Abstract
Parkinson's disease is characterized by dopaminergic neuron loss and dopamine (DA) depletion in the striatum. Standard treatment is still focused on the restoration of dopamine with exogenous L-Dopa, which however causes L-Dopa-induced dyskinesia (LID). Several studies have shown that antagonism of the metabotropic glutamate receptor 5 alleviates LID, but the underlying mechanisms have remained unclear. We set out to determine where this alleviation may depend on restoring the equilibrium between the two main striatofugal pathways. For this purpose, we examined molecular markers of direct and indirect pathway involvement (prodynorphin and proenkephalin, resp.) in a rat model of LID treated with the mGluR5 antagonist MTEP. Our results show that MTEP cotreatment significantly attenuates the upregulation of prodynorphin mRNA induced by L-Dopa while also decreasing the expression levels of proenkephalin mRNA. We also examined markers of the mGluR5-related PKC/MEK/ERK1/2 signaling pathway, finding that both the expression of PKC epsilon and the phosphorylation of MEK and ERK1/2 had decreased significantly in the MTEP-treated group. Taken together, our results show that pharmacological antagonism of mGluR5 normalizes several abnormal molecular responses in the striatum in this experimental model of LID.
Highlights
The loss of dopaminergic neurons in the substantia nigra and the depletion of dopamine are main neuropathological features of Parkinson’s disease (PD) [1, 2]
Sgroi et al pointed out that, on the one hand, the preproenkephalin level was increased before the use of L-Dopa after 6-OHDA lesion, and it remained high after L-Dopa washout; on the other hand, there is a correlation between the rotational abnormal involuntary movement (AIM) and preproenkephalin level in the on state [8]
It is established that 6-OHDA-lesioned Parkinsonian rats have an abnormal increase in the mRNA level of the direct and indirect markers [5, 7, 8]; in this present study, we found that striatal mRNA of proenkephalin was increased in PD rats and continued to increase after intermittent use of L-Dopa; as for the mRNA level of prodynorphin, it exhibited a minor drop in 6-OHDAlesioned PD rats and this tendency reversed significantly after priming with L-Dopa in the following days (Figures 5(a) and 5(b)); these were consistent with the findings of Sgroi et al [8]
Summary
The loss of dopaminergic neurons in the substantia nigra and the depletion of dopamine are main neuropathological features of Parkinson’s disease (PD) [1, 2]. Sgroi et al pointed out that, on the one hand, the preproenkephalin level was increased before the use of L-Dopa after 6-OHDA lesion, and it remained high after L-Dopa washout; on the other hand, there is a correlation between the rotational AIM and preproenkephalin level in the on state [8] All these phenomenons suggested that the increased proenkephalin mRNA level may be a prerequisite to the locomotor sensitization before L-Dopa treatment [8]. It is of great importance to investigate the extent to which the blockade of the metabotropic receptor 5 affects the imbalance between direct and indirect pathways and to investigate what the molecular alterations in the mGluR5-related signaling pathway are, in order to interpret the antidyskinesia effect of the antagonists of mGluR5.
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