Outlook for PPARγ Agonists Not So Rosi
Hope that thiazolidinedione agonists of PPARγ (Peroxisome Proliferator Activated Receptor-γ) will prove beneficial for Alzheimer's patients (see ARF recent live discussion) may be tempered slightly by a report in this week's Mayo Clinic Proceedings.
Asra Kermani and Abhimanyu Garg, at the Department of Veterans Affairs Medical Center, Dallas, Texas, report that pioglitazone and rosiglitazone, which have been used for some time now to treat type II diabetes, can contribute to cardiac and renal failure. Kermani and Garg reviewed records of six elderly patients with symptoms of congestive heart failure and pulmonary edema, and who had just started treatment with, or had just had their dose of thiazolidinedione increased. Five of the patients had no prior history of congestive heart failure, though four of these had a history of poor kidney function. On admission to the center, all of the patients were placed on diuretics to reduce plasma volume and in five cases thiazolidinedione treatment was immediately stopped. Over the next three days to four weeks, these patients' symptoms disappeared. The sixth patient was also given diuretics but thiazolidinedione treatment continued. Thirteen months later, he returned with the same symptoms, was again given diuretics and this time the thiazolidinedione treatment was halted. The patient fully recovered after about 10 weeks.
This study builds on earlier reports that a small number of patients on troglitazone develop pulmonary edema as a result of fluid retention. This drug, which had been sold under the name Rezulin, was withdrawn from the market in March 2000 following FDA concerns about liver toxicity. Because the second generation of thiazolidinediones, including pioglitazone and rosiglitazone, were milder on the liver, it was hoped that they would have fewer, less serious side effects. In the present study, the six patients represent less than one percent of patients treated with the drugs at the Veterans Center. Nevertheless, the authors conclude that "thiazolidinediones can cause pulmonary edema or exacerbate heart failure," and recommend that "further study is needed to identify patient groups at risk of this complication."
Suzanne Craft, University of Washington, Seattle, who is currently directing clinical trials of pioglitazone and rosiglitazone in 30 AD patients (see ARF related news story) does not see this as a major setback. "It indicates some potential guidelines that will need to be followed," she ventured, adding that "chronic renal insufficiency or cardiomyopathy may be exclusionary conditions for prescribing these drugs." This suggests that only a small fraction of glitazone candidates would be denied potential benefits.
This study comes on the heels of a recent paper in Science by Ronald Evans and colleagues at the Salk Institute for Biological Studies, La Jolla, California, and the Brigham and Women's Hospital, Boston, Massachusetts, which showed the importance of another isoform of PPAR, namely PPARδ, in promoting the growth of atherosclerotic plaques.
First author Chih-Hao Lee and coworkers showed that deleting the PPARδ gene from foam cells-lipid-laden macrophages that advance atherosclerosis by promoting an inflammatory response-reduces atherosclerotic lesions by about 50 percent. This raises the possibility of using PPARδ inhibitors to regulate cardiovascular disease.—Tom Fagan
No Available Further Reading
- Kermani A, Garg A. Thiazolidinedione-associated congestive heart failure and pulmonary edema. Mayo Clin Proc. 2003 Sep;78(9):1088-91. PubMed.
- 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. PubMed.
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Univ of Illinois
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. PubMed.
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