Lee CH, Chawla A, Urbiztondo N, Liao D, Boisvert WA, Evans RM, Curtiss LK.
Transcriptional repression of atherogenic inflammation: modulation by PPARdelta.
Science. 2003 Oct 17;302(5644):453-7.
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Recent observerations that thiazolidinediones (TZDs) may exert cardiotoxic effects may reflect events not mediated by the PPARγ receptor. We showed that TZDs have direct effects on astrocyte metabolism Dello Russo et al., 2003). The basis for this effect involves a direct inhibition of mitochondrial state III respiration, followed by a subsequent hyperpolarization leading to increased δ psi due to intramitochondrial hydrolysis of glycolytically derived ATP. In the case of normal astrocytes, there is sufficient glycolysis to offset the inhibitory actions of the TZDs on oxidative respiration and, therefore, eventually the cells return to a "healthy" state in which the δ psi is higher than in resting cells. These astrocytes are less susceptible to several noxious stimuli including hypoglycemia and staurosporine-induced apoptosis. However, in other cell types, for example transformed glioma cell lines, the same doses of TZDs induce apoptosis, and the increased metabolism observed in astrocytes does not occur.
It is, therefore, feasible that cardiotoxic effects of TZDs involve PPARγ-independent mechanisms that cause direct perturbation of cardiac mitochondrial function, and which, as is the case for glioma cells, cannot be sufficiently compensated for by increased anaerobic glycolysis. The benefits of using TZDs for neurological treatment, therefore, has to be considered in light of both PPARγ-dependent as well as independent effects. Hopefully it will be possible to target the receptor-independent, metabolic actions of TZDs without comprising their receptor-dependent beneficial effects (i.e., antiinflammatory) in brain.
Dello Russo C, Gavrilyuk V, Weinberg G, Almeida A, Bolanos JP, Palmer J, Pelligrino D, Galea E, Feinstein DL.
Peroxisome proliferator-activated receptor gamma thiazolidinedione agonists increase glucose metabolism in astrocytes.
J Biol Chem. 2003 Feb 21;278(8):5828-36.
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