CONF.DR.

DANIEL GRIGORIE

Why Zebras Dont 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 stress
Definitie: 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. paraventricular
Sist. simpatic central (locul ceruleus)

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

RASPUNSUL GENERAL LA STRESS

Stressorii 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 response
Functions 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 stress

Este 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.

ALOSTAZA
the 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 systems
the fear/anger system; f-b pozitiv cu amigdala
reward systems; sistemul dopaminergic

mezolimbic
the wakesleep centers of the brain;
the growth, reproductive and thyroid-hormone
axes
the gastrointestinal, cardiorespiratory, metabolic,
and immune systems.

DEPRIVAREA DE SOMN
Sleep 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 HIPOCAMPULUI
Hippocampus= 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.

CONTINUARE
Astfel 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.

CONTINUARE
Stressori 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 CRH
Fct 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 UROCORTINELOR

Hiperactivitatea 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 CRH

Adm 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 CLINICE
Dezvoltarea 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 metabolic
Activarea 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 REPRODUCTIVA
Poate 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
Obsessivecompulsive 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 clinice
Aplicatii 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

catecolaminica
In stressul acut catecolaminele au rol adaptativ

prin cresterea AV, TA

In stressul cronic, cresterea cronica a
catecolaminelor produce modificari
fiziopatologice cardio-vasculare (HTA,
ateroscleroza, infarct)