Genetic ablation of tumor necrosis factor-alpha (TNF-α) and pharmacological inhibition of TNF-synthesis attenuates MPTP toxicity in mouse striatum

Boris Ferger, Andreas Leng, Anna Mura, Bastian Hengerer, Joram Feldon

Research output: Contribution to journalArticlepeer-review

Abstract

The impact of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) in the pathology of Parkinson's disease (PD) and in MPTP neurotoxicity remains unclear. Here, male TNF-α (-/-) deficient mice and C57bL/6 mice were treated with MPTP (4 x 15mg/kg, 24 h intervals) and in one series, thalidomide was administered to inhibit TNF-α synthesis. Real-time RT-PCR revealed that the striatal mRNA levels of TNF-α, of the astrocytic marker glial fibrillary acidic protein (GFAP) and of the marker for activated microglia, macrophage antigen complex-1 (MAC-1), were significantly enhanced after MPTP administration. Thalidomide (50 mg/kg, p.o.) partly protected against the MPTP-induced dopamine (DA) depletion, and TNF-α (-/-) mice showed a significant attenuation of striatal DA and DA metabolite loss as well as striatal tyrosine hydroxylase (TH) fiber density, but no difference in nigral TH and DA transporter immunoreactivity. TNF-α deficient mice suffered a lower mortality (10%) compared to the high mortality (75%) seen in wild-type mice after acute MPTP treatment (4 x 20mg/kg, 2 h interval). HPLC measurement of MPP+ levels revealed no differences in TNF-α (-/-), wild-type and thalidomide treated mice. This study demonstrates that TNF-α is involved in MPTP toxicity and that inhibition of TNF-α response may be a promising target for extending beyond symptomatic treatment and developing antiparkinsonian drugs for the treatment of the inflammatory processes in PD.

Original languageEnglish
Pages (from-to)822-833
Number of pages12
JournalJournal of Neurochemistry
Volume89
Issue number4
DOIs
StatePublished - May 2004
Externally publishedYes

Keywords

  • Cytokine
  • Inflammation
  • MPTP
  • Parkinson's disease
  • TNF-α
  • Thalidomide

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