Mitochondrial dysfunction and oxidative stress occur in Parkinson's disease (PD), but little is known about the molecular mechanisms controlling these events. Peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) is a transcriptional coactivator that is a master regulator of oxidative stress and mitochondrial metabolism. We show here that transgenic mice overexpressing PGC-1α 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. PGC-1α overexpression also protected against MPTP-induced striatal loss of dopamine, and mitochondria from PGC-1α transgenic mice showed an increased respiratory control ratio compared with wild-type animals. To modulate PGC-1α, 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-1α overexpression. As studied in vitro, RSV activated PGC-1α in dopaminergic SN4741 cells via the deacetylase SIRT1, and enhanced PGC-1α gene transcription with increases in SOD2 and Trx2. Taken together, the results reveal an important function of PGC-1α in dopaminergic neurons to combat oxidative stress and increase neuronal viability. RSV and other compounds acting via SIRT1/PGC-1α may prove useful as neuroprotective agents in PD and possibly in other neurological disorders.

The role of the ATP-gated receptor, P2X(7), has been evaluated in the unilateral 6-OHDA rat model of Parkinson's disease using the P2X(7) competitive antagonist A-438079. Nigral P2X(7) immunoreactivity was mainly located in microglia but also in astroglia. A-438079 partially but significantly prevented the 6-OHDA-induced depletion of striatal DA stores. However, this was not associated with a reduction of DA cell loss. Blockade of P2X(7) receptors may represent a novel protective strategy for striatal DA terminals in Parkinson's disease and warrants further future investigation.

Insulin-like growth factor-II (IGF-II) is a naturally occurring peptide that exerts known pleiotropic effects ranging from metabolic modulation to cellular development, growth and survival. IGF-II triggers its actions by binding to and activating IGF (IGF-I and IGF-II) receptors. In this study, we assessed the neuroprotective effect of IGF-II on corticosterone-induced oxidative damage in adult cortical neuronal cultures and the role of IGF-II receptors in this effect. We provide evidence that treatment with IGF-II alleviates the glucocorticoid-induced toxicity to neuronal cultures, and this neuroprotective effect occurred due to a decrease in reactive oxygen species (ROS) production and a return of the antioxidant status to normal levels. IGF-II acts via not only the regulation of synthesis and/or activity of antioxidant enzymes, especially manganese superoxide dismutase, but also the restoration of mitochondrial cytochrome c oxidase activity and mitochondrial membrane potential. Although the antioxidant effect of IGF-I receptor activation has been widely reported, the involvement of the IGF-II receptor in these processes has not been clearly defined. The present report is the first evidence describing the involvement of IGF-II receptors in redox homeostasis. IGF-II may therefore contribute to the mechanisms of neuroprotection by acting as an antioxidant, reducing the neurodegeneration induced by oxidative insults. These results open the field to new pharmacological approaches to the treatment of diseases involving imbalanced redox homeostasis. In this study, we demonstrated that the antioxidant effect of IGF-II is at least partially mediated by IGF-II receptors.

SUMMARY1. Cortex-free adrenal glands previously labelled with the isotope "Ca have been perfused with Locke or modified Locke solution to assess Ca2+ movements under different conditions.2. Substitution of Na+ by either sucrose or choline during perfusion with Ca2+-free Locke solution induced a significant and sustained decrease in the 4"Ca effilux. Concomitant with this effect there was an increase in the output of catecholamines from the perfused gland.3. In the presence of Ca2+ (2.2 mM) in the perfusion fluid, Na+ omission induced an increase in the 45Ca efflux. This increase was significantly reduced if 3 x 10-4 M methoxyverapamil (D-600) was present in the perfusion fluid. However, the increased catecholamine output in response to Na+ deprivation remained unchanged. 4. Excess of Mg2+ (20 mM) in the extracellular medium blocked the increase in catecholamine output in response to Na+ omission. However, the decrease in the 4"Ca efflux produced by Na+ deprivation in the presence of this high concentration of Mg2+ was similar to that observed in the presence of 1-2 mM-Mg2+.5. In the absence of Mg2+ in the extracellular medium, substitution of Na+ by either sucrose or choline induced a sharp and transient increase in the 45Ca efflux rate coefficient. This increased 4"Ca efflux, which has similar time course as the enhanced catecholamine output, was not affected by the presence of 3 x 10-4 M methoxyverapamil.6. In the absence of Mg2+, the graded substitution of Na+ in the perfusion medium by sucrose enhanced the efflux of "Ca. This increase in the "Ca outward movement was linearly related to the logarithm of the extracellular Na+ concentration.7. After perfusion of glands with Ca2+-free Locke solution, the 372 J. AGUIRRE, J. E. B. PINTO AND J. M.