title: CNI-1493 attenuates neuroinflammation and dopaminergic neurodegeneration in the acute MPTP mouse model of Parkinson's disease.
abstract: BACKGROUND
  Parkinson's disease (PD) is associated with neurodegeneration of dopaminergic neurons in the substantia nigra. Neuroinflammatory processes have been shown to be a key component of this neurodegeneration and, as such, small molecule compounds which inhibit these inflammatory events are a critical research focus.
  
  
  OBJECTIVE
  CNI-1493 is an anti-inflammatory compound that strongly inhibits macrophages and also stimulates the cholinergic anti-inflammatory pathway. We have examined whether CNI-1493 has a neuroprotective effect in the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD.
  
  
  METHODS
  CNI-1493 (8 mg/kg i.p.) or placebo administration was started 1 day before MPTP intoxication and repeated daily until sacrifice after MPTP intoxication. C57/Bl6 mice - either treated with CNI-1493 or with placebo - were injected intraperitoneally 4 times at 2-hour intervals with either 20 mg/kg MPTP-HCl or a corresponding volume of saline. Two or 7 days after the end of the MPTP intoxication, the animals were killed and their brains were processed for further analysis.
  
  
  RESULTS
  Administration of CNI-1493 markedly protected tyrosine hydroxylase-positive substantia nigra neurons against MPTP neurotoxicity. CNI-1493 treatment in the MPTP model was also accompanied by a profound reduction of activated microglia within the substantia nigra, as measured by ionized calcium-binding adapter molecule-1 staining.
  
  
  CONCLUSIONS
  These findings support that CNI-1493 could reduce the MPTP-induced toxicity likely by inhibition of neuroinflammatory responses. The neuroprotective effect of CNI-1493 suggests that CNI-1493 might be a valuable neuroprotective candidate in the future treatment of PD.
authors.affiliation: Department of Neurology, Philipps University Marburg, Marburg, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Noelker
authors.forename: Vanessa
authors.initials: V
authors.lastname: Stuckenholz
authors.forename: Jens-Peter
authors.initials: JP
authors.lastname: Reese
authors.forename: Daniel
authors.initials: D
authors.lastname: Alvarez-Fischer
authors.forename: Roman
authors.initials: R
authors.lastname: Sankowski
authors.forename: Tanja
authors.initials: T
authors.lastname: Rausch
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Oertel
authors.forename: Andreas
authors.initials: A
authors.lastname: Hartmann
authors.forename: Sonya
authors.initials: S
authors.lastname: van Patten
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
authors.forename: Michael
authors.initials: M
authors.lastname: Bacher
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000473:pathology*; D006835:Hydrazones / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000473:pathology; D010300:Parkinson Disease / Q000188:drug therapy* / Q000473:pathology; D000813:Anilides; D006146:Guanidines
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D006835:Hydrazones; C097256:semapimod; D000813:Anilides; D006146:Guanidines