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

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.

Author information

1
Department of Physiology, Emory University School of Medicine, Atlanta, GA, USA.
2
FPRT Bio, Inc., Scranton, PA, USA.

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.

KEYWORDS:

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

PMID:
25061061
PMCID:
PMC4154985
DOI:
10.3233/JPD-140410
[Indexed for MEDLINE]
Free PMC Article

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