title: Peripheral administration of the selective inhibitor of soluble tumor necrosis factor (TNF) XPro®1595 attenuates nigral cell loss and glial activation in 6-OHDA hemiparkinsonian rats.
abstract: BACKGROUND
  Parkinson's disease (PD) is a complex multi-system age-related neurodegenerative disorder. Targeting the ongoing neuroinflammation in PD patients is one strategy postulated to slow down or halt disease progression. Proof-of-concept studies from our group demonstrated that selective inhibition of soluble Tumor Necrosis Factor (solTNF) by intranigral delivery of dominant negative TNF (DN-TNF) inhibitors reduced neuroinflammation and nigral dopamine (DA) neuron loss in endotoxin and neurotoxin rat models of nigral degeneration.
  
  
  OBJECTIVE
  As a next step toward human clinical trials, we aimed to determine the extent to which peripherally administered DN-TNF inhibitor XPro®1595 could: i) cross the blood-brain-barrier in therapeutically relevant concentrations, ii) attenuate neuroinflammation (microglia and astrocyte), and iii) mitigate loss of nigral DA neurons in rats receiving a unilateral 6-hydroxydopamine (6-OHDA) striatal lesion.
  
  
  METHODS
  Rats received unilateral 6-OHDA (20 μg into the right striatum). Three or 14 days after lesion, rats were dosed with XPro®1595 (10 mg/kg in saline, subcutaneous) every third day for 35 days. Forelimb asymmetry was used to assess motor deficits after the lesion; brains were harvested 35 days after the lesion for analysis of XPro®1595 levels, glial activation and nigral DA neuron number.
  
  
  RESULTS
  Peripheral subcutaneous dosing of XPro®1595 achieved plasma levels of 1-8 microgram/mL and CSF levels of 1-6 ng/mL depending on the time the rats were killed after final XPro®1595 injection. Irrespective of start date, XPro®1595 significantly reduced microglia and astrocyte number in SNpc whereas loss of nigral DA neurons was attenuated when drug was started 3, but not 14 days after the 6-OHDA lesion.
  
  
  CONCLUSIONS
  Our data suggest that systemically administered XPro®1595 may have disease-modifying potential in PD patients where inflammation is part of their pathology.
authors: Department of Physiology, Emory University School of Medicine, Atlanta, GA, USA.
authors: Christopher J
authors: CJ
authors: Barnum
authors: Department of Physiology, Emory University School of Medicine, Atlanta, GA, USA.
authors: Xi
authors: X
authors: Chen
authors: Department of Physiology, Emory University School of Medicine, Atlanta, GA, USA.
authors: Jaegwon
authors: J
authors: Chung
authors: Department of Physiology, Emory University School of Medicine, Atlanta, GA, USA.
authors: Jianjun
authors: J
authors: Chang
authors: Department of Physiology, Emory University School of Medicine, Atlanta, GA, USA.
authors: Martha
authors: M
authors: Williams
authors: Department of Physiology, Emory University School of Medicine, Atlanta, GA, USA.
authors: Nelly
authors: N
authors: Grigoryan
authors: FPRT Bio, Inc., Scranton, PA, USA.
authors: Raymond J
authors: RJ
authors: Tesi
authors: Department of Physiology, Emory University School of Medicine, Atlanta, GA, USA.
authors: Malú G
authors: MG
authors: Tansey
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D002452:Cell Count; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology; D004660:Encephalitis / Q000517:prevention & control; D005911:Gliosis / Q000517:prevention & control; D008297:Male; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects* / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000493:pharmacokinetics
chemical_list: D014409:Tumor Necrosis Factor-alpha; C540591:XENP 1595; D016627:Oxidopamine
keywords: $XPro^{\reg}1595$; 6-OHDA; Parkinson's disease; astrocytes; inflammation; microglia; substantia nigra; tumor necrosis factor