The New Inhibitor of Monoamine Oxidase, M30, has a Neuroprotective Effect Against Dexamethasone-Induced Brain Cell Apoptosis

Shakevia Johnson,Junming Wang,Moussa B. H. Youdim,Chandra Johnson,Deyin Lu,Grazyna Rajkowska,Xiao-Ming Ou,Shawna Tazik

doi:10.3389/fnins.2010.00180

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.

Highlights

Stress encompasses the specific responses that affect the normal physiological state of the body
With regards to monoamine oxidase (MAO) A, the results indicated that M30 significantly (*P < 0.05) decreased MAO A catalytic activity by 37% (Figure 1A, lanes 2 vs. 1); there was a 26% decrease due to rasagiline (Figure 1A, lanes 4 vs. 3) and a 24% decrease in MAO A enzymatic activity after treatment with selegiline (Figure 1A, lanes 6 vs. 5)
Results from the MAO A and B enzymatic activity assays and the MTT assay were further validated by the TUNEL assay (Figure 3) which uses TUNEL staining to measure fragmented DNA due to cellular apoptosis caused by an MAO catalytic activity-linked increase in H2O2 production (Phillips, 2003)

Summary

Introduction

Stress encompasses the specific responses that affect the normal physiological state of the body. The chief organ that responds to stress is the brain. Stress interferes with the emotional, social, physiological, mental and physical aspects of health, and well being and often leads to depression. According to the World Health Organization, major depression is among the most burdensome diseases in the world. Depression is a major public health concern that costs the United States 83 billion dollars, annually. A major response to stress is the production of glucocorticoids which are steroid hormones secreted from the adrenal gland. Due to an improved understanding of the cellular changes that occur during stressful events, antidepressants such as monoamine oxidase (MAO) inhibitors are a traditional drug class used for treatment

Methods

Results

Conclusion