CONF.DR.DANIEL GRIGORIE

Why Zebras Don’t Get Ulcers ?

Because they do not worry!

Stress is a word used to describe

experiences that are challenging emotionally and physiologically

The brain is the central organ of the stress

response and determines what is stressful, as well as the behavioral and physiological responses to potential and actual stressors.

The brain is also a target of stress and it changes structurally and chemically in response to both acute and chronic stressors.

Sistemul de stressDefinitie: Stress = o stare de amenintare a

homeostaziei care poate fi contracarata de o serie de raspunsuri fiziologice si comportamentale care au ca scop restabilirea echilibrului (raspunsul adaptativ la stress).

Componente centrale:Neuronii CRH si AVP din nc. paraventricularSist. simpatic central (locul ceruleus)

Componente periferice:Axa HPASist. simpato-adrenal periferic (MSR+SNS)

RASPUNSUL GENERAL LA STRESSStressorii fiziologici si psihologici semnificativi evoca un

raspuns adaptativ care include activarea axei HPA si a sistemului simpatoadrenal.

Produsii finali ai acestor cai ajuta la mobilizarea resurselor necesare pt a face fata necesitatilor fiziologice din situatii de urgenta, in mod acut prin raspunsul lupta sau fugi, si pe termen lung prin efectele sistemice ale glucocorticoizilor asupra unor functii, cum sunt gluconeogeneza si mobilizarea energiei.

Axa HPA are roluri homeostatice unice, specifice stressului, cel mai bun exemplu fiind rolul GC in reglarea raspunsului imun sau inflamator.

Central and peripheral functions of the stress responseFunctions of the central nervous system Facilitation of arousal, alertness, vigilance, cognition,

attention and aggression Inhibition of vegetative functions (e.g. reproduction,

feeding, growth) Activation of counter-regulatory feedback loops Peripheral functions Increase of oxygenation Nutrition of brain, heart and skeletal muscles Increase of cardiovascular tone and respiration Increase of metabolism (catabolism, inhibition of

reproduction and growth) Increase of detoxification of metabolic products and foreign

substances Activation of counter-regulatory feedback loops (includes

immunosuppression)

Rapunsul adaptativ la stressEste determinat de factori:

Genetici Ontogenetici De mediu

Functiile nonvitale consumatoare de energie (reproductive, digestive, crestere) sunt inhibate tranzitor cu scopul prezervarii energiei si directionarii oxigenului si nutrientilor catre SNC si zonele afectate de stress.

Raspunsul inadecvat (insuficient, excesiv, prelungit) la stressori este nociv si poate produce boala.

De aceea stress-ul cronic (stare patologica de amenintare prelungita a homeostaziei prin stressori persistenti sau repetitivi) conduce progresiv la stari de boala.

ALOSTAZAthe term “allostasis” was introduced by Sterling

and Eyer (Sterling and Eyer, 1988) to refer to the active process by which the body responds to daily events and maintains homeostasis (allostasis literally means “achieving stability through change” and is not intended to replace “homeostasis”).

ALOSTAZA

INCARCARE ALOSTATICA

The burden of chronic stress and accompanying changes in personal behaviors (smoking, eating too much, drinking, poor quality sleep; otherwise referred to as “lifestyle”) is called allostatic overload

Tintele mediatorilor stresului

the executive and/or cognitive systemsthe fear/anger system; f-b pozitiv cu amigdalareward systems; sistemul dopaminergic

mezolimbicthe wake–sleep centers of the brain;the growth, reproductive and thyroid-hormone

axesthe gastrointestinal, cardiorespiratory, metabolic,

and immune systems.

DEPRIVAREA DE SOMNSleep deprivation produces an allostatic

overload that can have deleterious consequences. The effects include elevated evening cortisol, insulin and blood glucose, elevated blood pressure, reduce parasympathetic activity and elevated levels of proinflammatory cytokines, as well as the gut hormone, ghrelin, which increases appetite.

Hunger for comfort foods and increased caloric intake are one result, along with depressed mood and cognitive impairment

ROLUL HIPOCAMPULUIHippocampus= a brain region that is important

for spatial, episodic, and contextual memory formation

plays a role in shutting off the HPA stress response

“glucocorticoid cascade hypothesis” of stress and aging

Adaptarea la stresul cronic=plasticitate neuronala

The role of this plasticity may be to protect against permanent damage. As a result, the hippocampus undergoes a number of adaptive changes in response to acute and chronic stress.

One type of change involves replacement of neurons

Another form of structural plasticity is the remodeling of dendrites in the hippocampus

adrenal steroids are important mediators of remodeling of hippocampal neurons during repeated stress

the most important interactions are those with excitatory amino acids such as glutamate

Neuroimunomodulare

Citokine ca Il -1 beta activeaza axa HPA si stimuleaza secretia de GC, care fac f-b negativ asupra sist imun pt a limita raspunsul acestuia. In general GC inhiba majoritatea componentelor raspunsului imun, reactii care stau la baza actiunilor lor anti-inflamatorii.

Acest f-b neg este reglator si benefic pt ca altfel am fi vulnerabili la inflamatie; in acelasi timp un f-b exagerat poate avea consecinte fiziopatologice, intrucit activarea cronica a axei HPA este nociva; de ex stresul cronic produce imunosupresie.

CONTINUAREAstfel secretia de cortizol creste ca raspuns la

febra, interv chir, arsuri, hipoglicemie, hipotensiune, efort fizic

Stresul psihologic acut creste de asem secretia de cortizol, dar secretia este normala la pacientii cu anxietate cronica sau boli psihotice.

Totusi, depresia este asociata cu conc crescute de cortizol.

CONTINUAREStressori diferiti determina patternuri de activare

diferite in cele 3 grupe neuronale din nc.PV, masurate prin c-Fos(marker de activare neuronala).

Stresorii fiziologici sau sistemici activeaza neuronii CRH pe calea nc tract solit si a organelor circumventric

Stressorii neurogeni (emotionali, psihogeni) implica cai nociceptive si somatosenzoriale ca si centrii cerebrali afectivi si cognitivi.

FUNCTIILE CRHFct primara: stimularea secretiei de ACTH de catre

corticotropele hipofizare prin legare de CRH-R1 si stimularea adenilat ciclazei.

Functii extrahipofizare ale CRH si urocortinelor:Central, aceste peptide au activitati

comportamentale implicate in anxietate, afect, trezire, locomotie, rasplata si hranire si stimuleaza activarea sistemului nervos simpatic. Aceste activitati sunt complementare activarii axei HPA in mentinerea homeostaziei dupa expunerea la stress.

In periferie, au fost raportate activitati in imunitate, functiile cardiaca, gastrointestinala si reproducere.

FCT CRH SI UROCORTINELORHiperactivitatea axei HPA este frecventa in bolile

afective si normalizarea reglarii axei HPA are valoare predictiva asupra succesului terapeutic.

Supresia incompleta la DXM a secretiei CRH se observa nu numai la pacientii depresivi ci si la subiectii sanatosi cu antecedente familiale de depresie.

La pacientii depresivi exista conc crescute de CRH in LCR

Testarea comportamentala extensiva la o varietate de soareci mutanti(CRH si/sau receptori) sustine ipoteza ca activarea cailor centrale ale CRH reprezinta un substrat neurobiologic critic al starilor de anxietate si depresie.

Functiile extrahipofizare ale CRHAdm centrala de CRH sau urocortine activeaza

grupuri neuronale implicate in controlul cardiovascular si produce cresterea TA, alurii ventric si a debitului cardiac.

Citokinele au un rol important in stingerea raspunsului inflamator prin activarea neuronilor CRH si AVP si cresterea ulterioara a secretiei de glucocorticoizi, care au efect anti-inflamator.

Interesant, CRH este in general pro-inflamator in periferie, unde se gaseste in eferentele simpatice, aferentele senzoriale, leucocite si macrofage.

APLICATII CLINICEDezvoltarea de molecule mici, cu adm orala,

antag de CRH-R1 ca trat potential pt anxietate si depresie.

Studii de faza I si II au demonstrat reducerea semnificativa a scorurilor de anxietate si depresie, fara efecte secundare endocrine sau asupra greutatii corporale.

Stress-ul cronic=factor de risc pentru sindromul metabolicActivarea cronica a axei HPA favorizeaza

dezvoltarea adipozitatii viscerale si a sindromului metabolic

Mecanism: cortizolul stimuleaza proliferarea adipocitara => cresterea productiei de citokine => stimularea axei HPA

FUNCTIA REPRODUCTIVAPoate fi alterata de expunerea cronica la stress.Multe forme de stress fizic (restrictia calorica, exercitiile, stress

termic, infectiile, durerea) si psihologic(acut si cronic) supreseaza activitatea axei reproductive.

Daca expunerea la stress este scurta se poate produce supresia acuta a secretiei de GT si ovariene dar fertilitatea nu este de obicei afectata. In contrast expunerea prelungita la un stress semnificativ poate duce la alterarea completa a fct reproductive, cu inhibitia axei HPgonadale.

In anovulatia hipot fct stressori ca efortul fizic intens sau stressul emotional pot activa cronic axa HPA

CRH este un factor important in inhibitia pulsatilitatii GnRH, efect care poate fi prevenit de antagonistul opioid naloxona, ceea ce arata ca CRH activeaza sistemul opioid endogen(analgezia de stress).

Mec inhibitiei GnRH ar putea fi specifice stressorului.

Increased activity of the HPA axis

Cushing syndrome Chronic stress Melancholic depression Anorexia nervosa Obsessive–compulsive disorder Panic disorder Excessive exercise (obligate athleticism) Chronic, active alcoholism Alcohol and narcotic withdrawal Diabetes mellitus Central obesity (metabolic syndrome) Post-traumatic stress disorder in children Hyperthyroidism Pregnancy

Decreased activity of HPA axis

Adrenal insufficiency Atypical/seasonal depression Chronic fatigue syndrome Fibromyalgia Premenstrual tension syndrome Climacteric depression Nicotine withdrawal Following cessation of glucocorticoid therapy Following Cushing syndrome cure Following chronic stress Postpartum period Adult post-traumatic stress disorder Hypothyroidism Rheumatoid arthritis Asthma, eczema

Adaptive responses to evolutionary stressors and related diseases in modern human societies

BOALA GRAVES

Multe paciente identifica legatura dintre debutul bolii si un episod de stress major in ultimele 12 luni

Sresul produce imunosupresie dupa care apare o hipercompensare a sistemului imun ce poate fi o cond favorabila la cei cu predisp genetica

Mec similar dupa sarcina, per de imunosupresie

CATECOLAMINELE

Termenul de catecolamine se refera la substante care contin nucleul catecolic si o grupare amino in lantul lateral.

adrenalina – sintetizata si depozitata in MSR de unde este eliberata in circulatia sistemica

noradrenalina- este sintetizata si depozitata nu numai in MSR ci si in nervii simpatici periferici

dopamina – este precursor al NE in MSR si nervii simpatici periferici; functioneza in principal ca un neurotransmitator in SNC.

ACTIUNILE CATECOLAMINELOR CT au multe efecte cardiovasculare si metabolice, care includ:

stimularea ritmului cardiac, TA, contractilitatea si viteza de conducere in miocard. Actiunile CT sunt mediate de 3 tipuri de receptori adrenergici ( alfa, beta, DA) si de subtipurile lor (a1, a2, b1, b2, b3, DA1, DA2).

Subtipul a1 este un receptor postsinaptic care mediaza contractia muschilor vasculari si netezi, ceea ce produce vasoconstrictie si cresterea TA.

Receptorii a2 sunt localizati pe terminatiile presinaptice ale nn. simpatici si activarea lor inhiba eliberarea NE, ceea ce determina supresia fluxului simpatic central si hipotensiune.

Receptorul b1 – stimularea lui are efecte inotrope si cronotrope cardiace, stimuleaza secretia renala de renina si lipoliza in adipocite

Receptorul b2 – mediaza relaxarea muschilor netezi vasculari, bronsici si uterin; stimularea produce bronhodilatatie, vasodilatatie in muschii scheletici, glicogenoliza

Receptorul b3- regleaza cheltuiala de energie si lipoliza

ACTIUNILE CATECOLAMINELOR

Receptorii DA1- sunt localizati in sistemele vasculare cerebral, renal, mezenteric si coronarian si stimularea lor produce vasodilatatie

Receptorii DA2 – sunt presinaptici si localizati in terminatiile nn. simpatici, ggl simpatici si creier; stimularea lor inhiba eliberarea NE, transmisia ggl si secretia de prolactina

Aplicatii cliniceAplicatii clinice ale manipularii farmacologice a

receptorilor adrenergici:Antagonisti selectivi ai b1 (atenolol, metoprolol) –

tratament standard pt angor, HTA, aritmii;Agonisti selectivi b2 (terbutalina, albuterol) –

tratamentul astmului bronsic.

SEMNE SI SIMPTOME PAROXISTICE

 Anxiety and fear of impending death  Diaphoresis  Dyspnea  Epigastric and chest pain  Headache  Hypertension  Nausea and vomiting  Pallor  Palpitation (forceful heartbeat)  Tremor

Inadaptarea la stress – reactia catecolaminicaIn stressul acut catecolaminele au rol adaptativ

prin cresterea AV, TAIn stressul cronic, cresterea cronica a

catecolaminelor produce modificari fiziopatologice cardio-vasculare (HTA, ateroscleroza, infarct)