FIGURE 2.

Targeting signaling upstream/downstream of Ras/Raf/MEK/ERK pathway modulation in LID. In the experimental model of PD, L-DOPA administration causes abnormal activation of the RAS/RAF/ERK pathway and results in the emergence of dyskinetic behavior. Activation of D1R, Trk-B, or NMDA receptor causes activation of RAS-GDP molecular switch by Ras-guanyl nucleotide-releasing factor 1 (Ras-GRF1), which facilitates the conversion of RAS-GTP to Ras-GDP. Ras-GDP further causes the activation of Raf protein kinase, which in turn leads to the phosphorylation of mitogen-activated protein kinase/ERK kinase (MEK) and ERK. Activation of ERK enhances expression of the transcription factor ΔFosB- and ERK-dependent activation of mTORC1, which results in the inhibition of long-term depression in striatal neurons and development of the abnormal involuntary movement in PD patients. Attenuation of Ras-GRF1 in the knock-out mice model results in the attenuation of LID. A similar reduction in LID was resulted in the inhibition of Ras (by simvastatin) and MEK (by SL327) expression. On the other hand, the inhibition of ΔFosB by short hairpin RNA and blockade of mTORC1 by rapamycin has been shown to mitigate LID. Various NMDA receptor antagonists have also been reported to reduce the expression of the Ras/Raf pathway and support their efficacy in LID.