| Background:Alcoholism and depression are all neurodegenerative diseases, which have common features of a large number neuronal apoptosis in specific brain regions, accompanied by reduced nerve regeneration. Also, alcoholism and depression showed a high rate of comorbidity. Clinical evidence also indicates that depression that emerges during abstinence from chronic alcohol use has a greater negative impact on relapse. Although no single neurobiological mechanism can account for the behavioral pathologies associated with these devastating disorders, converging evidence suggests that aspects of both alcoholism and depression are linked to reductions in neurogenesis.Brain-derived neurotrophic factor (BDNF) can affect the neuronal development and survival in the central nervous system. Many studies have suggested alcoholism and depression are caused by changes of adult hippocampal neurogenesis. Thus, we propose such an idea:changes of neurogenesis are the common neurobiological mechanisms of these two neuropsychiatric disorders-alcoholism and depression. Therefore, this study mainly covers: the expressions of BDNF and proBDNF and their receptors in depression and alcoholism, and to explore the depression symptoms occurred during the process of the alcohol withdrawal; the last are the interactions of the2diseases.Methods:1. The association studies of proBDNF and its receptors in human depression and alcoholism:40female depression patients and30male alcoholism patients were recruited from Yunnan Mental Hospital, which were all met the1CD-10diagnosis criteria of depression and alcoholism in the year from2010to2011. The control groups were the matched men and women50cases respectly. The serum, RNA and protein were extracted from the blood samples, and the proBDNF, BDNF, p75NTR, sotilin and TrkB factors were assayed by western blotting, RT-qPCR and ELISA techniques and the relationships between the factors and the two kinds of diseases were observation. Meanwhile the PANSS were used to evaluate the depression scores in the alcoholism patients before and after alcohol withdrawal and discuss the expression changes of proBDNF and its receptor.2. The researches of the expressions of proBDNF and its receptors in the chronic alcoholism mice model:50mice were used to establish a chronic alcoholism mouse model. And all the mice were divided into normal control group, group of chronic alcoholism, alcohol withdrawal one day group, alcohol withdrawal3days group and anti-proBDNF group. The chronic alcoholism mouse model was used to observe the changes of expressions of BDNF, proBDNF and their receptors. Then the FST test was used to explore the depression behaviors after alcohol withdrawal.Results:1. ProBDNF, sortilin and p75NTR protein levels were higher in major depression and chronic alcoholism patients than in control groups and TrkB protein level was decreased. The expression trends of proBDNF, p75NTR, sortilin and TrkB levels in the serum were consistent with the changes of lymophocytes protein levels.2. In major depressive patients, the expression levels of BDNF, TrkB and p75NTR at the mRNA level changed consistently with their trends in protein levels. The serum concentrations in the major depressive patients were significantly higher than in the control group’s (P<0.05). In the major depressive patients, the proBDNF levels in the serum had negative relationship with the mBDNF levels in the serum.3. In the major depressive patients, the expressions of proBDNF, p75NTR and sortilin in lymphocytes and serum had positive correlations with the extent of depression (HRSD-21score); while the serum levels of mBDNF and TrkB were negatively correlated with HRDS-21item scores4. In the human blood samples, before alcohol withdrawal, either in lymophocytes or in serum, the expression levels of proBDNF, sortilin and p75NTR were higher in chronic alcoholism group than in the control group, while mBDNF and TrkB levels were lower in patients’group. After a week of abstinence, proBDNF, sortilin and p75NTR expression levels were significantly reduced in chronic alcoholism group when compared with control group and mBDNF and TrkB levels were significantly increased. Through ELISA test, serum mBDNF level was found reduced before the alcohol withdrawal when compared with normal control group, but a week after the withdrawal it significantly increased. proBDNF/mBDNF balance was broken in patients with chronic alcoholism.5. In the human blood samples, mBDNF and TrkB expression levels in patients with chronic alcoholism were negatively correlated with average daily alcohol consumption; proBDNF, p75NTR and sortilin expression levels in chronic alcoholism patients were positively correlated with average daily alcohol consumption.6. In the human samples, the depression symptoms during alcohol withdrawal were more abvious after one week’s alcohol withdrawal than before abstinence and control group, but the significance did not reach statistical significance.7. Through behavioral tests, we found that after56days of chronic alcohol solution intragastric administration, the mice body weight, hair color, mental status, level of motivation activity, exploratory behavior, and cognitive function all significantly changed, it suggested that chronic alcoholism mice model was successfully established.8. Withdrawal behavioral experiments of mice, we found that with the withdrawal time, the level of motivation activities, explore behaviour and cognitive functions were gradually restored after alcohol abstinence, and some results had been close to or more than the normal control group. But after one day’s abstinence, the absolute immobility time was the longest among three days FST in the chronic alcohohlism group. With the withdrawal time, the absolute immobility time decreased in chronic alcoholism group, but still longer than normal control mice.9. In the intracerebroventricular injection of anti-proBDNF experiment, after icv anti-proBDNF, cognitive function in the chronic alcoholism group was significantly improved, but had not yet reached the normal levels.10. The proBDNF, sortilin and p75NTR protein levels in mice brain were the highest in the chronic alcoholism group than in the withdrawal group and the normal control group, while mBDNF and TrkB level were the lowest. And with the withdrawal time, the proBDNF, sortilin, p75NTR and TrkB levels were gradually restored, and some had been close to or more than the normal control group. After intracerebroventricular injection of anti-proBDNF, proBDNF, sortilin, p75NTR and TrkB expression levels were all recovered, but had not yet reached normal levels.11. The real-time quantitative PCR results showed that BDNF, sortilin, p75NTR and TrkB mRNA levels in mice brain were consistent with their protein expression levels. That was after the withdrawal, BDNF and TrkB mRNA levels were increased, but did not return to the normal levels; sortilin and p75NTR mRNA levels were decreased, but did not return to normal levels.Conlusions:1. Our preliminary findings showed that in major depressive patients and chronic alcoholism patients, proBDNF and its receptors p75NTR and sortilin were upregulated, and TrkB and BDNF levels lowered. That was that the balance between proBDNF/p75NTR/sortilin and mBDNF/TrkB signaling pathways was destroyed. Although there are many limitations of our study, but the results suggested that in major depressive patients and chronic alcoholism patients, the proBDNF/p75NTR/sortilin signaling pathway played a potential role in the neuropsychiatries disorders. It also suggested that there was common molecular mechanism in the pathology of depression and alcoholism, which might also be the two molecular basis of the comorbidity of these two diseases. But this was just a start of the study, the role of BDNF in depression and chronic alcoholism still require further in-depth study in order to know more about the two diseases and provide a new treatment direction.2. Whether chronic alcohol intoxication in humans or mice model, we had found that proBDNF/p75NTR/soritlin signaling pathway expression increased, which led to dysfunctios of hippocampus and prefrontal cortex and other brain regions in chronic alcoholism mice. Through the intervention (withdrawal or intracerebroventricular injection of anti-proBDNF), the weakened proBDNF/p75NTR/soritlin signaling pathway had less inhibition of neurogenesis and mBDNF and TrkB expression level was able to rebound significantly so that to promoted regeneration of neurons in the brain, but also to improve cognitive and behavioral skills caused by chronic alcohol poisoning.3. Whether in human chronic alcoholism blood samples or chronic alcoholism mice model, the depression symptoms occurred during alcohol abstinence. The reason might be the balance of proBDNF/mBDNF was broken during chronic alcohol intoxication, which beyond the ability of the body and led to the inhibition of neurogenesis in the brain. However, with the abstinence time, the compensation functions of the body recovered and the neuroregeneration began, so the depression symptoms alleviated. |
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