Lu D, Johnson C, Johnson S, Tazik S, Ou XM. The neuroprotective effect of antidepressant drug via inhibition of TIEG2-MAO B mediated cell death. Drug Discov Ther 2: 289-295

Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216.
Drug discoveries & therapeutics 10/2008; 2(5):289-295.
Source: PubMed


Alcohol use disorders are common in the world. However, the development of novel drugs to prevent alcohol-induced brain damage is based upon an improved neurobiological understanding on the cellular changes that take place in the brain. We previously reported that ethanol exposure lowered cell proliferation and increased cell apoptosis in all cell types, but affects brain cell lines the most, while ethanol and the anti-depressant drug deprenyl, an monoamine oxidase B (MAO B) inhibitor, exposure in unison increases cell viability. Here we investigated the molecular mechanism of the neuroprotective effect of deprenyl (0.25 nM) on ethanol (75 mM)-induced harmful effect. Transforming growth factor-beta-inducible early gene 2 (TIEG2) is an activator for MAO B. MAO B levels increase has been shown to contribute to neuronal cell death. This study uses the neuronal cell line to address whether ethanol induced cell death is through the activation of TIEG2-MAO B apoptotic pathway, and whether deprenyl protects cells from the effects of alcohol through the inhibition of this pathway. We have found that ethanol exposure increases the levels of mRNA and protein/catalytic activity for both TIEG2 and MAO B, while ethanol and deprenyl exposure in unison reduce the expression of both TIEG2 and MAO B, however it increases cell viability. Additionally, TIEG2-overexpressed cells display more cellular death-induced by ethanol than control cells. In summary, this study demonstrates the role of TIEG2 in ethanol induced cell death. The inhibition of the TIEG2-MAO B pathway may be one of the mechanisms for the neuroprotective effect of deprenyl.

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    • "Through this key biochemical mechanism KLF11 regulates multiple cellular processes including cell growth, differentiation, apoptosis, endocrine disorders, and malignancy (Buck et al, 2006; Cook et al, 1998; Fernandez-Zapico et al, 2003; Tachibana et al, 1997). Relevant to the current study, we have previously shown that KLF11 (Fernandez-Zapico et al, 2003; Zhang et al, 2001) is a robust transcriptional activator for MAO B (Lu et al, 2008; Ou et al, 2004), increasing the transcription of this gene via distinct GC-rich sites, which are located adjacent to its transcription start sites (Ou et al, 2004). Similarly, the MAO A promoter also contains Sp1- binding sites which have been recently reported to be a target of KLF11, increasing the expression of this gene (Grunewald et al, 2012). "
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    ABSTRACT: The biochemical pathways underlying major depressive disorder (MDD) and chronic stress are not well understood. However, it has been reported that monoamine oxidase A (MAO A, a major neurotransmitter-degrading enzyme) is significantly increased in the brains of human subjects affected with MDD and rats exposed to chronic social defeat (CSD) stress, which is used to model depression. In the current study, we compared the protein levels of a MAO A-transcriptional activator, Kruppel-like factor 11 (KLF11 , also recognized as transforming growth factor-beta-inducible early gene 2) between the brains of 18 human subjects with MDD and 18 control subjects. We found that, indeed, the expression of KLF11 is increased by 36% (p<0.02) in the postmortem prefrontal cortex of human subjects with MDD compared with controls. We also observed a positive correlation between KLF11 levels and those of its target gene, MAO A, both in association with MDD. KLF11 protein expression was also increased by 44% (p<0.02) in the frontal cortex of KLF11 wild-type mice (Klf11+/+) vs Klf11−/− when both exposed to CSD stress. In contrast, locomotor activities, central box duration and sucrose preference were significantly reduced in the stressed Klf11+/+ mice, suggesting that Klf11+/+ mice are more severely affected by the stress model compared with Klf11−/− mice. These results serve to assign an important role of KLF11 in upregulating MAO A in MDD and chronic social stress, suggesting that inhibition of the pathways regulated by this transcription factor may aid in the therapeutics of neuropsychiatric illnesses. Thus, the new knowledge derived from the current study extends our understanding of transcriptional mechanisms that are operational in the pathophysiology of common human diseases and thus bears significant biomedical relevance.
    Full-text · Article · Dec 2014 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    • "Recent in vitro and in vivo work demonstrates a role for KLF11 in alcohol use disorders. For example, exposure of neuronal cells to EtOH augments KLF11(TIEG2)-mediated MAO B activation (Lu et al., 2008) and the KLF11-MAO B cell death cascade is increased in rat brains following exposure to EtOH (Ou et al., 2010a). These observations emphasize the important role of KLF11 as a transcriptional activator of MAO B (Ou et al., 2004). "
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    ABSTRACT: The biochemical pathways underlying alcohol abuse and dependence are not well understood, although brain cell loss and neurotoxicity have been reported in subjects with alcohol dependence. Monoamine oxidase B (MAO B; an enzyme that catabolizes neurotransmitters such as dopamine) is consistently increased in this psychiatric illness. MAO B has been implicated in the pathogenesis of alcohol dependence and alcohol-induced brain neurotoxicity. Recently, the cell growth inhibitor protein, Kruppel-like factor 11 (KLF11), has been reported to be an MAO transcriptional activator. KLF11 is also known as TIEG2 (transforming growth factor-beta-inducible early gene 2) and mediates apoptotic cell death. This study investigates the protein expression of KLF11 and its relationship with MAO B using human postmortem prefrontal cortex from subjects with alcohol dependence. Twelve subjects with alcohol dependence and the respective psychiatrically normal control subjects were investigated. Expression of KLF11 and MAO B proteins in the prefrontal cortex was measured by Western blot analysis. Correlation studies involving KLF11 and MAO B protein expression were performed. Localization of KLF11 in the human prefrontal cortex was also determined by immunohistochemistry. Levels of KLF11 protein were significantly increased by 44% (p < 0.03) in the postmortem prefrontal cortex of subjects with alcohol dependence as compared to age- and gender-matched, psychiatrically normal control subjects. Furthermore, KLF11 levels were significantly and positively correlated with both the increased MAO B protein levels and blood alcohol content in alcohol-dependent subjects. In addition, KLF11 protein expression was visualized in both neuronal and glial cells. This novel study shows the important role of KLF11, an MAO transcriptional activator, in human alcohol dependence. It further supports that the KLF11-MAO B cell death cascade may contribute to chronic alcohol-induced brain damage. This argues a case for KLF11-MAO B inhibition as a novel therapeutic strategy that may impact this highly prevalent illness.
    Full-text · Article · Aug 2013 · Alcoholism Clinical and Experimental Research
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    • "Rasagiline is reportedly more effective than selegiline due to the differences in metabolite formation. Aminoindan, the metabolite of rasagiline, reinforces the neuroprotectivity of rasagiline as it, in fact, possesses its own neuroprotective properties (Lu et al., 2008; Bar-Am et al., 2009; Ou et al., 2009a). In contrast, the metabolite of selegiline, methamphetamine, counteracts the neuroprotectivity afforded by selegiline (Chen and Ly, 2006). "
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    ABSTRACT: Stress detrimentally affects the brain and body and can lead to or be accompanied by depression. Although stress and depression may contribute to each other, the exact molecular mechanism underlying the effects is unclear. However, there is a correlation between stress and an increase in glucocorticoid secretion which causes a subsequent increase in monoamine oxidase (MAO) activity during stress. Consequently, MAO inhibitors have been used as traditional antidepressant drugs. Cellular treatment with the synthetic glucocorticoid, dexamethasone (a cellular stressor), has been reported to markedly increase both MAO A and MAO B catalytic activities, as well as apoptosis. This study compares the neuroprotective abilities of M30 (a new generation inhibitor of both MAO A and MAO B) with rasagiline (Azilect(®), another new MAO B inhibitor) and selegiline (Deprenyl(®), a traditional MAO B inhibitor) in the prevention of dexamethasone-induced brain cell death and MAO activity in human neuroblastoma cells, SH-SY5Y. M30 demonstrated the highest inhibitory effect on MAO A; however, M30 showed the lowest inhibitory effect on MAO B enzymatic activity in comparison to rasagiline and selegiline. Although, M30 exhibited the greatest neuroprotective effect by decreasing cell death rates and apoptotic DNA damage compared to rasagiline and selegiline, these neuroprotective effects of M30 were, overall, similar to rasagiline. Summarily, M30 has a generally greater impact on neuroprotection than the MAO B inhibitors, selegiline and rasagiline. Our results suggest that M30 may have great potential in alleviating disorders involving increases in both MAO A and MAO B, such as stress-induced disorders.
    Full-text · Article · Nov 2010 · Frontiers in Neuroscience
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