PDE10A and PDE10A-dependent cAMP catabolism are dysregulated oppositely in striatum and nucleus accumbens after lesion of midbrain dopamine neurons in rat: a key step in parkinsonism physiopathology.

Loss of dopamine neurons in experimental parkinsonism results in altered cyclic nucleotide cAMP and cGMP levels throughout the basal ganglia. Our objective was to examine whether expression of phosphodiesterase 10A (PDE10A), an isozyme presenting a unique distribution in basal ganglia, is altered after unilateral injection of 6-hydroxydopamine in the medial forebrain bundle, eliminating all midbrain dopaminergic neurons, such that cyclic nucleotide catabolism and steady state could be affected. Our study demonstrates that PDE10A mRNA levels were decreased in striatal neurons 10 weeks after 6-hydroxydopamine midbrain lesion. Such changes occurred in the striatum ipsilateral to lesion and were paralleled by decreased PDE10A protein levels and activity in striatal neurons and in striato-pallidal and striato-nigral projections. However, PDE10A protein and activity were increased while PDE10A mRNA was unchanged in the nucleus accumbens ipsilateral to the 6-hydroxydopamine midbrain lesion. Accordingly, cAMP levels were down-regulated in the nucleus accumbens, and up-regulated in the striatum ipsilateral to the lesion, but they were not significantly changed in substantia nigra and globus pallidus. Unlike cAMP, cGMP levels were decreased in all dopamine-deafferented regions. The opposite variations of cAMP steady state in striatum and nucleus accumbens are concordant and likely dependent, at least in part, on the down-regulation of PDE10A expression and activity in the former and its up-regulation in the latter. On the other hand, the down-regulation of cGMP steady state in the striato-nigral and striato-pallidal complex is not consistent with and is likely independent from the concomitant down-regulation of PDE10A. Therefore, dopamine loss inversely regulates PDE10A gene expression in the striatum and PDE10A post-transcription in the nucleus accumbens, therein differentially modulating PDE10A-dependent cAMP catabolism.

Lowered cAMP and cGMP signalling in the brain during levodopa-induced dyskinesias in hemiparkinsonian rats: new aspects in the pathogenetic mechanisms.

Dysregulation of dopamine receptors is thought to underlie levodopa-induced dyskinesias in experimental models of Parkinson's disease. It is unknown whether an imbalance of the second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), is involved in the alterations of levodopa/dopamine signal transduction. We examined cAMP and cGMP signalling in the interconnected cortico-striatal-pallidal loop at the peak of levodopa-induced dyskinesias in rats with 6-hydroxydopamine lesions in the substantia nigra. In addition, we examined the role of phosphodiesterase (PDE) and the rate of cAMP and cGMP degradation on the severity of levodopa-induced dyskinesias in animals pretreated with PDE inhibitor, zaprinast. Unilateral lesion of substantia nigra led to an increase in cAMP but a decrease in cGMP levels in the ipsilateral basal ganglia. After chronic levodopa treatment, cAMP and cGMP were differentially regulated in eukinetic animals: the cAMP level increased in the cortex and striatum but decreased in the globus pallidus of both hemispheres, whereas the cGMP decreased below baseline levels in the contralateral cortico-striatal-pallidal regions. In dyskinetic animals chronic levodopa treatment led to an absolute decrease in cAMP and cGMP levels in cortico-striatal-pallidal regions of both hemispheres. Pretreatment with zaprinast reduced the severity of levodopa-induced dyskinesias, and partly prevented the decrease in cyclic nucleotides compared with pretreatment with saline-levodopa. In conclusion, using a rat model of hemiparkinsonism, we observed a significant reduction in the levels of cyclic nucleotides in both hemispheres at the peak of levodopa-induced dyskinesias. We propose that such a decrease in cyclic nucleotides may partly result from increased catabolism through PDE overactivity.

RANTES and human sperm fertilizing ability: effect on acrosome reaction and sperm/oocyte fusion.

Beta-chemokine, regulated on activation and normally T-cell expressed and presumably secreted (RANTES), is present in both the male and female genital tract fluids where its levels increase in diseases related to infertility, such as endometriosis and male genital tract infections. beta-Chemokine receptors (CCR3 and CCR5) are expressed on freshly ejaculated human sperm cells and a sperm chemoattractant effect for RANTES has been reported. No information exists on other possible roles of RANTES on sperm functions involved in the fertilization process. In the present study, the exposure of sperm suspensions to high concentrations of the chemokine, comparable to those observed in inflammatory diseases, significantly decreased the stimulatory effect exerted by progesterone on sperm/oocyte fusion, evaluated by means of the hamster egg penetration test. Accordingly, a large proportion of spermatozoa preincubated under capacitating conditions with high concentrations of RANTES underwent a premature acrosome reaction (AR) that prevented subsequent progesterone-induced AR. Finally, sperm samples exposed to the same high levels of chemokine showed a significant increase in the intracellular levels of cAMP, which is involved in capacitation and AR dynamics. These results indicate a negative interference of high levels of RANTES on the sperm fertilizing ability, thereby suggesting a potential contribution of this chemokine to subfertility associated with endometriosis and genital tract inflammatory diseases.