Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system

Randy L. Hunter, Natasa Dragicevic, Kristen Seifert, Dong Young Choi, Mei Liu, Hyoung Chun Kim, Wayne A. Cass, Patrick G. Sullivan, Guoying Bing

Research output: Contribution to journalArticlepeer-review

291 Scopus citations

Abstract

Evidence suggests that chronic inflammation, mitochondrial dysfunction, and oxidative stress play significant and perhaps synergistic roles in Parkinson's disease (PD), where the primary pathology is significant loss of the dopaminergic neurons in the substantia nigra. The use of anti-inflammatory drugs for PD treatment has been proposed, and inhibition of cyclo-oxygenase-2 (COX-2) or activation of peroxisome proliferator-activated receptor gamma (PPAR-γ) yields neuroprotection in MPTP-induced PD. Lipopolysaccharide (LPS) induces inflammation-driven dopaminergic neurodegeneration. We tested the hypothesis that celecoxib (Celebrex, COX-2 inhibitor) or pioglitazone (Actos, PPAR-γ agonist) will reduce the LPS-induced inflammatory response, spare mitochondrial bioenergetics, and improve nigral dopaminergic neuronal survival. Rats were treated with vehicle, celecoxib, or pioglitazone and were intrastriatally injected with LPS. Inflammation, mitochondrial dysfunction, oxidative stress, decreased dopamine, and nigral dopaminergic neuronal loss were observed post-LPS. Celecoxib and pioglitazone provided neuroprotective properties by decreasing inflammation and restoring mitochondrial function. Pioglitazone also attenuated oxidative stress and partially restored striatal dopamine as well as demonstrated dopaminergic neuroprotection and reduced nigral microglial activation. In summary, intrastriatal LPS served as a model for inflammation-induced dopaminergic neurodegeneration, anti-inflammatory drugs provided protective properties, and pioglitazone or celecoxib may have therapeutic potential for the treatment of neuro-inflammation and PD.

Original languageEnglish
Pages (from-to)1375-1386
Number of pages12
JournalJournal of Neurochemistry
Volume100
Issue number5
DOIs
StatePublished - Mar 2007

Keywords

  • Celecoxib
  • Lipopolysaccharide
  • Parkinson's disease
  • Pioglitazone

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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