Angiotensins, especially angiotensin IV (Ang IV), have recently been found to be potent cognitive... more Angiotensins, especially angiotensin IV (Ang IV), have recently been found to be potent cognitive enhancers in rodents. However, the precise mechanisms of their memory improving effects remain unknown. In this study we tested the hypothesis that D 2 dopamine receptors at least partially mediate cognitive effects of Ang IV and its derivative des-Phe 6 Ang IV. Namely, the well known cognitive effects of both peptides [facilitation of a conditioned avoidance responses (CARs) acquisition, increase of a passive avoidance behavior (PAB) retrieval, and improvement of object recognition] were evaluated in rats either pretreated or not with a selective D 2 dopamine receptor antagonist remoxipride {(S)-(−)-3-Bromo-N-[(1-ethyl-2-pyrrolidinylOmethyl]2,6-dimethoxybenzamide hydrochloride}. To control for the unspecific motor and emotional effects of our treatments that could confound results of the memory tests we used respectively, 'open' field and elevated 'plus' maze tests. Ang IV as well as des-Phe 6 Ang IV remarkably improved learning of CARs, recall of PAB and recognition of the previously seen objects. D 2 receptors blockade by remoxipride abolished all these effects of both peptides. In the elevated 'plus' maze remoxipride abolished anxiogenic effects of both Ang IV and des-Phe 6 Ang IV. Also, the drug followed by Ang IV decreased number of crossings and by des-Phe 6 Ang IV number of crossings and rearings. The results point to importance of the functional D 2 dopamine receptors in cognitive effects of Ang IV and its naturally occurring product devoid of C-terminal Phe 6 .
An important role for angiotensin IV (Ang IV) in the processes of learning and memory has now bee... more An important role for angiotensin IV (Ang IV) in the processes of learning and memory has now been well established. We have previously found that intracerebroventricular (ICV) administration of Ang IV as well as des-Phe 6 -Ang IV enhances learning of conditioned avoidance responses (CARs), facilitates recall of a passive avoidance (PA) task, and improves object recognition (OR) in rats. Since the dopaminergic system is crucial for the cognitive processes, in this study our aim was to determine the dopaminergic D 1 mediation of these effects using SCH 23390 as a selective D 1 receptor antagonist. Male Wistar rats (180-200 g), pretreated with SCH 23390 (R-[+]-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) 0.05 mg/kg intraperitoneally (IP), were given Ang IV or des-Phe 6 -Ang IV (1 nmol ICV) 1 h later and then tested in the above cognitive paradigms, as well as in the open field and an elevated 'plus' maze to control for the unspecific, respectively, motor and emotional, effects of our treatments. Both, Ang IV and des-Phe 6 -Ang IV effectively enhanced learning of CARs (P < 0.05), recall of PA (P < 0.001), and improved OR (P < 0.001). Pretreatment with SCH 23390 abolished the cognitive effects of both peptides. SCH 23390, Ang IV, and des-Phe 6 -Ang IV, given at the same doses and routes as in the cognitive tests, did not significantly influence crossings, rearings and bar approaches in the open field, nor the parameters measured in the elevated 'plus' maze, thus making a major contribution of the unspecific effects of our treatments to the results of the memory tests improbable. In conclusion, these results indicate that the functional dopaminergic D 1 receptors are necessary for the Ang IV and des-Phe 6 -Ang IV cognitive effects to occur.
Journal of the Renin-Angiotensin-Aldosterone System, 2014
Introduction: Despite recognition of stress as a causation of severe neuropsychological dysfuncti... more Introduction: Despite recognition of stress as a causation of severe neuropsychological dysfunctions, no casual and clinically effective anti-stress therapeutic strategy has yet been found. We have previously shown that blockade of initial stress response by angiotensin receptor blockers alleviates the negative effect of prolonged stress on cognitive non-spatial functions of rats. Here we aimed to find whether telmisartan reduces stress-related memory decline in spatial hippocampaldependent learning tasks conditioned upon differences in level of stress induced by aversive nature of memory tests. Methods: Male Wistar rats were exposed to chronic restraint stress for three weeks and daily treated with either vehicle or telmisartan (1 mg/kg). Afterwards rats were tested in three spatial learning and memory paradigms: Morris water maze (MWM), radial arm maze (RAM), and Barnes maze (BM). Results: Stressed animals demonstrated significantly impaired performance in all the tests, which was normalized in the animals stressed and treated with telmisartan. Interestingly, despite the fact that MWM and RAM are more stressful, which affects animal behavior, therefore considered less sensitive than BM, more significant effect of telmisartan was found in MWM and RAM than BM. Conclusions: AT1 angiotensin receptor blockade attenuates negative effect of both acute and chronic stress on spatial memory.
We have recently found that postsynaptic D3 dopamine (DA) receptors appear not to participate in ... more We have recently found that postsynaptic D3 dopamine (DA) receptors appear not to participate in the memory enhancing effects of the angiotensin AT4 receptor agonists angiotensin IV (Ang IV) and des-Phe(6)-Ang IV. In this study we evaluated role of the presynaptic DA D3 receptors in these effects. For that purpose effect of (+)-UH 232, a selective D3 DA receptors partial agonist preferring presynaptic sites, on the pro-cognitive action of intracerebroventricularly (icv) injected Ang IV and des-Phe(6)-Ang IV was examined. Male Wistar rats weighing 180-200 g were used. Both peptides given at the dose of 1 nmol facilitated recall of a passive avoidance (PA) behaviour, improved object recognition (OR), and increased apomorphine-induced stereotype behaviour. In the auxiliary tests performed to control for the unspecific influence of motor (open field, OF) and emotional (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;plus&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; maze, PM) effects of our treatments on the results of the memory tests they had either no (OF) or negligible (PM) effects. Intraperitoneal pre-treatment of the animals with an ineffective on its own dose (1 mg/kg) of (+)-UH 232 abolished or markedly diminished effects of both peptides on PA and OR but did not influence enhancement of stereotypy caused by the peptides.
This study explores behavioral effects of angiotensin II (Ang II) and a potent AT(1) receptor inh... more This study explores behavioral effects of angiotensin II (Ang II) and a potent AT(1) receptor inhibitor valsartan ((S)-N-valeryl-N-{[2&amp;amp;#39;-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl}-valine). Male Wistar rats (160-180 g) were administered valsartan (10 mg/kg) orally followed, 2 hr later, by Ang II (1 nmol) given intracerebroventricularly (i.c.v., right lateral ventricle). Then 15 min later rats underwent behavioral testing: acquisition of conditioned avoidance responses (CARs), recall of a passive avoidance behavior, open field, elevated &amp;amp;quot;plus&amp;amp;quot; maze, and &amp;amp;quot;chimney&amp;amp;quot; test. Object recognition was tested 60 min after the i.c.v. injections. In addition, effect of valsartan on Ang II stimulated drinking of water was tested. We found that valsartan did not modify the Ang II facilitation of CARs acquisition but abolished the Ang II improvement of memory retrieval and consolidation. The lack of effect of our treatments on the rats&amp;amp;#39; motor activity in the open field makes unspecific contribution of the drug-induced performance changes to the cognitive tests improbable. The anxiogenic action of Ang II, decreased by valsartan, makes an unspecific influence of anxiety possible. The prevention of Ang II increase of drinking by orally given valsartan confirmed effective blockade of the brain AT(1) receptors by the drug. valsartan appears to affect cognitive effects of i.c.v. Ang II in rats in a similar way to losartan; anxiolytic activity of valsartan appears to be slightly weaker than that of losartan.
In this study we attempted to determine behavioural, including cognitive, consequences of the bra... more In this study we attempted to determine behavioural, including cognitive, consequences of the brain AT 1 (losartan, 2 nmol), AT 2 (PD 123319, 1.5 nmol), and joint AT 1 /AT 2 angiotensin receptors blockade. Male Wistar rats (160-180 g) were injected into the left cerebral ventricle with the above doses of the blockers dissolved in 0.9% NaCl solution (vehicle) or with the vehicle alone. Five minutes later they received, to the right cerebral ventricle, 1 nmol of angiotensin II (Ang II) dissolved in vehicle or the vehicle alone. Ang II consistently increased rate of acquisition of conditioned avoidance respones (CARs) and facilitated recall of the passive avoidance behaviour. In one out of the three series of experiments in open field Ang II stimulated rats locomotor activity. Losartan and PD 123319, both ineffective alone, given prior to Ang II abolished all the behavioural changes produced by the peptide except for the Ang II facilitation of CARs acquisition, which was unchanged by losartan. Interestingly, joint injection of losartan and PD 123319 significantly decreased the rate of CARs acquisition both in control and Ang II treated animals. In conclusion, the present data suggest significant though different involvement of both AT 1 and AT 2 angiotensin receptors in cognitive processes.
This study was aimed at the estimation of influence of enalapril and captopril on emotional proce... more This study was aimed at the estimation of influence of enalapril and captopril on emotional processes in hypertensive patients. Hypertensive subjects evaluated before introducing drug treatment and normotensive persons comprised the control groups. All groups were examined with the psychological methods (BDI, HSC, Raven&amp;amp;amp;amp;#39;s Matric test). In BDI, there were no significant differences between the groups in the total score and particular factors as well. In HSC, there were significant differences in the total ratings between untreated hypertensive subjects and the normotensive group (p &amp;amp;amp;amp;lt; 0.05). The depression/anxiety profile was the main contributing factor being itself significantly different (p &amp;amp;amp;amp;lt; 0.05) in those groups. Enalapril and captopril reversed the negative behavioural changes caused by hypertension only moderately with no statistical significance. There were no alterations in intellectual abilities tested by the Raven&amp;amp;amp;amp;#39;s Matric test in any group examined. In conclusion, significant negative emotional effects of high blood pressure are only partly reversed by the antihypertensive doses of enalapril and captopril.
Streszczenie: Behawioralne, anatomiczne i molekularne badania ostatnich lat przynios³y znaczny po... more Streszczenie: Behawioralne, anatomiczne i molekularne badania ostatnich lat przynios³y znaczny postêp w rozumieniu mechanizmów uczenia siê i pamiêci. Opisano regiony mózgu odpowiedzialne za uczenie siê i pamiêae, jak równie¿ szereg czynników, które mog¹ modyfikowaae te procesy. Badania behawioralne wykaza³y, ¿e poszczególne peptydy angiotensynowe, zw³aszcza angiotensyna II i angiotensyna IV, uczestnicz¹ w procesach uczenia siê i pamiêci, ale mechanizmy odpowiedzialne za te procesy s¹ niejasne. Badania in vitro wykaza³y, ¿e wa¿nym ogniwem sygnalizacji za porednictwem receptora AT1 jest wzrost aktywnoci kinaz MAP, prowadz¹cy do aktywacji czynników transkrypcyjnych i syntezy poszczególnych bia³ek. Prokognitywne dzia³anie angiotensyny IV odnotowane w badaniach behawioralnych zosta³o potwierdzone przez jej zwi¹zek z niektórymi neurotransmiterami i neuropeptydami uczest-nicz¹cymi w procesach pamiêci i metabolizmie glukozy. Praca opisuje udzia³ receptorów angiotensynowych w procesach poznawczych.
Journal of physiology and pharmacology: an official journal of the Polish Physiological Society
cAMP responsive element binding protein (CREB) plays an important role in transcriptional machine... more cAMP responsive element binding protein (CREB) plays an important role in transcriptional machinery. CREB signaling is altered in patients with asthma. However, the role of CREB in chronic obstructive pulmonary disease (COPD) is less clear. In the present study we assessed changes in subcellular CREB distribution and activation (CREB-P) in 35 stable COPD patients treated with formoterol (F), formoterol+budesonide (F/ICS), and formoterol+budesonide+theophylline (F/ICS/Th) b.i.d. for 4 weeks, using SDS-PAGE/WB in cytosol and nuclear extracts of induced sputum cells. The expression of CREB was increased after F/ICS in both cytosolic and nuclear fractions by about 40% and 24%, respectively (P&lt;0.001, P&lt;0.01), while CREB-P increased after F/ICS by about 50% (P&lt;0.01) in both compartments. These changes were not affected by theophylline. In F/ICS-treated patients, relative accumulation of CREB in cytosol was observed. These findings indicate, that poor response to ICS therapy may be related to increased CREB-associated signaling.
Journal of physiology and pharmacology: an official journal of the Polish Physiological Society
We assessed the effect of therapy on nuclear signaling related to inflammatory processes in sputu... more We assessed the effect of therapy on nuclear signaling related to inflammatory processes in sputum cells of patients with chronic obstructive pulmonary disease (COPD). Patients were treated with formoterol (F) or formoterol plus budesonide (F/ICS) b.i.d. for 4 weeks, their sputum cells were isolated and subjected to RNA extraction or lysis, followed by differential centrifugation. Signaling protein levels were assessed by Western blots, their specific mRNAs were quantified using qRTPCR, while 8-isoprostane levels were examined using enzyme immunoassay kit. Cytosolic 8-isoprostane levels and nuclear glucocorticoid receptor expression (protein and mRNA) were not significantly different in both groups, while nuclear cAMP response element binding protein (CREB; protein and mRNA) and peroxisome proliferator-activated receptor gamma (PPARgamma protein and mRNA) were significantly higher in cells from F/ICS-treated patients. CREB-binding protein (CBP; protein and mRNA) levels were signific...
Pneumonologia i alergologia polska: organ Polskiego Towarzystwa Ftyzjopneumonologicznego, Polskiego Towarzystwa Alergologicznego, i Instytutu Gruzlicy i Chorob Pluc
Chronic obstructive pulmonary disease (COPD) is a 4(th) major cause of morbidity and mortality wo... more Chronic obstructive pulmonary disease (COPD) is a 4(th) major cause of morbidity and mortality worldwide. Cigarette smoking and oxidative/nitrosative stress leading to chronic inflammation is considered as a major cause of COPD but up to now, details of molecular pathways responsible for development of disease are unknown. Recent reports indicate the role of disruption in histone function in promoting synthesis of inflammatory cytokines through increased gene transcription which underlies disease development. Core histone acetylation/deacetylation regulate their transcription activity and drug induced changes of its intensity may be an interesting field of further research. In this article the opinions about the role of steroids as inhibitors of the inflammatory process as well as resistance to steroids have been presented. Findings from studies which aimed to explore the anti-inflammatory activity of drugs such as theophylline and N-acetylcysteine and their ability to suppress oxid...
Journal of physiology and pharmacology: an official journal of the Polish Physiological Society
Chronic obstructive pulmonary disease (COPD) is one of the most frequent diseases worldwide. Ciga... more Chronic obstructive pulmonary disease (COPD) is one of the most frequent diseases worldwide. Cigarette smoke is considered the main pathological cause of the disorder, although evidence is growing concerning other etiological factors, such as environmental pollution, biomass combustion, infections, genetic predisposition, which may explain why some individuals develop COPD with no history of smoking. Chronic inflammation and remodeling of the small airways characterize the disease at the cellular level, and oxidative stress is considered the main driving force that stands behind COPD inflammation. Recently, chromatin remodeling and epigenetic changes have been found to underlie disease pathology and progression. In this review, the authors gave a short update on the recent hypothesis and findings that may imply novel approach to pharmacotherapy of the disease, focusing on the role of glucocorticosteroids, theophylline, and antioxidants.
Journal of physiology and pharmacology: an official journal of the Polish Physiological Society
There is increasing evidence that histone acetylation, controlled by histone acetyltransferases (... more There is increasing evidence that histone acetylation, controlled by histone acetyltransferases (HAT), reversed by histone deacetylases (HDAC) plays a critical role in the process of regulation of inflammatory genes and in mediating the anti-inflammatory effects of corticosteroids in asthma patients. There is evidence of an increase in HAT activity in asthmatics, which leads to increased expression of multiple inflammatory genes that are regulated by proinflamatory factors, such as nuclear factor NF-kappaB. Reduction in HDAC activity, secondary to oxidative and nitrative stress and severe inflammation, may account for the amplified inflammation in chronic obstructive pulmonary disease (COPD). Corticosteroids switch off inflammatory genes through the inhibition of HAT activity and by recruitment of HDAC2 to the activated transcription complex. Several new strategies to control inflammations in COPD, aiming at restoration of the HDAC-2 activity and/or mitigation of HAT-related signali...
Advances in Experimental Medicine and Biology, 2015
Cigarette smoke (CS) is considered as a major etiological factor in the pathogenesis of chronic o... more Cigarette smoke (CS) is considered as a major etiological factor in the pathogenesis of chronic obstructive pulmonary disease. In this study we used A549 cells and THP-1 cells grown for 24 h in monoculture or in co-culture in CS-conditioned media and changes in their proliferation, viability, acetylated histone H3 levels and expression of extracellular antigens CD14, HLA-DR, CD11a, and CD11b were assessed. CS was highly toxic to A549 cells but not to THP1 cells. In A549 cells, oxidative stress reached the highest values after 1 h of CS exposure and then decreased. In THP1 cells oxidative stress was lower and increased progressively with time. CS decreased proliferation of A549 and THP1 cells by about 80 % and 21 %, respectively. CS did not alter acetylated histone H3 levels in A549 cells, while in THP1 cells the levels were reduced by about 35 %. CS significantly increased expression of CD14, HLA-DR, CD11a, and CD11b in THP1 cells. In co-culture, naïve or CS-pretreated THP1 cells significantly protected A549 cells against CS toxicity but had higher death rates. These results show that epithelial cells are more fragile to CS than monocytes and that CS-activated monocytes may protect epithelial cells against CS-induced cytotoxicity.
Despite the development of neuroscience and spectacular discoveries, the clear functions and the ... more Despite the development of neuroscience and spectacular discoveries, the clear functions and the role of histamine are still not fully understood, especially in the context of the negative impact of prolonged stress exposure on the cognition. The purpose of this study was to evaluate the participation of hypercortisolemia in the detrimental effect of stress on cognitive function and their preclusion by affecting the histaminergic system with ciproxifan. Specifically, we attempted to characterize the preventive action of a single dose of ciproxifan (3mg/kg, i.p.) against an impairment caused by chronic restraint stress as well as parallel exogenous corticosterone (equivalent to that seen in chronically stressed rats), and show differences in the interaction on reference and working memories tested in both aversive (Morris water maze - MWM) and appetitive (Barnes maze-BM) incentives. We found that administration of ciproxifan potently prevented equally deleterious effects of chronic r...
Advances in experimental medicine and biology, 2013
Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation a... more Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation and chronic inflammation of airways and lung parenchyma. Our aim was to assess two important elements of intracellular signaling involved in regulation of inflammation in COPD in patients subjected to long-acting beta2-agonist or long-acting beta2-agonist plus long-acting antimuscarinic: peroxisome proliferator-activated receptor gamma (PPARγ) protein, which has antiinflammatory and immunomodulatory properties and cAMP response element binding protein (CREB) and activated (CREB-P) protein which has histone acetyltransferase activity and increases histone acetylation and transcriptional activation of chromatin. Twenty one stable COPD patients (18 males and 3 females, mean age 65 years) receiving 12 μg B.I.D formoterol were assayed before and after 3 month add-on therapy, consisting of 18 μg Q.D. tiotropium. In all patients, sputum induction, spirometry, lung volumes, and DLCO were performe...
Immunophilin FKBP51 assists polypeptide folding, participates in glucocorticoid actions and may p... more Immunophilin FKBP51 assists polypeptide folding, participates in glucocorticoid actions and may play a role in glucocorticoid resistance. FKBP51 is altered in patients with asthma, but its role in chronic obstructive pulmonary disease (COPD) characterized by dysregulation of several pro/antiinflammatory genes is less clear. We assessed changes in nuclear/cytosolic FKBP51 protein using SDS-PAGE/WB and FKBP51 mRNA by qRT-PCR in cells isolated from induced sputum of stable COPD patients treated with formoterol/budesonide or formoterol/budesonide/theo?phylline for 4 wk. Expression of FKBP51 was higher in formoterol/ budesonide/theophylline-treated patients, compared with formoterol/budesonide group in both cytosolic and nuclear fractions by about 57% and 31%, respectively (P<0.001, P<0.01). FKBP51 mRNA was only slightly, but not significantly, higher in patients on formoterol/ budesonide/theophylline. Increased FKBP51 in COPD patients treated with formoterol/ budesonide/theophylli...
Angiotensins, especially angiotensin IV (Ang IV), have recently been found to be potent cognitive... more Angiotensins, especially angiotensin IV (Ang IV), have recently been found to be potent cognitive enhancers in rodents. However, the precise mechanisms of their memory improving effects remain unknown. In this study we tested the hypothesis that D 2 dopamine receptors at least partially mediate cognitive effects of Ang IV and its derivative des-Phe 6 Ang IV. Namely, the well known cognitive effects of both peptides [facilitation of a conditioned avoidance responses (CARs) acquisition, increase of a passive avoidance behavior (PAB) retrieval, and improvement of object recognition] were evaluated in rats either pretreated or not with a selective D 2 dopamine receptor antagonist remoxipride {(S)-(−)-3-Bromo-N-[(1-ethyl-2-pyrrolidinylOmethyl]2,6-dimethoxybenzamide hydrochloride}. To control for the unspecific motor and emotional effects of our treatments that could confound results of the memory tests we used respectively, 'open' field and elevated 'plus' maze tests. Ang IV as well as des-Phe 6 Ang IV remarkably improved learning of CARs, recall of PAB and recognition of the previously seen objects. D 2 receptors blockade by remoxipride abolished all these effects of both peptides. In the elevated 'plus' maze remoxipride abolished anxiogenic effects of both Ang IV and des-Phe 6 Ang IV. Also, the drug followed by Ang IV decreased number of crossings and by des-Phe 6 Ang IV number of crossings and rearings. The results point to importance of the functional D 2 dopamine receptors in cognitive effects of Ang IV and its naturally occurring product devoid of C-terminal Phe 6 .
An important role for angiotensin IV (Ang IV) in the processes of learning and memory has now bee... more An important role for angiotensin IV (Ang IV) in the processes of learning and memory has now been well established. We have previously found that intracerebroventricular (ICV) administration of Ang IV as well as des-Phe 6 -Ang IV enhances learning of conditioned avoidance responses (CARs), facilitates recall of a passive avoidance (PA) task, and improves object recognition (OR) in rats. Since the dopaminergic system is crucial for the cognitive processes, in this study our aim was to determine the dopaminergic D 1 mediation of these effects using SCH 23390 as a selective D 1 receptor antagonist. Male Wistar rats (180-200 g), pretreated with SCH 23390 (R-[+]-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) 0.05 mg/kg intraperitoneally (IP), were given Ang IV or des-Phe 6 -Ang IV (1 nmol ICV) 1 h later and then tested in the above cognitive paradigms, as well as in the open field and an elevated 'plus' maze to control for the unspecific, respectively, motor and emotional, effects of our treatments. Both, Ang IV and des-Phe 6 -Ang IV effectively enhanced learning of CARs (P < 0.05), recall of PA (P < 0.001), and improved OR (P < 0.001). Pretreatment with SCH 23390 abolished the cognitive effects of both peptides. SCH 23390, Ang IV, and des-Phe 6 -Ang IV, given at the same doses and routes as in the cognitive tests, did not significantly influence crossings, rearings and bar approaches in the open field, nor the parameters measured in the elevated 'plus' maze, thus making a major contribution of the unspecific effects of our treatments to the results of the memory tests improbable. In conclusion, these results indicate that the functional dopaminergic D 1 receptors are necessary for the Ang IV and des-Phe 6 -Ang IV cognitive effects to occur.
Journal of the Renin-Angiotensin-Aldosterone System, 2014
Introduction: Despite recognition of stress as a causation of severe neuropsychological dysfuncti... more Introduction: Despite recognition of stress as a causation of severe neuropsychological dysfunctions, no casual and clinically effective anti-stress therapeutic strategy has yet been found. We have previously shown that blockade of initial stress response by angiotensin receptor blockers alleviates the negative effect of prolonged stress on cognitive non-spatial functions of rats. Here we aimed to find whether telmisartan reduces stress-related memory decline in spatial hippocampaldependent learning tasks conditioned upon differences in level of stress induced by aversive nature of memory tests. Methods: Male Wistar rats were exposed to chronic restraint stress for three weeks and daily treated with either vehicle or telmisartan (1 mg/kg). Afterwards rats were tested in three spatial learning and memory paradigms: Morris water maze (MWM), radial arm maze (RAM), and Barnes maze (BM). Results: Stressed animals demonstrated significantly impaired performance in all the tests, which was normalized in the animals stressed and treated with telmisartan. Interestingly, despite the fact that MWM and RAM are more stressful, which affects animal behavior, therefore considered less sensitive than BM, more significant effect of telmisartan was found in MWM and RAM than BM. Conclusions: AT1 angiotensin receptor blockade attenuates negative effect of both acute and chronic stress on spatial memory.
We have recently found that postsynaptic D3 dopamine (DA) receptors appear not to participate in ... more We have recently found that postsynaptic D3 dopamine (DA) receptors appear not to participate in the memory enhancing effects of the angiotensin AT4 receptor agonists angiotensin IV (Ang IV) and des-Phe(6)-Ang IV. In this study we evaluated role of the presynaptic DA D3 receptors in these effects. For that purpose effect of (+)-UH 232, a selective D3 DA receptors partial agonist preferring presynaptic sites, on the pro-cognitive action of intracerebroventricularly (icv) injected Ang IV and des-Phe(6)-Ang IV was examined. Male Wistar rats weighing 180-200 g were used. Both peptides given at the dose of 1 nmol facilitated recall of a passive avoidance (PA) behaviour, improved object recognition (OR), and increased apomorphine-induced stereotype behaviour. In the auxiliary tests performed to control for the unspecific influence of motor (open field, OF) and emotional (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;plus&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; maze, PM) effects of our treatments on the results of the memory tests they had either no (OF) or negligible (PM) effects. Intraperitoneal pre-treatment of the animals with an ineffective on its own dose (1 mg/kg) of (+)-UH 232 abolished or markedly diminished effects of both peptides on PA and OR but did not influence enhancement of stereotypy caused by the peptides.
This study explores behavioral effects of angiotensin II (Ang II) and a potent AT(1) receptor inh... more This study explores behavioral effects of angiotensin II (Ang II) and a potent AT(1) receptor inhibitor valsartan ((S)-N-valeryl-N-{[2&amp;amp;#39;-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl}-valine). Male Wistar rats (160-180 g) were administered valsartan (10 mg/kg) orally followed, 2 hr later, by Ang II (1 nmol) given intracerebroventricularly (i.c.v., right lateral ventricle). Then 15 min later rats underwent behavioral testing: acquisition of conditioned avoidance responses (CARs), recall of a passive avoidance behavior, open field, elevated &amp;amp;quot;plus&amp;amp;quot; maze, and &amp;amp;quot;chimney&amp;amp;quot; test. Object recognition was tested 60 min after the i.c.v. injections. In addition, effect of valsartan on Ang II stimulated drinking of water was tested. We found that valsartan did not modify the Ang II facilitation of CARs acquisition but abolished the Ang II improvement of memory retrieval and consolidation. The lack of effect of our treatments on the rats&amp;amp;#39; motor activity in the open field makes unspecific contribution of the drug-induced performance changes to the cognitive tests improbable. The anxiogenic action of Ang II, decreased by valsartan, makes an unspecific influence of anxiety possible. The prevention of Ang II increase of drinking by orally given valsartan confirmed effective blockade of the brain AT(1) receptors by the drug. valsartan appears to affect cognitive effects of i.c.v. Ang II in rats in a similar way to losartan; anxiolytic activity of valsartan appears to be slightly weaker than that of losartan.
In this study we attempted to determine behavioural, including cognitive, consequences of the bra... more In this study we attempted to determine behavioural, including cognitive, consequences of the brain AT 1 (losartan, 2 nmol), AT 2 (PD 123319, 1.5 nmol), and joint AT 1 /AT 2 angiotensin receptors blockade. Male Wistar rats (160-180 g) were injected into the left cerebral ventricle with the above doses of the blockers dissolved in 0.9% NaCl solution (vehicle) or with the vehicle alone. Five minutes later they received, to the right cerebral ventricle, 1 nmol of angiotensin II (Ang II) dissolved in vehicle or the vehicle alone. Ang II consistently increased rate of acquisition of conditioned avoidance respones (CARs) and facilitated recall of the passive avoidance behaviour. In one out of the three series of experiments in open field Ang II stimulated rats locomotor activity. Losartan and PD 123319, both ineffective alone, given prior to Ang II abolished all the behavioural changes produced by the peptide except for the Ang II facilitation of CARs acquisition, which was unchanged by losartan. Interestingly, joint injection of losartan and PD 123319 significantly decreased the rate of CARs acquisition both in control and Ang II treated animals. In conclusion, the present data suggest significant though different involvement of both AT 1 and AT 2 angiotensin receptors in cognitive processes.
This study was aimed at the estimation of influence of enalapril and captopril on emotional proce... more This study was aimed at the estimation of influence of enalapril and captopril on emotional processes in hypertensive patients. Hypertensive subjects evaluated before introducing drug treatment and normotensive persons comprised the control groups. All groups were examined with the psychological methods (BDI, HSC, Raven&amp;amp;amp;amp;#39;s Matric test). In BDI, there were no significant differences between the groups in the total score and particular factors as well. In HSC, there were significant differences in the total ratings between untreated hypertensive subjects and the normotensive group (p &amp;amp;amp;amp;lt; 0.05). The depression/anxiety profile was the main contributing factor being itself significantly different (p &amp;amp;amp;amp;lt; 0.05) in those groups. Enalapril and captopril reversed the negative behavioural changes caused by hypertension only moderately with no statistical significance. There were no alterations in intellectual abilities tested by the Raven&amp;amp;amp;amp;#39;s Matric test in any group examined. In conclusion, significant negative emotional effects of high blood pressure are only partly reversed by the antihypertensive doses of enalapril and captopril.
Streszczenie: Behawioralne, anatomiczne i molekularne badania ostatnich lat przynios³y znaczny po... more Streszczenie: Behawioralne, anatomiczne i molekularne badania ostatnich lat przynios³y znaczny postêp w rozumieniu mechanizmów uczenia siê i pamiêci. Opisano regiony mózgu odpowiedzialne za uczenie siê i pamiêae, jak równie¿ szereg czynników, które mog¹ modyfikowaae te procesy. Badania behawioralne wykaza³y, ¿e poszczególne peptydy angiotensynowe, zw³aszcza angiotensyna II i angiotensyna IV, uczestnicz¹ w procesach uczenia siê i pamiêci, ale mechanizmy odpowiedzialne za te procesy s¹ niejasne. Badania in vitro wykaza³y, ¿e wa¿nym ogniwem sygnalizacji za porednictwem receptora AT1 jest wzrost aktywnoci kinaz MAP, prowadz¹cy do aktywacji czynników transkrypcyjnych i syntezy poszczególnych bia³ek. Prokognitywne dzia³anie angiotensyny IV odnotowane w badaniach behawioralnych zosta³o potwierdzone przez jej zwi¹zek z niektórymi neurotransmiterami i neuropeptydami uczest-nicz¹cymi w procesach pamiêci i metabolizmie glukozy. Praca opisuje udzia³ receptorów angiotensynowych w procesach poznawczych.
Journal of physiology and pharmacology: an official journal of the Polish Physiological Society
cAMP responsive element binding protein (CREB) plays an important role in transcriptional machine... more cAMP responsive element binding protein (CREB) plays an important role in transcriptional machinery. CREB signaling is altered in patients with asthma. However, the role of CREB in chronic obstructive pulmonary disease (COPD) is less clear. In the present study we assessed changes in subcellular CREB distribution and activation (CREB-P) in 35 stable COPD patients treated with formoterol (F), formoterol+budesonide (F/ICS), and formoterol+budesonide+theophylline (F/ICS/Th) b.i.d. for 4 weeks, using SDS-PAGE/WB in cytosol and nuclear extracts of induced sputum cells. The expression of CREB was increased after F/ICS in both cytosolic and nuclear fractions by about 40% and 24%, respectively (P&lt;0.001, P&lt;0.01), while CREB-P increased after F/ICS by about 50% (P&lt;0.01) in both compartments. These changes were not affected by theophylline. In F/ICS-treated patients, relative accumulation of CREB in cytosol was observed. These findings indicate, that poor response to ICS therapy may be related to increased CREB-associated signaling.
Journal of physiology and pharmacology: an official journal of the Polish Physiological Society
We assessed the effect of therapy on nuclear signaling related to inflammatory processes in sputu... more We assessed the effect of therapy on nuclear signaling related to inflammatory processes in sputum cells of patients with chronic obstructive pulmonary disease (COPD). Patients were treated with formoterol (F) or formoterol plus budesonide (F/ICS) b.i.d. for 4 weeks, their sputum cells were isolated and subjected to RNA extraction or lysis, followed by differential centrifugation. Signaling protein levels were assessed by Western blots, their specific mRNAs were quantified using qRTPCR, while 8-isoprostane levels were examined using enzyme immunoassay kit. Cytosolic 8-isoprostane levels and nuclear glucocorticoid receptor expression (protein and mRNA) were not significantly different in both groups, while nuclear cAMP response element binding protein (CREB; protein and mRNA) and peroxisome proliferator-activated receptor gamma (PPARgamma protein and mRNA) were significantly higher in cells from F/ICS-treated patients. CREB-binding protein (CBP; protein and mRNA) levels were signific...
Pneumonologia i alergologia polska: organ Polskiego Towarzystwa Ftyzjopneumonologicznego, Polskiego Towarzystwa Alergologicznego, i Instytutu Gruzlicy i Chorob Pluc
Chronic obstructive pulmonary disease (COPD) is a 4(th) major cause of morbidity and mortality wo... more Chronic obstructive pulmonary disease (COPD) is a 4(th) major cause of morbidity and mortality worldwide. Cigarette smoking and oxidative/nitrosative stress leading to chronic inflammation is considered as a major cause of COPD but up to now, details of molecular pathways responsible for development of disease are unknown. Recent reports indicate the role of disruption in histone function in promoting synthesis of inflammatory cytokines through increased gene transcription which underlies disease development. Core histone acetylation/deacetylation regulate their transcription activity and drug induced changes of its intensity may be an interesting field of further research. In this article the opinions about the role of steroids as inhibitors of the inflammatory process as well as resistance to steroids have been presented. Findings from studies which aimed to explore the anti-inflammatory activity of drugs such as theophylline and N-acetylcysteine and their ability to suppress oxid...
Journal of physiology and pharmacology: an official journal of the Polish Physiological Society
Chronic obstructive pulmonary disease (COPD) is one of the most frequent diseases worldwide. Ciga... more Chronic obstructive pulmonary disease (COPD) is one of the most frequent diseases worldwide. Cigarette smoke is considered the main pathological cause of the disorder, although evidence is growing concerning other etiological factors, such as environmental pollution, biomass combustion, infections, genetic predisposition, which may explain why some individuals develop COPD with no history of smoking. Chronic inflammation and remodeling of the small airways characterize the disease at the cellular level, and oxidative stress is considered the main driving force that stands behind COPD inflammation. Recently, chromatin remodeling and epigenetic changes have been found to underlie disease pathology and progression. In this review, the authors gave a short update on the recent hypothesis and findings that may imply novel approach to pharmacotherapy of the disease, focusing on the role of glucocorticosteroids, theophylline, and antioxidants.
Journal of physiology and pharmacology: an official journal of the Polish Physiological Society
There is increasing evidence that histone acetylation, controlled by histone acetyltransferases (... more There is increasing evidence that histone acetylation, controlled by histone acetyltransferases (HAT), reversed by histone deacetylases (HDAC) plays a critical role in the process of regulation of inflammatory genes and in mediating the anti-inflammatory effects of corticosteroids in asthma patients. There is evidence of an increase in HAT activity in asthmatics, which leads to increased expression of multiple inflammatory genes that are regulated by proinflamatory factors, such as nuclear factor NF-kappaB. Reduction in HDAC activity, secondary to oxidative and nitrative stress and severe inflammation, may account for the amplified inflammation in chronic obstructive pulmonary disease (COPD). Corticosteroids switch off inflammatory genes through the inhibition of HAT activity and by recruitment of HDAC2 to the activated transcription complex. Several new strategies to control inflammations in COPD, aiming at restoration of the HDAC-2 activity and/or mitigation of HAT-related signali...
Advances in Experimental Medicine and Biology, 2015
Cigarette smoke (CS) is considered as a major etiological factor in the pathogenesis of chronic o... more Cigarette smoke (CS) is considered as a major etiological factor in the pathogenesis of chronic obstructive pulmonary disease. In this study we used A549 cells and THP-1 cells grown for 24 h in monoculture or in co-culture in CS-conditioned media and changes in their proliferation, viability, acetylated histone H3 levels and expression of extracellular antigens CD14, HLA-DR, CD11a, and CD11b were assessed. CS was highly toxic to A549 cells but not to THP1 cells. In A549 cells, oxidative stress reached the highest values after 1 h of CS exposure and then decreased. In THP1 cells oxidative stress was lower and increased progressively with time. CS decreased proliferation of A549 and THP1 cells by about 80 % and 21 %, respectively. CS did not alter acetylated histone H3 levels in A549 cells, while in THP1 cells the levels were reduced by about 35 %. CS significantly increased expression of CD14, HLA-DR, CD11a, and CD11b in THP1 cells. In co-culture, naïve or CS-pretreated THP1 cells significantly protected A549 cells against CS toxicity but had higher death rates. These results show that epithelial cells are more fragile to CS than monocytes and that CS-activated monocytes may protect epithelial cells against CS-induced cytotoxicity.
Despite the development of neuroscience and spectacular discoveries, the clear functions and the ... more Despite the development of neuroscience and spectacular discoveries, the clear functions and the role of histamine are still not fully understood, especially in the context of the negative impact of prolonged stress exposure on the cognition. The purpose of this study was to evaluate the participation of hypercortisolemia in the detrimental effect of stress on cognitive function and their preclusion by affecting the histaminergic system with ciproxifan. Specifically, we attempted to characterize the preventive action of a single dose of ciproxifan (3mg/kg, i.p.) against an impairment caused by chronic restraint stress as well as parallel exogenous corticosterone (equivalent to that seen in chronically stressed rats), and show differences in the interaction on reference and working memories tested in both aversive (Morris water maze - MWM) and appetitive (Barnes maze-BM) incentives. We found that administration of ciproxifan potently prevented equally deleterious effects of chronic r...
Advances in experimental medicine and biology, 2013
Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation a... more Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation and chronic inflammation of airways and lung parenchyma. Our aim was to assess two important elements of intracellular signaling involved in regulation of inflammation in COPD in patients subjected to long-acting beta2-agonist or long-acting beta2-agonist plus long-acting antimuscarinic: peroxisome proliferator-activated receptor gamma (PPARγ) protein, which has antiinflammatory and immunomodulatory properties and cAMP response element binding protein (CREB) and activated (CREB-P) protein which has histone acetyltransferase activity and increases histone acetylation and transcriptional activation of chromatin. Twenty one stable COPD patients (18 males and 3 females, mean age 65 years) receiving 12 μg B.I.D formoterol were assayed before and after 3 month add-on therapy, consisting of 18 μg Q.D. tiotropium. In all patients, sputum induction, spirometry, lung volumes, and DLCO were performe...
Immunophilin FKBP51 assists polypeptide folding, participates in glucocorticoid actions and may p... more Immunophilin FKBP51 assists polypeptide folding, participates in glucocorticoid actions and may play a role in glucocorticoid resistance. FKBP51 is altered in patients with asthma, but its role in chronic obstructive pulmonary disease (COPD) characterized by dysregulation of several pro/antiinflammatory genes is less clear. We assessed changes in nuclear/cytosolic FKBP51 protein using SDS-PAGE/WB and FKBP51 mRNA by qRT-PCR in cells isolated from induced sputum of stable COPD patients treated with formoterol/budesonide or formoterol/budesonide/theo?phylline for 4 wk. Expression of FKBP51 was higher in formoterol/ budesonide/theophylline-treated patients, compared with formoterol/budesonide group in both cytosolic and nuclear fractions by about 57% and 31%, respectively (P<0.001, P<0.01). FKBP51 mRNA was only slightly, but not significantly, higher in patients on formoterol/ budesonide/theophylline. Increased FKBP51 in COPD patients treated with formoterol/ budesonide/theophylli...
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