Involvement of Bax Protein in the Prevention of Glucocorticoid-Induced Thymocytes Apoptosis by Melatonin

Abstract

The antiapoptotic effect of melatonin has been described in several systems. In this study, the antagonistic effect of the methoxyindole on dexamethasone-induced apoptosis in mouse thymocytes was examined. Melatonin decreased both DNA fragmentation, and the number of annexin V-positive cells incubated in the presence of dexamethasone. Analysis of the expression of the members of the Bcl-2 family indicated that the synthetic glucocorticoid increased Bax protein levels without affecting the levels of Bcl-2, Bcl-XL, Bcl-XS, or Bak. This effect correlated with an increase in thymocytes bax mRNA levels. Dexamethasone also increased the release of cytochrome C from mitochondria. All of these effects were reduced in the presence of melatonin, which was ineffective per se on these parameters. In addition, the involvement of cAMP on glucocorticoid/melatonin antagonism was examined. Both melatonin and dexamethasone decreased the levels of this nucleotide in mouse thymocytes, indicating that the antagonistic action between both hormones involves a cAMP-independent pathway. In summary, the present results suggest that the antiapoptotic effect of melatonin on glucocorticoid-treated thymocytes would be a consequence of an inhibition of the mitochondrial pathway, presumably through the regulation of Bax protein levels.

The triterpene echinocystic acid and its 3-O-glucoside derivative are revealed as potent and selective glucocorticoid receptor agonists

“…The molecular mechanisms of the GCs-mediated induction of apoptosis involve down regulation or inhibition of anti-apoptotic molecules, such as Bcl-2, as well as upregulation or activation of pro-apoptotic molecules such as BAX-2 (Lotem and Sachs, 1995;Salomons et al, 1997;Rieger et al, 1999;Murphy et al, 2000;Das et al, 2004;Almawi et al, 2004;Hoijman et al, 2004;Mahmoud et al, 2009;Lopez-Royuela et al, 2010;Melarangi et al, 2012;Zaman et al, 2014). The (Tong et al, 2004a(Tong et al, , 2004bLee et al, 2005, Kim et al, 2015, Cho et al, 2016.…”

Therapeutic benefit of melatonin in refractory central serous chorioretinopathy

“…In addition to its antioxidant effects, several other mechanisms may be involved in neuroprotection induced by melatonin, like the inhibition of the nitridergic pathway, 17 decrease in vascular endothelial growth factor (VEGF) levels, 6 as well as its inhibitory effect on glucocorticoid actions. 18 At present, there are no optimal therapies for CSCR; current treatments have limited effectiveness and a significant number of side effects. It has been demonstrated that even at very high concentrations given during pregnancy, melatonin had no maternal or fetal toxicity.…”

Melatonina: modulador de morte celular

“…Some authors show an anti-apoptotic action of melatonin in different organs, such as thymus, kidney, brain and liver, attributing this mainly to its antioxidating properties [7][8][9][10][11][12]33,34 when eliminating radicals hydroxyl (OH -), peroxyl (ROO -) 26, superoxides 4 and cardiolipin oxidation from mitochondrias 35 . In the lacrimal glands of hamsters, this hormone prevents cell damage caused by the buildup of porphyrins, due to its capacity of decreasing the RNAm synthesis of aminolevulinate synthetase, enzyme involved in the production of porphyrins, and also due to increasing the levels of RNAm of antioxidating enzymes such as manganese superoxide dismutase (Mn-SOD) and copper-zinc superoxide dismutase (Cu-Zn-SOD) 36 .…”

“…On the other hand, in thymocytes treated with dexamethasone, it has been observed that the administration of melatonin was able to reverse the apoptotic process caused by the glycocorticoid, reducing DNA fragmentation and Bax (proapoptotic protein of the Bax RNAm) levels 10 . In that sense, studies have shown that melatonin is capable of reducing the activity in caspases-9 and 3 induced buy the increased concentration of cytoplasmic calcium in human leukocytes, due to the activation of Bax with release of cytochrome C, thus leading to reduced apoptotic activity 44 .…”

“…It influences the regulation of the neuroendocrine Review Article system, the control of circadian rhythms for various physiological processes, and the anti-apoptotic system in various cell deathinduced vertebrate tissues [9][10][11][12] . However, the mechanism through which melatonin exerts its inhibitory effect on cell death remains unclear.…”