Schizophrenia

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Por: Amelia Molina Astrid Carolina Salazar

Transcript of Schizophrenia

Por: Amelia Molina Astrid Carolina Salazar

Introduction SCHIZOPHRENIA Is a complex disorder affected by

genetic as well as enviromental factors involving dysfunction in nearly all aspects of higher order behaviour.

• abnormal social

behavior• failure to

recognize what is real.

Common symptoms include • false beliefs

• unclear or confused thinking• auditory hallucinations

• reduced social engagement and emotional expression• inactivity

• Symptoms begin typically in young adulthood, and about 0.3–0.7% of people are affected during their lifetime.

• People with schizophrenia are likely to have additional conditions, including major depression and anxiety disorders; the lifetime occurrence of substance

use disorder is almost 50%

• The genetic influence of SZ remains unknown.

• Among the multiple genes implicated, those enconding for 14-3-3 proteins at locus 8q, 22q, 17p, have been repoted to be associated with SZ

PROTEINS The 14-3-3 protein family is formed by seven distinct isoforms (β, ε, γ, η, ζ, σ)

with abundant presence in the brain.

Their function is exerted by formig dimers.

Activates tyrosine hydroxylase.

Are involved in multiple cellular process such as neurotransmission, cell signalling, ion

channel functioning, intracellular trafficking/targeting, transcription, cell

division and differenciation and apoptosis.

• 14-3-3 protein beta/alpha is a protein that in humans is encoded by the YWHAB gene.

• Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways.

• Negative regulator of osteogenesis.

• Blocks the nuclear translocation and apoptosis

• 14-3-3 protein zeta/delta is a protein that in humans is encoded by the YWHAZ gene

• The encoded protein has a role on the regulation of insulin sensitivity

• A multifunctional regulator of the cell signaling processes.

• Interacts with α2

adrenoreceptor and could have a role in the supersensitivity of this receptor in major depression disorder (MD)

Biological process:

• response to drug• platelet activation• histamine secretion by mast cell• establishment of Golgi localization• gene expression• blood coagulation• signal transduction• protein targeting to mitochondrion• negative regulation of apoptosis

Psychotropic Treatment

• Psychotropic medications are drugs that are typically prescribed to treat mental health conditions. These include:

1. depression2. Anxiety3. obsessive compulsive disorder4. Schizophrenia5. bipolar disorder 6. attention deficit disorder.

• The term, psychotropic refers to a drug whose primary or significant effects are on the central nervous system.

• Most psychotropic act by altering neurotransmission process, stimulating or inhibiting activity.

• The mainstay of treatment is antipsychotic medication, which primarily suppresses dopamine receptor activity.

Example Queatiapina is a neuroleptic drug belonging to the group called antipsychotics used in the treatment of schizophrenia and severe manic and depressive episodes of bipolar disorder.

• Exerts its antipsychotic effect in part through its activity as an antagonist of serotonin receptors and dopamine

Relay • Various studies have reported descreases in mRNA and protein

expression of diverese 14-3-3 isoforms in different brain areas of subjects with schizophrenia.

• Modulation of 14-3-3β and 14-3-3ζ isoforms has been described in cellular and in animal models after chronic antidepressant treatment.

• A number of studies have identified down-regulations of 14-3-3 mRNAs in the brain samples of schizophrenia patients.

• In addition, proteomic analyses have determined a reduction of 14-3-3 proteins in schizophrenic brains, with 14-3-3ζ decreased expression having been consistently reported in multiple studies

• Studies of prefrontal cortical show gene expression in schizophrenia, reported that certain groups of genes regulating presynaptic, postsynaptic, and metabolic functions were consistently and significantly decreased in schizophrenia

• 14-3-3 protein family describes this alterations in SZ subjects:1. Dopaminergic, serotonergic and/or glutaminergic

dysregulation2. Epigenetic alterations3. Neurodevelopmental deviances4. Cortical atrophy

General Objective

• See if the expression of the 14-3-3 protein (ζ,β) in the prefrontal cortex of schizophrenia subjects differs with control subjects y and see in what way the psicothropic treatment deacrease or increase levels of proteins and in what way this contributes to the syntoms

Materiales y Métodos

• SUJETOS se obtuvieron cerebros humanos postmortem del instituto Basque y de la universidad centro de medicina legal.

• Se usaron muestras del área de broadman, se diseccionaron y se almacenaron

• Control 52( ninguna evidencia de desordenes neuropsiquiatricos o abuso de drogas

• Sujetos con SZ 22• Sujetos con MD 21

Fueron clasificados en antipsicoticos/antidepresivos

libres o tratados

Materiales y Métodos

• Western blot es una técnica analítica usada para detectar proteínas específicas en una muestra determinada.

1. Mediante una electroforesis en gel se separan las proteínas atendiendo al criterio que se desee: peso molecular, estructura, hidrofobicidad, etc.

2. Luego son transferidas a una membrana adsorbente (típicamente de nitrocelulosa o de PVDF) para poder buscar la proteína de interés con anticuerpos específicos contra ella.

3. Finalmente, se detecta la unión antígeno-anticuerpo por actividad enzimática, fluorescencia entre otros métodos.

• De esta forma se puede estudiar la presencia de la proteína en el extracto y analizar su cantidad relativa respecto a otras proteínas.

3. Resultados

Se evaluaron 3 parámetros

3.1 Variables epidemiológicas y metodológicas que contribuyen a los niveles de inmunoreactividad de las proteínas en la corteza prefrontal humana

14-3-3β 14-3-3ζ

Género (β = −0.376, p = 0.007) Género (β = −0.297, p = 0.031)

PMD (β = 0.349, p = 0.011) Edad (β = −0.309, p = 0.025)

Línea de regresión positiva en PMD Línea de regresión negativa en edad

Edad y tiempo de almacenamiento PMD y tiempo de almacenamiento

Inmunoreactividad 29% mayor en hombres

Los niveles de etanol en la sangre no fueron significativos

3. Resultados • 3.2 Inmunoreactividad de 14-3-3β y 14-3-3ζ en las personas

con esquizofrenia tratadas con antipsicóticos y libres de antipsicóticos

Sin antipsicóticos Con antipsicóticos

Niveles de 14-3-3β Significativo incremento (∆: 25 ± 5% n:11 p:0,046)

No hay un incremento significativo( p: 0,156)

14-3-3β fue 30% mas alta en sujetos con esquizofrenia sin antipsicóticos (p:0,011)

Resultado independiente del género (p:0,012)y PMD (p:0,015)

Sujetos con esquizofrenia Sujetos control

Niveles de 14-3-3β No se presento una diferencia significativa

Con antipsicótico Sin antipsicótico

Niveles de 14-3-3 ζ No hay incremento significativo(∆: -5 ± 9% n:10 p:0,697)

Hay incremento significativo(∆: 29 ± 6% n:12 p:0,012)

14-3-3 ζ fue 46% mas alta en sujetos con esquizofrenia sin antipsicóticos (p:0,0007)

Resultado independiente del género (p:0,0015) y edad (p:0,0012)

3. Resultados

• 3.3 inmunoreactividad de 14-3-3β y 14-3-3ζ en sujetos con trastornos depresivos

la inmunoreactividad de las proteínas 14-3-3β y 14-3-3ζ en la corteza prefrontal de los sujetos

con trastornos depresivos no fue significativamente diferente a los sujetos de

control.

3. Resultados

3. Resultados

3. Resultados

3.Resultados

3. Resultados

4. Discussion

4. Discussion Person or entity Contribution Agree or disagreeMcCullumsmith, 2013 «The utilization of postmortem

tissue is of great relevance for the study of complex mental illnesses thaht are difficult to model in animals »

Agree

Pandey and Dwivedi, 2010

«In the present study, the majority of both SZ and MD subjects were suicide victims (17 of 22 in the SZ group and 17 of 21 in the MD group) regardless of the psychotropic treatment. Some neurobiologicalabnormalities associated with suicide have been suggested to be independent of psychiatric diagnoses and to be a common feature of suicidal behaviour»

Disagree

4. Discussion Person o entity Contribution Agree or disagreeMiddleton , 2005 “In the present study, postmortem brain

samples of SZ and MD subjects were used valuably reflecting neuroplastic changes from a lifetime of mental illness and psychopharmacological treatment”.

Disagree

Carboni, 2006; Cecconi, 2007;Malki, 2012.

“With respect to MD, no alteration was observed in 14-3-3β and 14-3-3ζ protein levels neither in antidepressant-free nor in antidepressant-treated MD subjects. To our knowledge, this is the first time 14-3-3 protein status in MD is studied. The unaltered levels suggest no role for these proteins in MD and no modulation of protein levels by antidepressant treatment despite the modulation by antidepressants suggested in cellular and in animal models”.

Agree

5. Conclusions

In depressive disorders we don’t see any change in proteins so we could indicate that this disease has nothing to do with

14-3-3ζ and 14-4-4β but can not asegurate because it is the first time that

relate these variables

To make a good research is necessary to understand very well the variables because this allows us a good interpretation, one of

the foundations of this research is to understand how no differences in levels of

proteins occurs in people with schizophrenia and control, but the

treatment with antipsychotics alters everything

14-3-3 regulatory proteins that are present from the most primitive organisms bind to

signaling proteins, affecting its stability, activity or cellular localization. Therefore,

they are involved in regulating various cellular processes including apoptosis, cell

cycle and the stress response.

one of the objectives that need to be evaluated more thoroughly was each

genetic polymorphism may influence the response of patients to treatment with

antipsychotics because the study present a possible consequence of suicides is that this

not responding to treatment

Conclusions

Mapa Conceptual.

Mapa Conceptual.