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
TIPURI DE INCARCARE
ALOSTATICA
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)