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
; 4(3): 349-60, 2014.
Article
em En
| MEDLINE
| ID: mdl-25061061
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Substância Negra
/
Fator de Necrose Tumoral alfa
/
Transtornos Parkinsonianos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article