MAO+and+Schizophrenia

=**MAO and Schizophrenia**=

Schizophrenia is a neurological disorder that are characterized by delusion, hallucination, paranoia, disorganized speech and behaviour.(1) It is a common disorder with prevalence of 0.30-0.66% across the world.(1) Moreover, increasing levels of schizophrenia indicates the milestone of growing social burden. Structural symptoms of schizophrenic patient are reduced cortex size in hippocampus, frontal and temporal lobes than normal population.(2) Since schizophrenia affects various parts of the brain, it is known to be the collection of neurological disorders. Exact cause is complex, hence the complete cure is not found yet. Currently the cause of schizophrenia is best explained by dopamine hypothesis, which explains the existence of irregular dopamine concentration due to misfiring of dopaminergic neurons. Monoamine oxidase(MAO) catabolises dopamine and is implicated as the potential cause of schizophrenia. Also, deficiency in MAO is known to cause many abnormal behaviours like anger and social awkwardness.(3) Moreover correlations are found in regards to MAO and schizophrenia which further strengthens MAO’s implications. These findings includes: decreased in MAO activity in blood platelets(4) and increased in methylation of MAO gene promoter regions.(5) Lastly with MAO in mind, clinical treatment of schizophrenia is developing. MAOB inhibitor and gene therapy may hold the future in treating schizophrenia.

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=MAO on Brain=

**Physical changes in the brain **
MAO is an essential enzyme in both developing and developed brain. It not only regulates neurotransmitters but it also participates in many signalling cascades like cell apoptotic pathways. MAO-A and R1 – a repressor of MAO-A gene – is found to be downstream of p38 kinase and Bcl-2 and upstream of caspase-3.(6) P38 kinase, bcl-2 and caspase-3 are proteins that plays significant roles in commencing and executing controlled cell death.Similarly MAO-A also plays an essential role in maintaining telencephalic neural progenitor cells. It has been shown that if MAO-A are extinguished during late gestation period in mice, there will be decreased proliferation of neural stem cells(NSC). (7) Moreover MAO-A siRNA //in vitro // study demonstrated that knockdown of MAO-A mRNA expression level significantly decreases the size of the crown lump and impairs cerebral development.(8) Affected areas include crown lump, hind brain and mid brain of mice. This further suggests that MAO-A plays critical roles in a developing brain. MAO-B on the other hand provided disappointing result in showing no significant effects on the embryonic brain. (8) Absence of MAO during early period of development causes physical abnormality leading into abnormal behaviours. This is proved by Mejia and et al as they demonstrated how MAO-A knockout during gestation period leads into pathological aggressive behaviours in mice.(9) = =

**Lead into MAO and schizophrenia **


The cause of these abnormality is largely characterized by two factors, R1 and functional polymorphism in MAO promoters and genes. (10) Reduction of R1 has been found to cause major depressive disorder as well as increased cell apoptosis in the brain. (11)Moreover the polymorphism in promoter and gene of MAO A causes bipolar disease (12), severe case of Norrie disease (13), violent and antisocial behaviours (14). Also, it showed great correlation in neurological disease such as Parkinson disease and Alzheimer.(15) MAO enzymes localize where dopamine is predominantly produced, areas like substantia nigra, nucleus locus coeruleus and periventricullar region of hypothalamus.(16) Spatially and functionally MAO became an astounding candidate for the cause of schizophrenia. Study conducted on approximately 200 patients, which comprised of schizophrenic and controlled, have found that dopaminergic pathways such as COMT and ALDH3 correlates strongly in causing schizophrenia. (17) COMT and ALDH3 are both enzymes that catabolises dopamine and catecholamine like MAO. Moreover direct evidence on disrupted dopaminergic pathways within schizophrenic patient have been found. (18)These finding strongly influenced researchers in conducting further studies with MAO as it also takes part in dopamine catabolism.

=MAO and Schizophrenia=

**Platelet level **


Historically researchers found correlation between schizophrenia and MAO by finding that its level is significantly lower in blood platelet.(19) After this discovery they began to investigate MAO platelet level within different subtypes of schizophrenia. Subtypes include: paranoid (P), non-paranoid (NP), hallucinating (H) and non-hallucinating (NH) schizophrenia. Comparison was conducted between P vs. NP, P vs. Normal control (NC), NP vs. NC, H vs. NH, H vs. NC and NH vs. NC. This meta-analysis indicated that for P vs. NP, with approximately 300 candidates, P patients showed lower MAO activity than that of 61% of NP patients.(20) P patient also scored lower MAO activity than 79% of NC patients in about 1000 sample size. NP vs. NC indicated lower MAO activity in NP than that of 75% of NC patients. H vs. NH showed that H patients had lower MAO in platelet than 84% of NH population while for H vs. NC H had less MAO than 80% of NC. Lastly for NH vs. NC, NH scored lower MAO level than that of 64% of NC patients. Overall, despite discrepancies existing between subtypes of schizophrenia, platelet MAO level was proven to be lower than that of normal population. Investigating MAO expression in blood platelet however quickly fell out of style due to its lack of correlation and uncertainty on whether it actually causes schizophrenia.(21)

**MAO gene and promoter polymorphism **
Investigating the effects of functional polymorphism in MAO gene became the next generation of study in assessing the causation of schizophrenia. MAO promoter and gene regions were heavily investigated to discover if variable number tandem repeat (VNTR) and single nucleotide polymorphism (SNP) indeed caused schizophrenia. Despite its promising expectations, results came out to be controversial. It became apparent that polymorphism in MAO-B, though it showed implications in psychotic disorder, was not directly associated with schizophrenia specifically.(22) Moreover polymorphism in both MAO-A and MAO-B became statistically insignificant in predicting aggressive behaviour in schizophrenia.(23) Promoter polymorphism in 941T allele in MAO A on the other hand showed promising report in that they showed strong correlation in its involvement towards schizophrenic Swedish male population.(24) This however was quickly refuted from the follow up study by Fan J.B. and et al. Although they have worked with VNTR in promoter of promising regions indicated from previous study, there was no significant correlation found in Han Chinese population in MAO-A.(25) This however was also refuted by later study done on similar Han Chinese population. Showing with Haplotype analysis, 941T allele and 3 short allele VNTR polymorphism was predominant in male schizophrenic patients compared to the normal control.(26) Later study done by Kang S. G. and et al showed that although there are no direct effects of MAO-A VNTR and MAO-B gene A644G polymorphism on restless leg syndrome (RLS) of schizophrenic patient, the combination of these two polymorphism have significant influence on RLS on schizophrenia.(27) These findings suggests that first, the cause of schizophrenia may be different among populations. Second, individual gene or promoter polymorphism is not be enough to cause schizophrenia but the combination between them may be responsible.

**<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">Methylation on MAO promoter **
<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">Methylation status on gene promoter is a good indicator of whether a particular gene is being silence or active. Promoter contains cpG islands and e-boxes that regulates the rate of transcription. Relative methylation increase on these allele indicates that the gene is silenced. Chen Y. and et al performed a methylation status check on two MAO-A promoters in schizophrenic patient.(28) Based on their previous background knowledge, they found that MAO-A gene contains two CpG islands, having in total of 80 CpG residues. (28) Analysis was performed on entire length of the promoter and exon1 in MAO-A gene. Result for overall methylation status of the assessed allele showed no significant differences between schizophrenic and normal patients.(28) Individual CpG residue however showed interesting outcome as there were significant increase in methylation on six residues in male population. Whereas for female, they had 15 CpG residue that had some differences in terms of methylation, half being decreased and others being increased. These findings suggests that disturbance in MAO-A gene expression due to promoter methylation can cause leads to negative behaviours of schizophrenia.

=Clinical approach=

**<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">MAO B inhibitor in treating schizophrenia **
<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">As mentioned previously, schizophrenia may be caused by faulty dopaminergic activity in the brain. With this in mind MAO-B inhibitor became apparent treatment in schizophrenia. [|Selegiline] also known as deprenyl is a MAO-B inhibitor that selectively increases the dopaminergic activity.(29) Not only it enhances the activity it does not disturb MAO- A activity, which is clinically significant as it can negate side effects from inhibition of MAO-A such as behavioural hyperactivity. (30) Over 6 weeks duration of small dose selegiline treatments, patients found that 34.7% reduction in their negative symptoms like anhedonia asociality, apathy and affective flattening. (31) These values were measured with Scale for the Assessment of Negative Symptoms(SANS). Moreover, there was 36.8% drop in depressive symptoms as well.(31) Selegiline administered with risperidone also showed its potential in clinically decreasing negative schizophrenic behaviours.(32) Selegine may also rescue dopaminergic neurons from apoptosis by inhibiting cell death signals however clinically it is not confirmed yet.(33) Although selegiline seem to decrease negative symptoms of schizophrenia, it is still questionable to pursue it as a standard treatment. Although the comparison between placebo and selegiline treatments showed decrease in negative symptoms for selegiline treatments, patients nonetheless suffered with adversity of schizophrenia through the completion of the study.(34) As of now, MAO-B inhibitor has no significant breakthrough clinically and are still questionable in treating this psychotic disease.

**<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">See also **
<span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">Schizophrenia <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">[|Schizophrenia Diagnosis Criteria] <span style="background-color: white; font-family: 'Times New Roman',serif; font-size: 12pt;">Treatment of Schizophrenia

**<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">References **

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