pyrimidinones and Parkinsonian-Disorders

The accumulation of α-syn which induce endoplasmic reticulum stress (ERS) and mediate various signaling pathways involved in DA neuronal degeneration, and the apoptosis of dopamine (DA) neurons are pathological markers of Parkinson's disease (PD). High-temperature requirement protein A2 (HtrA2) is synthesized in the endoplasmic reticulum, and the expression level of HtrA2 can be upregulated by drugs or by unfolded proteins. Ucf-101 is a specific inhibitor of HtrA2, and studies have shown that Ucf-101 reduced apoptosis in PC12 cells. Our study showed that PC12 cells treated with 60 μM 6-OHDA for 24 h had significantly decreased cell viability compared to that of controls. A low concentration (2.5 μM) of Ucf-101 decreased the apoptosis rate of the PD cell model, but a high concentration (≥10 μM) increased the apoptosis rate, compared to that of controls. 6-OHDA upregulated the expression of HtrA2, α-syn, CHOP, Grp78 and active caspase-3 and reduced the levels of TH and XIAP. Ucf-101 reduced the level of ERS and apoptosis bothin vivoandin vitro. The ratio of p-GSK3β (Tyr216 to Ser9) increased in PD rats. However, Ucf-101 down-regulated the activation of GSK3β and activated the Wnt/β-catenin pathway that was caused by 6-OHDA. Ucf-101 activated the Wnt/β-catenin pathway and significantly attenuated 6-OHDA-induced neurotoxicity, which was related to the inhibition of ERS and the reduction of the apoptosis rate of PC12 cells and DA neurons in the midbrain of PD rats. Ucf-101 has certain neuroprotective effects.

Topics: Animals; Apoptosis; beta Catenin; Cell Survival; Dopaminergic Neurons; Endoplasmic Reticulum Stress; Neuroprotective Agents; Parkinsonian Disorders; PC12 Cells; Pyrimidinones; Rats; Thiones; Wnt Signaling Pathway

The aim of the present study was to evaluate the role of the nitric oxide/cyclic guanosine monophosphate pathway in corticostriatal long-term depression induction in a model of levodopa-induced dyskinesia in experimental parkinsonism. Moreover, we have also analysed the possibility of targeting striatal phosphodiesterases to reduce levodopa-induced dyskinesia. To study synaptic plasticity in sham-operated rats and in 6-hydroxydopamine lesioned animals chronically treated with therapeutic doses of levodopa, recordings from striatal spiny neurons were taken using either intracellular recordings with sharp electrodes or whole-cell patch clamp techniques. Behavioural analysis of levodopa-induced abnormal involuntary movements was performed before and after the treatment with two different inhibitors of phosphodiesterases, zaprinast and UK-343664. Levodopa-induced dyskinesia was associated with the loss of long-term depression expression at glutamatergic striatal synapses onto spiny neurons. Both zaprinast and UK-343664 were able to rescue the induction of this form of synaptic plasticity via a mechanism requiring the modulation of intracellular cyclic guanosine monophosphate levels. This effect on synaptic plasticity was paralleled by a significant reduction of abnormal movements following intrastriatal injection of phosphodiesterase inhibitors. Our findings suggest that drugs selectively targeting phosphodiesterases can ameliorate levodopa-induced dyskinesia, possibly by restoring physiological synaptic plasticity in the striatum. Future studies exploring the possible therapeutic effects of phosphodiesterase inhibitors in non-human primate models of Parkinson's disease and the involvement of striatal synaptic plasticity in these effects remain necessary to validate this hypothesis.

Topics: Animals; Corpus Striatum; Cyclic GMP; Dyskinesia, Drug-Induced; Levodopa; Long-Term Synaptic Depression; Male; Microinjections; Neurons; Oxidopamine; Parkinsonian Disorders; Phosphodiesterase Inhibitors; Piperazines; Purinones; Pyrimidinones; Rats; Rats, Wistar