title: Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system.
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-gamma) 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-gamma 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.
authors.affiliation: Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky 40536-0298, USA.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Hunter
authors.forename: Natasa
authors.initials: N
authors.lastname: Dragicevic
authors.forename: Kristen
authors.initials: K
authors.lastname: Seifert
authors.forename: Dong Young
authors.initials: DY
authors.lastname: Choi
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.forename: Hyoung-Chun
authors.initials: HC
authors.lastname: Kim
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Cass
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Sullivan
authors.forename: Guoying
authors.initials: G
authors.lastname: Bing
mesh_terms: D000818:Animals; D000068579:Celecoxib; D016923:Cell Death; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D066298:In Vitro Techniques; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists; D000077205:Pioglitazone; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000096:biosynthesis; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D013449:Sulfonamides / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D008070:Lipopolysaccharides; D047495:PPAR gamma; D011720:Pyrazoles; D013449:Sulfonamides; D045162:Thiazolidinediones; D011972:Receptor, Insulin; D000068579:Celecoxib; D004298:Dopamine; D000077205:Pioglitazone