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Peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) is a transcriptional coactivator that is a master regulator of oxidative stress and mitochondrial metabolism. Mitochondrial dysfunction and oxidative stress occur in Parkinson’s disease (PD), but little is known about the molecular mechanisms controlling these events. We report that transgenic mice overexpressing PGC-1 in dopaminergic neurons are resistant against cell degeneration induced by the neurotoxin MPTP. The increase in neuronal viability was accompanied by elevated levels of mitochondrial antioxidants SOD2 and Trx2 in the substantia nigra of transgenic mice. To modulate PGC-1, we employed the small molecular compound resveratrol (RSV) that protected dopaminergic neurons against the MPTP-induced cell degeneration almost to the same extent as after PGC-1 overexpression. RSV also activated PGC-1 in dopaminergic SN4741 cells and enhanced PGC-1 gene transcription with increases in SOD2 and Trx2. Taken together the results reveal an important function of PGC-1 in dopaminergic neurons survival.

Over the past decade, many examples of activation of receptor tyrosine kinases in response to G-protein coupled receptor signaling have been reported, indicating that there are alternative modes of receptor tyrosine kinase activation (transactivation) in the absence of neurotrophic factor binding. In the present work, we aimed to examine if 5-HT receptor subtype activation may induce fibroblast growth factor receptor-1 (FGFR1) phosphorylation through transactivation of tyrosine kinase. The study has been performed in young adult rats treated with the selective 5-HT1A receptor agonist 8-OHDPAT at the dose of 0.4 mg/kg/i.p.. FGFR1 phosphorylation was evaluated by immunoprecipitation and western blotting in a time-course study ranging between 15 min and 24h. Among the brain regions, target of the 5-HT innervations, examined in this study (cingulate and frontal cortices, and the hippocampus), only in the hippocampus the FGFR1 phosphorylation was found upregulated 24 h following 8-OH-DPAT treatment. This FGFR1 activation was independent of its ligand FGF-2 changes, and using primary cultures of hippocampal neurons the FGFR1 transactivation by 5-HT receptors was further defined. The existence of FGFR1 transactivation in response to 5-HT receptor activation will increase our understanding the mechanisms of antidepressant drug effects, since 5-HT receptors have been implicated in anxiety and depression.

Resveratrol (3,4',5-trihydroxystilbene, RSV), a phytoalexins with a stilbene skeleton, exhibits a wide range of biological actions that includes neuroprotective effect against neurodegenerative diseases. In a previous study on RSV neuroprotective effects in mouse Parkinson’s model, we unexpectedly observed an upregulation of DAT in the striatum of female mice treated with RSV. Here we aimed to study in depth the effect of RSV on DAT expression, and additionally to verify the potential involvement of estrogen receptor activation by RSV, according with its striking similarity to the synthetic estrogen diethylstilbestrol. Daily repeated injection of RSV (20 mg/kg i.p.) for four days led, eight days after the first injection of RSV, to a significant increase of DAT protein expression levels in the striatum of female mice as compared to matched control. The same RSV injection protocol was not able to increase DAT levels in the striatum of male mice. Basic DAT levels did not show significant difference linked to sex. The pretreatment with the selective estrogen receptor antagonist ICI 182,780 led to a complete block of RSV effect on striatal DAT protein expression levels, whereas the treatment with ICI 182,780 alone was ineffective. The results achieved clearly show that striatal DAT up-regulation following RSV treatment is mediate by DAT estrogen receptors and indicate that RSV through the DAT regulation can exert beneficial influence in the nigrostriatal system of female mice.

Cx36 and Cx45 are considered the main connexins expressed in neuronal cells of central nervous system (Belluardo N. et al. Brain Res. 2000)), but at present no complete data are available on their expression in the neurons of crest-derived neuroendocrine organ, such as the adrenal medulla, the carotid body and the enteric nervous system. Therefore the present study was undertaken to evaluate using immunohistochemistry and western blotting procedures, both in rat and mouse, whether Cx36 and Cx45 were expressed in neuronal cells of the carotid body, adrenal medulla and myenteric plexus at ileum and colon level. In the carotid body of both mouse and rat only Cx45 was found expressed as diffuse punctate immunostaining. High amount of Cx36 expression was detected in the medulla and zona glomerulosa of mouse adrenal gland, but not in the rat. The Cx45 was found only in the mouse zona reticularis of adrenal gland cortex. Very low amount of Cx36 punctate immunostaining was found in the myenteric plexus of mouse colon and ileum but not in the rat. No Cx45 immunostaining was evidenced in the myenteric plexus of both mouse and rat, although it was found along the circular muscle of colon and ileum. Using western blotting analysis we confirmed for both Cx36 and Cx45 the results obtained by immunohistochemistry. Taken together our data increase our insight into types of gap-junctions localized in neuronal of sympatho-adrenal system and their different expression between species.