Thiazolidinedione (TZD) class of peroxisome proliferator receptor gamma (PPAR-gamma) agonists display neuroprotective effects in experimental Parkinson's disease (PD) models. Neurons and microglia express PPAR-gamma, therefore both of them are potential targets for neuroprotection, although the role of each cell type is not clear. Moreover, receptor-dependent as well as receptor-independent mechanisms have been involved. This study further investigated mechanisms of TZD-mediated neuroprotection in PD. We investigated the rosiglitazone effect in the progressive MPTP/probenecid (MPTPp) model of PD. C57BL/6J mice received MPTP (25 mg/kg) plus probenecid (100 mg/kg) twice per week for 5 weeks. Rosiglitazone (10 mg/kg) was given daily until sacrifice, starting on the fourth week of MPTPp treatment, in presence of an ongoing neurodegeneration with microgliosis. Changes in PPAR-gamma levels were measured by immunofluorescence and confocal microscopy in tyrosine hydroxylase (TH)-positive neurons and CD11b-positive microglia of the substantia nigra pars compacta (SNc). Chronic MPTPp treatment induced a PPAR-gamma overexpression in both TH-positive neurons and microglia (139.9% and 121.7% over vehicle, respectively). Rosiglitazone administration to MPTPp-treated mice, reverted PPAR-y overexpression in microglia without affecting TH-positive neurons. Thereafter, changes in CD11b and tumor necrosis factor alpha (TNF-alpha) immunoreactivity in microglia were evaluated in the SNc. MPTPp progressively increased CD11b immunoreactivity, conferring to microglia a highly activated morphology. Moreover, TNF-alpha levels were increased (457.38% over vehicle) after MPTPp. Rosiglitazone administration counteracted the increase in CD11b immunoreactivity caused by MPTPp. Moreover, rosiglitazone reverted TNF-alpha expression to control levels. Nigrostriatal degeneration was assessed by high pressure liquid chromatography (HPLC) measurement of striatal dopamine, and counting of TH-positive neurons in the SNc. MPTPp treatment caused a severe decline of striatal dopamine and a partial degenera- tion of the SNc. Rosiglitazone arrested the degenerative process in both areas. Results suggest that PPAR-gamma expression in microglia and TNF-alpha production by these cells are crucial changes by which rosiglitazone exerts neuroprotection in PD. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.
ROSIGLITAZONE DECREASES PEROXISOME PROLIFERATOR RECEPTOR-GAMMA LEVELS IN MICROGLIA AND INHIBITS TNF-ALPHA PRODUCTION: NEW EVIDENCES ON NEUROPROTECTION IN A PROGRESSIVE PARKINSON'S DISEASE MODEL
Pisanu A;
2011
Abstract
Thiazolidinedione (TZD) class of peroxisome proliferator receptor gamma (PPAR-gamma) agonists display neuroprotective effects in experimental Parkinson's disease (PD) models. Neurons and microglia express PPAR-gamma, therefore both of them are potential targets for neuroprotection, although the role of each cell type is not clear. Moreover, receptor-dependent as well as receptor-independent mechanisms have been involved. This study further investigated mechanisms of TZD-mediated neuroprotection in PD. We investigated the rosiglitazone effect in the progressive MPTP/probenecid (MPTPp) model of PD. C57BL/6J mice received MPTP (25 mg/kg) plus probenecid (100 mg/kg) twice per week for 5 weeks. Rosiglitazone (10 mg/kg) was given daily until sacrifice, starting on the fourth week of MPTPp treatment, in presence of an ongoing neurodegeneration with microgliosis. Changes in PPAR-gamma levels were measured by immunofluorescence and confocal microscopy in tyrosine hydroxylase (TH)-positive neurons and CD11b-positive microglia of the substantia nigra pars compacta (SNc). Chronic MPTPp treatment induced a PPAR-gamma overexpression in both TH-positive neurons and microglia (139.9% and 121.7% over vehicle, respectively). Rosiglitazone administration to MPTPp-treated mice, reverted PPAR-y overexpression in microglia without affecting TH-positive neurons. Thereafter, changes in CD11b and tumor necrosis factor alpha (TNF-alpha) immunoreactivity in microglia were evaluated in the SNc. MPTPp progressively increased CD11b immunoreactivity, conferring to microglia a highly activated morphology. Moreover, TNF-alpha levels were increased (457.38% over vehicle) after MPTPp. Rosiglitazone administration counteracted the increase in CD11b immunoreactivity caused by MPTPp. Moreover, rosiglitazone reverted TNF-alpha expression to control levels. Nigrostriatal degeneration was assessed by high pressure liquid chromatography (HPLC) measurement of striatal dopamine, and counting of TH-positive neurons in the SNc. MPTPp treatment caused a severe decline of striatal dopamine and a partial degenera- tion of the SNc. Rosiglitazone arrested the degenerative process in both areas. Results suggest that PPAR-gamma expression in microglia and TNF-alpha production by these cells are crucial changes by which rosiglitazone exerts neuroprotection in PD. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
