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

J Parkinsons Dis. 2014;4(3):349-60. doi: 10.3233/JPD-140410.


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.

Keywords: $XPro^{\reg}1595$; 6-OHDA; Parkinson's disease; astrocytes; inflammation; microglia; substantia nigra; tumor necrosis factor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier
  • Cell Count
  • Disease Models, Animal
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / pathology
  • Encephalitis / prevention & control
  • Gliosis / prevention & control
  • Male
  • Oxidopamine
  • Parkinsonian Disorders / drug therapy*
  • Parkinsonian Disorders / pathology*
  • Rats
  • Rats, Sprague-Dawley
  • Substantia Nigra / drug effects*
  • Substantia Nigra / pathology*
  • Tumor Necrosis Factor-alpha / administration & dosage*
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / pharmacokinetics


  • Tumor Necrosis Factor-alpha
  • XENP 1595
  • Oxidopamine