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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.

Gan J, Qi C, Liu Z - Drug Des Devel Ther (2015)

Bottom Line: 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.We also found that L-DOPA increased CaMKII autophosphorylation at T286 in striatal neurons.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Xinhua Hospital affiliated to Shanghai Jiao Tong University Medical School, Shanghai, People's Republic of China.

ABSTRACT

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus

Effects of KN-93 on l-DOPA-induced dyskinesia in PD rats.Notes: Group 1: the rats with 21 days of treatment of l-DOPA and benserazide followed by KN93 treatment on day 22. Group 2: the rats with 22 days of treatment of l-DOPA and benserazide. (A) Effects of KN93 on ALO scores. (B) Effects of KN-93 on AIM scores. (C) Effects of KN-93 on the duration of rotation. Chronic l-DOPA treatment induced a steady decrease in the duration of rotation and increases in AIM and ALO scores in both Group 1 and Group 2 on day 21 compared with day 2. On day 22, intrastriatal KN-93 administration reversed the decrease in the duration of rotation (C) and the increase in ALO/AIM scores (A, B) in Group 1, compared to Group 2. Data are expressed in terms of means±SEMs (n=6 per group 1). *P<0.05 compared with Group 1 on day 22. #P<0.05 compared with day 2 in two groups. ΔP<0.05 compared with day 21 in Group1.Abbreviations: ALO, axial, limb and orolingual; AIM, abnormal involuntary movements; KN-93, N-[2-[[[3- (4-chlorophenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide; PD, Parkinson’s disease; l-DOPA, l–3,4-dihydroxyphenylalanine; SEM, standard error of the mean.
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f1-dddt-9-2119: Effects of KN-93 on l-DOPA-induced dyskinesia in PD rats.Notes: Group 1: the rats with 21 days of treatment of l-DOPA and benserazide followed by KN93 treatment on day 22. Group 2: the rats with 22 days of treatment of l-DOPA and benserazide. (A) Effects of KN93 on ALO scores. (B) Effects of KN-93 on AIM scores. (C) Effects of KN-93 on the duration of rotation. Chronic l-DOPA treatment induced a steady decrease in the duration of rotation and increases in AIM and ALO scores in both Group 1 and Group 2 on day 21 compared with day 2. On day 22, intrastriatal KN-93 administration reversed the decrease in the duration of rotation (C) and the increase in ALO/AIM scores (A, B) in Group 1, compared to Group 2. Data are expressed in terms of means±SEMs (n=6 per group 1). *P<0.05 compared with Group 1 on day 22. #P<0.05 compared with day 2 in two groups. ΔP<0.05 compared with day 21 in Group1.Abbreviations: ALO, axial, limb and orolingual; AIM, abnormal involuntary movements; KN-93, N-[2-[[[3- (4-chlorophenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide; PD, Parkinson’s disease; l-DOPA, l–3,4-dihydroxyphenylalanine; SEM, standard error of the mean.

Mentions: The comparison of AIM score, ALO score and duration of rotation from day 2 through day 22 are shown in Figure 1. After 21 days of chronic l-DOPA treatment in PD rats, dyskinesia was observed in both Group 1 and 2 (displayed by the elevated AIM score [61.00±2.68 in Group 1, 63.20±2.33 in Group 2], the ALO score [45.83±2.76 in Group 1, 47.60±2.58 in Group 2] and the reduced duration of rotation [94.67±2.50 in Group 1, 96.00±3.85 in Group 2] on day 21 compared with that of day 2 respectively [P<0.05]). The AIM scores on day 2 were 50.00±3.22 in Group 1, 48.40±2.01 in Group 2; ALO scores were 34.67±2.76 in Group 1, 35.60±5.00 in Group 2; the duration of rotation was 130.33±3.02 in Group 1, 130.40±3.54 in Group 2 (Figure 1). On day 22, we found that intrastriatal KN-93 injection in Group 1 (l-DOPA+/KN-93+) significantly reduced the ALO score to 37.67±1.52 and the AIM score to 53.83±2.15 compared to Group 2 (l-DOPA+/KN-93−) (ALO: 47.00±2.30, AIM: 61.80±2.80, respectively) (P<0.05). At the same time, the duration of rotation in Group 1 returned to 112.33±2.43 while in Group 2 that was 98.00±3.63 (P<0.01). In Group 1, on day 22, the ALO score was lower than that on day 21 (P<0.05) and the duration of rotation was longer than that on day 21 (P<0.05). The AIM score showed a tendency of decrease compared with day 21, though there was no statistical difference (Figure 1). Altogether, these data show that intrastriatal inhibition of CaMKII ameliorates LID in PD rats.


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.

Gan J, Qi C, Liu Z - Drug Des Devel Ther (2015)

Effects of KN-93 on l-DOPA-induced dyskinesia in PD rats.Notes: Group 1: the rats with 21 days of treatment of l-DOPA and benserazide followed by KN93 treatment on day 22. Group 2: the rats with 22 days of treatment of l-DOPA and benserazide. (A) Effects of KN93 on ALO scores. (B) Effects of KN-93 on AIM scores. (C) Effects of KN-93 on the duration of rotation. Chronic l-DOPA treatment induced a steady decrease in the duration of rotation and increases in AIM and ALO scores in both Group 1 and Group 2 on day 21 compared with day 2. On day 22, intrastriatal KN-93 administration reversed the decrease in the duration of rotation (C) and the increase in ALO/AIM scores (A, B) in Group 1, compared to Group 2. Data are expressed in terms of means±SEMs (n=6 per group 1). *P<0.05 compared with Group 1 on day 22. #P<0.05 compared with day 2 in two groups. ΔP<0.05 compared with day 21 in Group1.Abbreviations: ALO, axial, limb and orolingual; AIM, abnormal involuntary movements; KN-93, N-[2-[[[3- (4-chlorophenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide; PD, Parkinson’s disease; l-DOPA, l–3,4-dihydroxyphenylalanine; SEM, standard error of the mean.
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Related In: Results  -  Collection

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f1-dddt-9-2119: Effects of KN-93 on l-DOPA-induced dyskinesia in PD rats.Notes: Group 1: the rats with 21 days of treatment of l-DOPA and benserazide followed by KN93 treatment on day 22. Group 2: the rats with 22 days of treatment of l-DOPA and benserazide. (A) Effects of KN93 on ALO scores. (B) Effects of KN-93 on AIM scores. (C) Effects of KN-93 on the duration of rotation. Chronic l-DOPA treatment induced a steady decrease in the duration of rotation and increases in AIM and ALO scores in both Group 1 and Group 2 on day 21 compared with day 2. On day 22, intrastriatal KN-93 administration reversed the decrease in the duration of rotation (C) and the increase in ALO/AIM scores (A, B) in Group 1, compared to Group 2. Data are expressed in terms of means±SEMs (n=6 per group 1). *P<0.05 compared with Group 1 on day 22. #P<0.05 compared with day 2 in two groups. ΔP<0.05 compared with day 21 in Group1.Abbreviations: ALO, axial, limb and orolingual; AIM, abnormal involuntary movements; KN-93, N-[2-[[[3- (4-chlorophenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide; PD, Parkinson’s disease; l-DOPA, l–3,4-dihydroxyphenylalanine; SEM, standard error of the mean.
Mentions: The comparison of AIM score, ALO score and duration of rotation from day 2 through day 22 are shown in Figure 1. After 21 days of chronic l-DOPA treatment in PD rats, dyskinesia was observed in both Group 1 and 2 (displayed by the elevated AIM score [61.00±2.68 in Group 1, 63.20±2.33 in Group 2], the ALO score [45.83±2.76 in Group 1, 47.60±2.58 in Group 2] and the reduced duration of rotation [94.67±2.50 in Group 1, 96.00±3.85 in Group 2] on day 21 compared with that of day 2 respectively [P<0.05]). The AIM scores on day 2 were 50.00±3.22 in Group 1, 48.40±2.01 in Group 2; ALO scores were 34.67±2.76 in Group 1, 35.60±5.00 in Group 2; the duration of rotation was 130.33±3.02 in Group 1, 130.40±3.54 in Group 2 (Figure 1). On day 22, we found that intrastriatal KN-93 injection in Group 1 (l-DOPA+/KN-93+) significantly reduced the ALO score to 37.67±1.52 and the AIM score to 53.83±2.15 compared to Group 2 (l-DOPA+/KN-93−) (ALO: 47.00±2.30, AIM: 61.80±2.80, respectively) (P<0.05). At the same time, the duration of rotation in Group 1 returned to 112.33±2.43 while in Group 2 that was 98.00±3.63 (P<0.01). In Group 1, on day 22, the ALO score was lower than that on day 21 (P<0.05) and the duration of rotation was longer than that on day 21 (P<0.05). The AIM score showed a tendency of decrease compared with day 21, though there was no statistical difference (Figure 1). Altogether, these data show that intrastriatal inhibition of CaMKII ameliorates LID in PD rats.

Bottom Line: 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.We also found that L-DOPA increased CaMKII autophosphorylation at T286 in striatal neurons.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Xinhua Hospital affiliated to Shanghai Jiao Tong University Medical School, Shanghai, People's Republic of China.

ABSTRACT

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus