Science review: The brain in sepsis – culprit and victim

On one side, brain dysfunction is a poorly explored complication of sepsis. On the other side, brain dysfunction may actively contribute to the pathogenesis of sepsis. The current review aimed at summarizing the current knowledge about the reciprocal interaction between the immune and central nervous systems during sepsis. The immune-brain cross talk takes part in circumventricular organs that, being free from blood-brain-barrier, interface between brain and bloodstream, in autonomic nuclei including the vagus nerve, and finally through the damaged endothelium. Recent observations have confirmed that sepsis is associated with excessive brain inflammation and neuronal apoptosis which clinical relevance remains to be explored. In parallel, damage within autonomic nervous and neuroendocrine systems may contribute to sepsis induced organ dysfunction

Pharmacological characterization of prostaglandin E2 EP receptors in the rodent brain: functional studies in locus coeruleus neurons and the preBötzinger complex

322 p.This work focuses on the study of the neuropharmacological mechanisms underlying prostaglandin E2 (PGE2) receptor (EP) activation in locus coeruleus (LC) neurons and the preBötzinger complex (preBötC). PGE2 is an inflammatory mediator synthesized by the brain constitutive cyclooxygenase (COX) enzyme, whose activity is blocked by the nonsteroidal anti-inflammatory drugs (NSAIDs). PGE2 binds to G protein-coupled EP1-4 receptors (EP1 to Gq, EP2 and EP4 to Gs, and EP3 to Gi/o). Activation of EP receptors by PGE2 has been shown to modulate synaptic transmission and neuronal activity in various brain regions. The noradrenergic nucleus LC, which is involved in the regulation of the sleep-wake cycle, arousal, cognition, pain, and reward behavior, expresses EP2, EP3, and EP4 receptors, but their functional role remains unexplored. Therefore, we aimed to characterize the EP2, EP3, and EP4 receptors pharmacologically in the rat LC by extracellular electrophysiological recordings in acute slices. On the other hand, the inspiratory pattern is generated by the preBötC, whose inspiratory neurons express ¿-opioid receptors (MOR) and respond to PGE2. Thus, administration of opioids produces respiratory depression while PGE2 increases the frequency of sighs and induces gasps under hypoxic circumstances. However, the possible interaction between both systems to cause major respiratory disturbances remains to be elucidated. For this purpose, we also examined the interaction between opioids and PGE2 in the mice preBötC by live time-lapse calcium imaging in organotypic slice cultures

Pharmacological characterization of prostaglandin E2 EP receptors in the rodent brain: functional studies in locus coeruleus neurons and the preBötzinger complex

322 p.This work focuses on the study of the neuropharmacological mechanisms underlying prostaglandin E2 (PGE2) receptor (EP) activation in locus coeruleus (LC) neurons and the preBötzinger complex (preBötC). PGE2 is an inflammatory mediator synthesized by the brain constitutive cyclooxygenase (COX) enzyme, whose activity is blocked by the nonsteroidal anti-inflammatory drugs (NSAIDs). PGE2 binds to G protein-coupled EP1-4 receptors (EP1 to Gq, EP2 and EP4 to Gs, and EP3 to Gi/o). Activation of EP receptors by PGE2 has been shown to modulate synaptic transmission and neuronal activity in various brain regions. The noradrenergic nucleus LC, which is involved in the regulation of the sleep-wake cycle, arousal, cognition, pain, and reward behavior, expresses EP2, EP3, and EP4 receptors, but their functional role remains unexplored. Therefore, we aimed to characterize the EP2, EP3, and EP4 receptors pharmacologically in the rat LC by extracellular electrophysiological recordings in acute slices. On the other hand, the inspiratory pattern is generated by the preBötC, whose inspiratory neurons express ¿-opioid receptors (MOR) and respond to PGE2. Thus, administration of opioids produces respiratory depression while PGE2 increases the frequency of sighs and induces gasps under hypoxic circumstances. However, the possible interaction between both systems to cause major respiratory disturbances remains to be elucidated. For this purpose, we also examined the interaction between opioids and PGE2 in the mice preBötC by live time-lapse calcium imaging in organotypic slice cultures

Functional Neuroanatomy of the Noradrenergic Locus Coeruleus: Its Roles in the Regulation of Arousal and Autonomic Function Part II: Physiological and Pharmacological Manipulations and Pathological Alterations of Locus Coeruleus Activity in Humans

The locus coeruleus (LC), the major noradrenergic nucleus of the brain, gives rise to fibres innervating most structures of the neuraxis. Recent advances in neuroscience have helped to unravel the neuronal circuitry controlling a number of physiological functions in which the LC plays a central role. Two such functions are the regulation of arousal and autonomic activity, which are inseparably linked largely via the involvement of the LC. Alterations in LC activity due to physiological or pharmacological manipulations or pathological processes can lead to distinct patterns of change in arousal and autonomic function. Physiological manipulations considered here include the presentation of noxious or anxiety-provoking stimuli and extremes in ambient temperature. The modification of LC-controlled functions by drug administration is discussed in detail, including drugs which directly modify the activity of LC neurones (e.g., via autoreceptors, storage, reuptake) or have an indirect effect through modulating excitatory or inhibitory inputs. The early vulnerability of the LC to the ageing process and to neurodegenerative disease (Parkinson’s and Alzheimer’s diseases) is of considerable clinical significance. In general, physiological manipulations and the administration of stimulant drugs, α2-adrenoceptor antagonists and noradrenaline uptake inhibitors increase LC activity and thus cause heightened arousal and activation of the sympathetic nervous system. In contrast, the administration of sedative drugs, including α2-adrenoceptor agonists, and pathological changes in LC function in neurodegenerative disorders and ageing reduce LC activity and result in sedation and activation of the parasympathetic nervous system

Effects of SIDS risk factors and hypoxia on cardiovascular control in infants

Background and aims. Sudden infant death syndrome (SIDS) is a rare lethal event occurring in 0.1 to 0.3 of infants. In Finland, 10 to 20 infants die from SIDS annually. Research has defined many risk factors for SIDS, but the cascade leading to death remains unexplained. Cardiovascular recordings of infants succumbing to SIDS, as well as animal models, suggest that the final sequelae involve cardiovascular collapse resembling hypotensive shock. There is also evidence of previous hypoxia in SIDS infants. In animal studies, vestibulo-mediated cardiovascular control has been shown to be important in hypotensive shock. Hence, we hypothetized that SIDS victims may have impaired vestibulo-mediated cardiovascular control, possibly due to previous hypoxic episodes. In this thesis, we studied cardiovascular control, and especially vestibulo-mediated cardiovascular control in infants with known risk factors for SIDS at 2 to 4 months of age when the risk for SIDS is highest. Study subjects. A full polysomnographic recording with continuous blood pressure (BP) measurement was performed in 50 infants at 2-4 months of age: 20 control infants, nine infants with univentricular heart (UVH) suffering from chronic hypoxia, 10 infants with bronchopulmonary dysplasia (BPD) with intermittent postnatal hypoxic events, and 11 infants whose mothers had smoked during pregnancy, and thus had been exposed to intrauterine hypoxia and nicotine, were studied. In addition, 20 preterm infants were studied at the gestational age of 34-39 weeks to evaluate developmental aspects of cardiovascular control during head-up tilt test and vestibular stimulus. Methods. Linear side motion and 45° head-up tilt tests were performed in quiet non-rapid eye movement sleep (NREM). Heart rate (HR) and BP responses were analysed from the tests without signs of subcortical or cortical arousal. In addition, HR variability during NREM sleep was assessed. As a general marker of cardiovascular reactivity, HR response to spontaneous arousal from NREM sleep was also evaluated. Results.Side motion test. In the side motion test, control infants presented a biphasic response. First, there was a transient increase in HR and BP. This was followed by a decrease in BP to below baseline, and a return to baseline in HR. All other infant groups showed altered responses. UVH infants and preterm infants near term age had markedly reduced responses. Infants with BPD presented with variable responses: some responded similarly to controls, whereas others showed no initial increase in BP, and the following BP decrease was more prominent. Infants with intrauterine exposure to cigarette smoke showed flat initial BP responses, and the following decrease was more prominent, similarly to a subgroup of BPD infants. Tilt test. Control infants presented with a large variability in BP responses to head-up tilting. On average, systolic BP remained, at first, close to baseline, and diastolic BP increased, after which both decreased and remained below baseline even at the end of the tilt test. On average, HR showed a biphasic response with an initial increase followed by a decrease to below and, finally, a return to baseline. UVH infants showed a similar BP response, but their HR response was tachycardic. Preterm infants with BPD presented with an even greater variability in their BP responses to head-up tilts than control infants, but the overall response as a group did not differ from that of the controls. The tilt response of infants exposed to maternal cigarette smoking during pregnancy did not markedly differ from the control response. Preterm infants near term age showed attenuated responses in both cardiovascular measures, together with greater inter-subject variability compared to the control infants. Discussion. In conclusion, the studied infants with SIDS risk factors showed altered vestibulo-mediated cardiovascular control during the linear side motion test and head-up tilt test. The findings support our initial hypothesis that some infants with SIDS risk factors have defective vestibulo-mediated cardiovascular control, which may lead to death in life-threatening situations.Kätkytkuolemat ovat harvinaisia, mutta ne ovat edelleen suurin yksittäinen syy täysiaikaisena syntyneiden imeväisten kuolemaan. Suomessa kätkytkuolemaan menehtyy vuosittain 10-20 lasta. Kätkytkuoleman syytä ei tiedetä. Epidemiologisten tutkimusten avulla kätkytkuoleman riskitekijät tunnetaan hyvin; näitä ovat mm. vatsallaan nukkuminen, äidin raskaudenaikainen tupakointi ja keskosuus. Selällään nukuttamisen yleistymisen myötä kätkytkuolemien määrä on vähentynyt olennaisesti. Koe-eläintöissä ja muutamassa kätkytkuoleman aikaisessa seurantanauhoituksessa on viitteitä siitä, että kätkytkuoleman mekanismi todennäköisesti muistuttaa verenvuotosokin loppuvaiheen kaltaista verenkiertoelimistön toiminnan romahtamista. Koe-eläintöiden perusteella tällaisessa sokkitilanteessa tasapainotumakevälitteinen verenkierron säätely on tärkeää. Tämän tutkimuskokonaisuuden pääolettaman mukaan kätkytkuolleilla on puutteellinen tasapainotumakevälitteinen sykkeen ja verenpaineen säätely. Koska kätkytkuolleilla on myös todettu merkkejä hapenpuutteesta ennen kuolemaa, voi poikkeavan tasapainotumakevälitteisen verenkierron säätelyn syynä olla edeltänyt hapenpuute: riskiryhmistä esimerkiksi keskosilla lyhytkestoiset hapenpuutejaksot ja äidin raskaudenaikaiselle tupakoinnille altistuneilla lapsilla pitkäaikainen lievä hapenpuute sikiöaikana. Myös pitkäaikaisesta syntymän jälkeisestä hapenpuutteesta kärsivillä yksikammiosydämisillä imeväisillä on todettu äkillisiä, kätkytkuoleman kaltaisia kuolemia. Tutkimme imeväisen verenkierron säätelyä unen aikana rekisteröimällä verenkiertovasteita sivuttaissiirto- ja kippilavatestille täysiaikaisilla imeväisillä sekä imeväisillä, joilla on yllämainittuja kätkytkuoleman riskitekijöitä tai hapenpuutetta. Unirekisteröinti tehtiin yhteensä 70 imeväiselle. 2-4 kuukauden korjatussa iässä tutkittiin 20 täysiaikaista verrokkia, 10 bronkopulmonaalisesta dysplasiasta kärsivää keskosta, 9 yksikammiosydämistä imeväistä sekä 11 imeväistä, joiden äidit tupakoivat raskauden aikana. Lisäksi tutkimme 20 keskosta 34-39 raskausviikon iässä sykkeen ja verenpaineen säätelyn kehityksen kartoittamiseksi. Sivuttaissiirtotesti sekä 45° kippilavatesti pää ylöspäin tehtiin rauhallisessa ei-REM-unessa. Terveiden täysiaikaisten verrokkien verenpaine- ja sykevasteita käytettiin vertailukohtana muiden ryhmien vasteita arvioitaessa. Syke- ja verenpainevasteet arvioitiin testeistä, joissa ei ollut viitettä havahtumisesta tai heräämisestä. Sydämen sykkeen vaihtelevuutta ja spontaanin heräämisen aiheuttamaa sykevastetta käytettiin kuvaamaan yleistä verenkiertoelimistön säätelyn herkkyyttä. Sivuttaissiirtotestissä verrokit reagoivat kaksivaiheisella syke- ja verenpainevasteella. Sekä verenpaine että syke nousivat aluksi, jonka jälkeen verenpaine laski alle lähtötason ennen paluuta lähtötasoon, ja syke palasi lähtötasoon. Muissa tutkituissa ryhmissä vasteet poikkesivat normaalivasteista. Yksikammiosydänlapsilla sekä lähellä laskettua aikaa tutkituilla keskosilla syke- ja verenpainevasteet sivuttaissiirrolle olivat hyvin vaimeat. Puolet bronkopulmonaalisesta dysplasiasta kärsivistä imeväisistä reagoi samoin kuin verrokit, mutta puolella verenpaineen nousu puuttui ja sitä seurannut verenpaineen lasku oli selvästi normaalia syvempi. Myös imeväisillä, joiden äidit olivat tupakoineet raskauden aikana, verenpaineen alkunousu puuttui ja sitä seurannut verenpaineen lasku oli verrokkeja syvempi. Kippilavatestissä täysiaikaisten verrokkien verenpainevasteet olivat hyvin vaihtelevat. Keskimäärin testin alussa systolinen verenpaine pysyi ennallaan ja diastolinen nousi. Testin jatkuessa molemmat laskivat alle lähtötason, jossa ne pysyivät vielä testin lopettamisen jälkeenkin. Verrokkien sykevasteet olivat selkeästi yhtenevämmät ja vaste oli kaksivaiheinen: alun sykkeen nousua seurasi sykkeen lasku alle lähtötason ja paluu takaisin lähtötasoon. Yksikammiosydänlasten verenpainevasteet olivat verrokkien kaltaiset, mutta heidän sykkeensä pysyi korkeana koko testin ajan. Bronkopulmonaalisesta dysplasiasta kärsivien imeväisten verenpainevasteissa oli vielä voimakkaampaa vaihtelua kuin verrokkien vasteissa, mutta ryhmänä heidän vasteensa ei eronnut verrokeista. Raskaudenaikaiselle tupakoinnille altistuneiden imeväisten verenkiertovasteet eivät eronneet verrokeista. Lähellä laskettua aikaa tutkittujen keskosten syke- ja verenpainevasteissa oli suurta vaihtelua verrattuna täysiaikaisiin verrokkeihin, mutta ryhmänä verenkiertovasteet olivat vaimeammat kuin verrokeilla. Tässä tutkimuksessa todettiin poikkeava tasapainotumakevälitteinen verenkierron säätely imeväisillä, joilla on yllämainittuja kätkytkuoleman riskitekijöitä ja edeltäneitä hapenpuutejaksoja. Tutkimustulokset tukevat etukäteisolettamustamme, että heikentynyt tasapainotumakevälitteinen verenkierron säätely imeväisillä voi olla osaltaan johtamassa kätkytkuolemaan henkeä uhkaavassa tilanteessa

Faculty Publications 2000

This Faculty bibliography contains 824 publications.https://digitalscholar.lsuhsc.edu/pastfacpubs/1052/thumbnail.jp

Regulation of the transcription factor nuclear factor kappa B in the neuroendocrine response to stress

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