of the SSRI citalopram against dyskinesia in two experimental models of PD, the 6-OHDA-lesioned rat and 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-treated macaque. First, we studied the acute and chronic effect of citalopram, given at different time points before L-DOPA, in L-DOPA-primed parkinsonian rats. Moreover, the acute effect of citalopram was also evaluated in dyskinetic MPTP-treated macaques. In L-DOPA-primed rats, a significant and long-lasting reduction of L-DOPA-induced dyskinesia (LID) was observed only when citalopram was given 30 min before L-DOPA, suggesting that the time of injection relative to L-DOPA is a key factor for the efficacy of the treatment. Interestingly, an acute challenge with the 5-HT1A/1B receptor agonist eltoprazine, given at the end of the chronic study, was equally effective in reducing LID in rats previously chronically treated with L-DOPA or L-DOPA plus citalopram, suggesting that no auto-receptor desensitization was induced by chronic citalopram treatment. In MPTP-treated macaques, citalopram produced a striking suppression of LID but at the expense of L-DOPA therapeutic efficacy, which represents a concern for possible clinical application.
Subject(s)
Antiparkinson Agents/adverse effects , Dyskinesia, Drug-Induced/metabolism , Levodopa/adverse effects , MPTP Poisoning/drug therapy , Parkinson Disease/drug therapy , Serotonin Plasma Membrane Transport Proteins/metabolism , Analysis of Variance , Animals , Citalopram/therapeutic use , Disease Models, Animal , Dyskinesia, Drug-Induced/drug therapy , Dyskinesia, Drug-Induced/etiology , Female , MPTP Poisoning/chemically induced , Macaca fascicularis , Male , Oxidopamine/toxicity , Parkinson Disease/etiology , Rats , Rats, Sprague-Dawley , Selective Serotonin Reuptake Inhibitors/therapeutic use , Time Factors , Tyrosine 3-Monooxygenase/metabolismABSTRACT
Viral RNA from fall armyworm (Spodoptera frugiperda) cells infected with Autographa californica nuclear polyhedrosis virus contains cap structures. Most of the cap labeled in vivo with [(3)H]methionine or (32)P(i) cochromatographed on DEAE-cellulose with the -5 charge marker; a minor component appeared at -4 net charge. The former is probably a cap 1 structure (m(7)GpppX(m) (p)Yp), and the latter is probably a cap 0 (m(7)GpppXp). On the basis of relative labeling of the two caps with [(3)H]adenosine and [(3)H]guanosine, we concluded that each cap contained at least one adenosine residue in addition to guanosine and, therefore, that cap 0 contained m(7)GpppAp. Cleavage of [(3)H]methionine-labeled viral RNA with tobacco acid pyrophosphatase released a labeled component that cochromatographed on polyethyleneimine-cellulose with m(7)Gp, confirming the m(7)GpppX linkage in the cap. These results were also seen with host polyadenylated RNA. The caps appeared in nearly equal abundance in viral polyadenylated and non-polyadenylated RNAs. The ratio of (32)P(i) incorporated into the cap to that incorporated into mononucleotides suggested average lengths for the polyadenylated and non-polyadenylated RNAs of 1,800 and 1,200 nucleotides, respectively.
