kn-93 and Dyskinesia--Drug-Induced

kn-93 has been researched along with Dyskinesia--Drug-Induced* in 3 studies

Other Studies

3 other study(ies) available for kn-93 and Dyskinesia--Drug-Induced

ArticleYear
CaMKII inhibition ameliorated levodopa-induced dyskinesia by downregulating tyrosine hydroxylase activity in an experimental model of Parkinson's disease.
    Brain research, 2018, 05-15, Volume: 1687

    Levodopa (L-dopa) remains the best treatment for Parkinson's disease (PD). However, long-term L-dopa treatment induces dyskinesia. The mechanism of L-dopa-induced dyskinesia (LID) is not fully understood. Enhanced activity of protein kinase A (PKA) and pulsatile dopamine (DA) stimulation plays an important role in LID. Tyrosine hydroxylase (TH) is the rate-limiting enzyme for DA synthesis. Decreased TH activity causes reduced pulsatile DA stimulation, which in turn reduces LID. Moreover, TH is a substrate of CaMKII. However, it is unknown whether inhibition of CaMKII reduces LID by downregulating the activity of TH. In this study, we found that CaMKII antagonist KN-93 reduced DA released in PC12 cells; in the meantime, KN-93 reduced phosphorylated levels of CaMKIIα and TH at Ser 40. Intrastriatal administration of KN-93 reduced LID without affecting the antiparkinsonian effect of L-dopa in PD mice. Mechanistically, KN-93 treatmentreduced phosphorylated CaMKIIα levels and subsequently downregulated phosphorylated TH at Ser 40 expression. Consequently, extracellular DA efflux was reduced andthe activation threshold of the PKA pathway was lowered. Moreover, KN-93 treatment reduced the expression of Arc and Penk, two immediate early genes, induced by chronic L-dopa. These data indicate that inhibition of CaMKIIα decreases LID at least partially by suppressing TH activity and subsequently reducing extracellular DA efflux and the activity of the PKA pathway, suggesting that CaMKIIα may be an alternative target for the treatment of LID.

    Topics: Animals; Antiparkinson Agents; Benzylamines; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Corpus Striatum; Disease Models, Animal; Dopamine; Dyskinesia, Drug-Induced; Levodopa; Male; Mice, Inbred C57BL; Oxidopamine; Parkinson Disease; Parkinson Disease, Secondary; PC12 Cells; Protein Kinase Inhibitors; Rats; Signal Transduction; Sulfonamides; Sympatholytics; Tyrosine 3-Monooxygenase

2018
Modulation of CaMKIIa-GluN2B interaction in levodopa-induced dyskinesia in 6-OHDA-lesioned Parkinson's rats.
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2018, Volume: 107

    Long-term treatment with L-dopa leads to involuntary aimless movements called L-dopa-induced dyskinesia (LID) has hindered its use in Parkinson's disease (PD) patients. Emerging evidence suggests a possible role of CaMKIIa and its interacting partners in the development of LID. In this study, we found that CaMKIIa was found to form complexes with GluN2B after chronic administration of L-dopa in adult rat striatal neurons. Intrastriatal injection of KN-93 significantly reduced the level of GluN2B in CaMKIIa precipitates with a dose dependent response, as well as reduced the Global ALO AIM score without ablation of the therapeutic response to L-dopa. In parallel, intrastriatal injection of MK-801 significantly alleviated the level of CaMKIIa in GluN2B precipitates compared to LID group (p < 0.01), and this is accompanied by realizing improvement of the Global ALO AIM score also without affect the efficacy of L-dopa. In summary, the present study indicated that CaMKIIa-GluN2B interaction had an important role in the development of LID. Disrupt of this link by intrastriatal infusion of KN-93 or MK-801 ameliorated dyskinesia in 6-OHDA-lesioned PD rats.

    Topics: Animals; Behavior, Animal; Benzylamines; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Corpus Striatum; Dizocilpine Maleate; Dyskinesia, Drug-Induced; Levodopa; Male; Neurons; Oxidopamine; Parkinson Disease; Phosphorylation; Protein Binding; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Sulfonamides

2018
Roles of Ca(2+)/calmodulin-dependent protein kinase II in subcellular expression of striatal N-methyl-D-aspartate receptors in l-3, 4-dihydroxyphenylalanine-induced dyskinetic rats.
    Drug design, development and therapy, 2015, Volume: 9

    The role of N-Methyl-D-aspartate (NMDA) receptors is critical to the development of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in Parkinson's disease (PD). Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is thought to regulate the expression and activation of NMDA receptors in LID, but the interaction between LID and CaMKII-modulated NMDA receptor activity is not clear so far.. We used 6-hydroxydopamine-lesioned rats to create PD rat model, and at least 21 days of L-DOPA was administrated followed with or without microinjection of CaMKII inhibitor KN-93 into the lesioned striatum of all the PD rats and sham rats. A surface receptor cross-linking assay was used to distinguish expression of striatal NMDA receptors in surface and intracellular compartments.. L-DOPA treatment enhanced surface levels of GluN1 expression and reduced its intracellular expression, but did not change total levels of GluN1 protein in the lesioned striatum. In contrast, l-DOPA decreased GluN2A surface expression but increased its intracellular expression. L-DOPA increased GluN2B expression preferentially in the surface compartment. We also found that L-DOPA increased CaMKII autophosphorylation at T286 in striatal neurons. The inhibition of CaMKII by microinjecting CaMKII inhibitor KN-93 into the lesioned striatum largely reversed the L-DOPA-induced changes in three subunits. In addition, dyskinetic behaviors of animals were observed alleviated after treatment of KN-93.. Our research indicates that long-term L-DOPA administration activates CaMKII in striatal neurons. Activated CaMKII is involved at least in part in mediating L-DOPA-induced changes of NMDA receptors surface/intracellular expression.

    Topics: Animals; Antiparkinson Agents; Benzylamines; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Levodopa; Male; Neostriatum; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Structure-Activity Relationship; Sulfonamides

2015