title: Lenalidomide reduces microglial activation and behavioral deficits in a transgenic model of Parkinson's disease.
abstract: BACKGROUND
  Parkinson's disease (PD) is one of the most common causes of dementia and motor deficits in the elderly. PD is characterized by the abnormal accumulation of the synaptic protein alpha-synuclein (α-syn) and degeneration of dopaminergic neurons in substantia nigra, which leads to neurodegeneration and neuroinflammation. Currently, there are no disease modifying alternatives for PD; however, targeting neuroinflammation might be a viable option for reducing motor deficits and neurodegeneration. Lenalidomide is a thalidomide derivative designed for reduced toxicity and increased immunomodulatory properties. Lenalidomide has shown protective effects in an animal model of amyotrophic lateral sclerosis, and its mechanism of action involves modulation of cytokine production and inhibition of NF-κB signaling.
  
  
  METHODS
  In order to assess the effect of lenalidomide in an animal model of PD, mThy1-α-syn transgenic mice were treated with lenalidomide or the parent molecule thalidomide at 100 mg/kg for 4 weeks.
  
  
  RESULTS
  Lenalidomide reduced motor behavioral deficits and ameliorated dopaminergic fiber loss in the striatum. This protective action was accompanied by a reduction in microgliosis both in striatum and hippocampus. Central expression of pro-inflammatory cytokines was diminished in lenalidomide-treated transgenic animals, together with reduction in NF-κB activation.
  
  
  CONCLUSIONS
  These results support the therapeutic potential of lenalidomide for reducing maladaptive neuroinflammation in PD and related neuropathologies.
authors.affiliation: Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0624, USA. evaleramartin@ucsd.edu.
authors.forename: Elvira
authors.initials: E
authors.lastname: Valera
authors.affiliation: Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0624, USA. mmante@ucsd.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Mante
authors.affiliation: Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0624, USA. scanderson@ucsd.edu.
authors.forename: Scott
authors.initials: S
authors.lastname: Anderson
authors.affiliation: Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0624, USA. erockenstein@ucsd.edu.
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.affiliation: Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0624, USA. emasliah@ucsd.edu.|Department of Pathology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0624, USA. emasliah@ucsd.edu.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002461:Cell Line, Transformed; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D000077269:Lenalidomide; D001523:Mental Disorders / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects*; D010300:Parkinson Disease / Q000150:complications* / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D007155:Immunologic Factors; D012333:RNA, Messenger; D051844:alpha-Synuclein; D013792:Thalidomide; D000077269:Lenalidomide; D004298:Dopamine