testing on a rotarod with a fixed and increasing speed and a balance beam paradigm. We could not detect any differences among Gpr139 KO mice, heterozygous mice, or wt mice. This may, however, be due to the fact that the mice were on a non-congenic background different from the ones used in earlier studies. 7 Bayer Andersen et al. GPR139 PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19815606 Agonists in Parkinson Model could block the protection, while the antagonist itself was not toxic to DA neuron cultures. Thus, together with the fact that three different agonists showed similar effects, and the low crossreactivity of the compounds in a broad pharmacology panel screen, assaying the ability to displace radioligand binding to the assayed targets, it is likely that the protection we observed is mediated through GPR139. Our data complement previous findings on the mechanism of GPR139 signal transduction. Most studies, including recent ones from our own group suggest that the receptor mobilizes intracellular calcium, which can be blocked with the Gq inhibitors YM-254890 and UBO-QIC, which is characteristic of Gq pathway activation. Moreover, as shown in rotenone would likely induce cell death in the entire cell population it becomes exposed to. Indeed, both in vivo and in vitro rotenone has been found to result in unspecific DA and non-DA neuronal cell death in some studies. However, using different experimental approaches, DA neurons are particularly vulnerable. It has been suggested that chronic exposure to low MPP+ or rotenone concentrations is selectively more toxic to DA neurons, whereas acutely administered high concentrations cause less discriminative cell death. DA neurons are more vulnerable to mitochondrial energy disruption than non-DA neurons, which might explain why DA neurons can be selectively killed by rotenone. While we observed an average DA neuronal cell death in the primary cultures of 60% after 24 h with 100 nM rotenone and 40% with 1 M MPP+, in our experience it also takes nM MPP+ concentrations to achieve 50% cell death in the neuroblastoma SH-SY5Y cell line. Nevertheless, as those cells express DA markers, they also provide a useful model system to study the mechanism of toxicity induced by substances used in PD models. Giordano et al. found a number of differences in the effects of MPP+ and rotenone on bioenergetics and cell death in differentiated SH-SY5Y neurons. 50% cell death was obtained after 24 h incubation with 5 nM rotenone, 5 mM MPP+ or 100 M 6-OHDA. Increasing doses of rotenone resulted in significant cell death and caspase 3 activation. Rotenone immediately inhibited the mitochondrial basal oxygen consumption rate with a resulting decrease of ATP-linked OCR, reserve capacity and a stimulation of glycolysis. With high doses of MPP+ nearly eliminating basal and ATP-linked OCR, less pronounced cell death was seen compared to that induced by rotenone. Cytotoxic 6-OHDA doses had much lower impact on bioenergetics functions and thus Giordano et al. suggests that its toxic effect is probably independent of these. While the inhibition of the mitochondrial complex I plays a substantial role in both the toxicity of MPP+ and rotenone, several studies have suggested that it cannot MedChemExpress BCTC account for the entire toxic effect seen in DA neurons. It is thus possible that GPR139 agonists have different effects in the two model systems due to the differential effects of MPP+ and rotenone on mitochondrial complex I inhibition, and on the other hand by acting on pathways independen
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