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PPAR-gamma-mediated neuroprotection in a chronic mouse model of Parkinson’s disease

Rosiglitazone is a commonly prescribed insulin‐sensitizing drug with a selective agonistic activity on the peroxisome proliferator‐activated receptor‐gamma (PPAR‐γ). PPAR‐γ 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‐γ agonists as a putative anti‐inflammatory therapy aimed at arresting PD progression, and suggest that assessment in PD clinical trials is warranted.

Sub-chronic exposure to atomoxetine up-regulates BDNF expression and signalling in the brain of adolescent spontaneously hypertensive rats: Comparison with methylphenidate

The stimulant methylphenidate and the non-stimulant atomoxetine are widely used for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD), but the molecular mechanisms of their therapeutic action are not fully understood. The aim of our study was to investigate, in adolescent rats, the sub-chronic effect of these two drugs on neuronal plasticity, through a detailed analysis of BDNF expression and signalling in order to establish the contribution of these mechanisms in the pharmacotherapy of ADHD. Atomoxetine (ATX) up-regulated BDNF mRNA levels in the hippocampus whereas methylphenidate (MPH) increased BDNF gene expression in the nucleus accumbens and caudate-putamen. Opposite effects were seen in the prefrontal cortex, a critical region in attention disorders, where ATX increased while MPH reduced total and exon IV BDNF mRNA levels. Analysis of BDNF-mediated signalling in the prefrontal cortex revealed that ATX enhanced AKT and GSK3β phosphorylation whereas MPH reduced the synaptic levels of trkB, the high-affinity BDNF receptor, and ERK1/2 activation. Our findings show that ATX and MPH exert an opposite modulation of the BDNF system, primarily in prefrontal cortex that, independently from the behavioral control exerted by the two drugs, may be important for long-term consequences on cognitive function.

Prenatal restraint stress: an in vivo microdialysis study on catecholamine release in the rat prefrontal cortex

There is substantial evidence that prenatal exposure to adverse environmental conditions might lead to the psychiatric disorders that can appear in adolescence or in adulthood; vulnerability to drug addiction may increase as well. It is currently accepted that the alteration of catecholamine transmission in the prefrontal cortex plays a prominent role in the etiology of psychiatric disorders. We assessed basal and stimulated dopamine and noradrenaline extracellular concentration in the medial prefrontal cortex by means of microdialysis in awake male adolescent and young adult offspring of rats exposed to restraint stress in the last week of pregnancy. Catecholamine stimulation was obtained by amphetamine or nicotine. We observed that prenatal stress (PNS) did not change dopamine but decreased noradrenaline basal output in both adolescents and adults. Moreover, it decreased amphetamine stimulated dopamine output and increased amphetamine stimulated noradrenaline output. PNS decreased nicotine stimulated noradrenaline (but not dopamine output) in adults, though not in adolescents. These data show that PNS stress modifies prefrontal cortex catecholamine transmission in a complex and age dependent manner. Our results support the view that prenatal stress may be a contributing factor for the development of psychiatric disorders and that its effect may augment drug addiction vulnerability.