Abstract
Cilostazol, a potent inhibitor of type 3 phosphodiesterase (PDE3), has recently been reported to exert neuroprotective effects during acute cerebral ischemic injury. These effects are, at least in part, mediated by the inhibition of oxidative cell death. However, the effects of cilostazol on glucose metabolism in brain cells have not been determined. In the present study, we examined the effects of cilostazol on the oxidative metabolism of glucose and the resultant formation of reactive oxygen species (ROS) in cultured neurons and astroglia. Cultures of neurons or astroglia were prepared from Sprague-Dawley rats. The cells were treated with cilostazol (0 – 30 μM) for 48 hours prior to the assay. L-[U-14C]lactate ([14C]lactate) or [1-14C]pyruvate ([14C]pyruvate) oxidation was measured. ROS production was determined using an H2DCFDA assay with a microplate reader. Forty-eight hours of exposure to cilostazol resulted in dose-dependent increases in [14C]lactate and [14C]pyruvate oxidation in both the neurons and astroglia. Dibutyryl cyclic AMP (0 – 0.5 mM) also increased [14C]lactate oxidation, indicating cAMP-mediated PDH activation. In contrast, free radical formation was not affected by cilostazol in either the neurons or astroglia. Cilostazol enhanced the oxidative metabolism of glucose in both neurons and astroglia, while it did not augment ROS production.
Highlights
Brain function is completely dependent on the oxidative metabolism of glucose for ATP synthesis
We examined the effects of cilostazol on the oxidative metabolism of glucose and the resultant formation of reactive oxygen species (ROS) in cultured neurons and astroglia
Cilostazol enhanced the oxidative metabolism of glucose in both neurons and astroglia, while it did not augment ROS production
Summary
Brain function is completely dependent on the oxidative metabolism of glucose for ATP synthesis. The functional activation of local brain lesions triggers ATP consumption by Na+, K+-ATPase, which restores the trans-membrane Na+ and K+ gradients in the local cells [1]. In contrast to the brain, the heart muscle is dependent on fatty acid oxidation in mitochondria for its energy production [2]. A type 3 phosphodiesterase (PDE3) inhibitor has been known to enhance cardiac contractile force by enhancing fatty acid metabolism [3]. An in vitro experiment has shown that two PDE inhibitors, enoximone and milrinone, suppress glucose oxidation in isolated cardiac myocytes [4] in accordance with Randle’s hypothesis [5], implying a reciprocal control of glucose oxidation and fatty acid oxidation in living organisms. As fatty acid is not an energy substrate for brain tissue under normal physiological conditions, the effect of PDE inhibitors on fatty acids does not affect brain energy metabolism, and the effect of PDE inhibitors on glucose metabolism in neural tissue has not been previously studied, as far as we know
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