title: Intrastriatal injections of KN-93 ameliorates levodopa-induced dyskinesia in a rat model of Parkinson's disease.
abstract: BACKGROUND
  Levodopa remains the most effective drug for the treatment of Parkinson's disease (PD). However, long-term levodopa treatment is associated with the emergence of levodopa-induced dyskinesia (LID), which has hampered its use for PD treatment. The mechanisms of LID are only partially understood. A previous study showed that KN-93, a Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibitor, could be used to ameliorate LID in rats. However, the precise mechanisms by which KN-93 acts as an antidyskinetic are not fully understood.
  
  
  METHODS
  In the present study, a rat model of PD was induced by 6-hydroxydopamine (OHDA) injections. Then, the successfully lesioned rats were intrastriatally administered with a different dose of KN-93 (1 μg, 2 μg, or 5 μg) prior to levodopa treatment. Abnormal involuntary movements (AIMs) scores and apomorphine-induced rotations were measured in PD rats. Phosphorylated levels of GluR1 at Serine-845 (pGluR1S845) levels were determined by western blot. Arc and Penk levels were measured by real-time polymerase chain reaction (PCR).
  
  
  RESULTS
  We found that both 2 μg and 5 μg KN-93 treatment lowered AIMs scores in levodopa priming PD rats without affecting the antiparkinsonian effect of levodopa. In agreement with behavioral analysis, KN-93 treatment (2 μg) reduced pGluR1S845 levels in PD rats. Moreover, KN-93 treatment (2 μg) reduced the expression of Gad1 and Nur77 in PD rats.
  
  
  CONCLUSIONS
  These data indicated that intrastriatal injections of KN-93 were beneficial in reducing the expression of LID by lowering the expression of pGluR1S845 via suppressing the activation of CaMKII in PD rats. Decreased expression of pGluR1S845 further reduced the expression of Gad1 and Nur77 in PD rats.
authors: Department of Neurology, Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors: Xinxin
authors: X
authors: Yang
authors: Na
authors: N
authors: Wu
authors: Lu
authors: L
authors: Song
authors: Zhenguo
authors: Z
authors: Liu
keywords: KN-93; Parkinson’s disease; levodopa-induced dyskinesia
references: PLoS One. 2010 Aug 23;5(8):e12322
references: 20808799
references: Synapse. 2010 Feb;64(2):177-80
references: 19852073
references: Neuropharmacology. 2010 Jan;58(1):286-96
references: 19576910
references: Neuroscience. 2010 Jun 2;167(4):1160-7
references: 20303391
references: J Neural Transm (Vienna). 2011 Dec;118(12):1661-90
references: 21881839
references: Mov Disord. 2011 Nov;26(13):2354-63
references: 21953539
references: J Pharm Pharmacol. 2012 May;64(5):637-43
references: 22471359
references: J Neuropathol Exp Neurol. 2005 Nov;64(11):936-47
references: 16254488
references: Neuroscience. 2011 Dec 15;198:245-51
references: 21840375
references: Mov Disord. 2011 Oct;26(12):2160-8
references: 21887711
references: J Neurochem. 2010 Jul;114(2):499-511
references: 20456008
references: J Neurosci. 2007 Jun 27;27(26):6995-7005
references: 17596448
references: Neurochem Res. 2009 Aug;34(8):1513-21
references: 19283475
references: Biol Psychiatry. 2009 Sep 15;66(6):603-13
references: 19520364
references: Neurobiol Dis. 2009 Oct;36(1):213-22
references: 19635563
references: Biol Psychiatry. 2007 Oct 1;62(7):800-10
references: 17662258
references: Eur J Pharmacol. 2012 May 15;683(1-3):71-7
references: 22410193
references: J Clin Neurosci. 2012 Mar;19(3):343-8
references: 22249009
references: Eur J Pharmacol. 2012 May 15;683(1-3):166-73
references: 22449381
references: Neuroscience. 2012 Jun 1;211:13-27
references: 22465440
references: Neurobiol Dis. 2012 Dec;48(3):379-90
references: 22759925
references: Exp Neurol. 2007 Nov;208(1):110-9
references: 17900568
references: Neurobiol Dis. 2012 Jan;45(1):573-82
references: 22001605
references: Mov Disord. 2012 Feb;27(2):284-8
references: 22161845
references: J Neurosci. 2012 Apr 25;32(17):5900-10
references: 22539851
references: Neurochem Res. 2011 Jun;36(6):1135-44
references: 21461922