Rosiglitazone is a commonly prescribed insulin-sensitizing drug with a selective agonistic activity on the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). PPAR-gamma can modulate inflammatory responses in the brain, and agonists might be beneficial in neurodegenerative diseases. In the present study we used a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine plus probenecid (MPTPp) mouse model of progressive Parkinson's disease (PD) to assess the therapeutic efficacy of rosiglitazone on behavioural impairment, neurodegeneration and inflammation. Mice chronically treated with MPTPp displayed typical features of PD, including impairment of motor and olfactory functions associated with partial loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNc), decrease of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) content and dynorphin (Dyn) mRNA levels in the caudate-putamen (CPu), intense microglial and astroglial response in the SNc and CPu. Chronic rosiglitazone, administered in association with MPTPp, completely prevented motor and olfactory dysfunctions and loss of TH-positive cells in the SNc. In the CPu, loss of striatal DA was partially prevented, whereas decreases in DOPAC content and Dyn were fully counteracted. Moreover, rosiglitazone completely inhibited microglia reactivity in SNc and CPu, as measured by CD11b immunostaining, and partially inhibited astroglial response assessed by glial fibrillary acidic protein immunoreactivity. Measurement of striatal MPP+ levels 2, 4, 6 h and 3 days after chronic treatment indicated that MPTP metabolism was not altered by rosiglitazone. The results support the use of PPAR-gamma agonists as a putative anti-inflammatory therapy aimed at arresting PD progression, and suggest that assessment in PD clinical trials is warranted.

Parkinson's disease (PD) is characterized by a progressive degeneration of dopamine (DA) neurons and gradual worsening of motor symptoms. The investigation of progressive degenerative mechanisms and potential neuroprotective strategies relies on experimental models of the chronic neuropathology observed in human. The present study investigated the progressive nature of neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTPp) chronic mouse model of PD. MPTP (25 mg/kg) plus probenecid (250 mg/kg) were administered twice a week for 5 weeks. We evaluated behavioral deficits (olfactory and motor impairment), neurodegeneration (loss of tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta, SNc), biochemical markers of functional impairment in the caudate-putamen (CPu) (striatal enkephalin mRNA, DA and DOPAC levels), and glial reactivity (CD11b and GFAP immunoreactivity in the SNc and CPu) at progressive time-points (after 1, 3, 7, and 10 administrations of MPTPp). Olfactory dysfunction already appeared after the 1st MPTPp injection, whereas motor dysfunction appeared after the 3rd and worsened upon subsequent administrations. Moreover, starting after three MPTPp injections, we observed a gradual decline of TH-positive cells in the SNc, and a gradual raise of enkephalin mRNA in the CPu. Striatal DA levels reduction was not different among all time-points evaluated, whereas DOPAC levels were similarly reduced after 1-7 MPTP injections, but were further decreased after the 10th injection. Reactive microglia and astroglia were observed in both the SNc and CPu from the 1st MPTPp administration. In the SNc, gliosis displayed a gradual increase over the treatment. After 2 months, TH, DA, DOPAC, and reactive glia in the SNc were still altered in MPTPp-treated mice as compared to controls. By showing a progressive development of behavioral deficits and nigral neurodegeneration, together with impairment of biochemical parameters and gradual increase of glial response, results suggest that the chronic MPTPp protocol is a model of progressive PD, which may be suitable to investigate chronic pathological processes and neuroprotective strategies in PD.

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These results suggest that catecholamine transmission in the BNST may be part of a common downstream pathway that is involved in the action mechanism of antidepressants. Consequently, it is hypothesized that a dysfunction of neuronal transmission in this brain area may have a role in the etiology of affective disorders.