The question of the reasons for the extreme variation in morbidity among the gene carriers of acute porphyria and the great diversity of the precipitating factors are approached by the aid of a model of interacting genomic circuits. It is based on the current paradigm of the acute porphyric attack as a result of a toxic proximal overload of the enzyme-
deficient heme-biosynthetic patway. Porphyrogenic influx of precursors is seen as a consequence of uncontrolled induction of its gate-keeping enzyme, ubiquitous 5-aminolevulinate synthase (ALAS1), due to attenuated post-translational control of the enzyme combined with activated gene transcription. Focus is directed on the genomic
control of the master-regulator of ALAS1-transcription, the nuclear receptor pair constitutively active receptor (CAR) and pregnane xenobiotic receptor (PXR). On activation by their ligands, i.e. lipophilic drugs, solvents, alcohols, hormonal steroids and biocides, these DNA-binding proteins transform xenobiotic or steroid stimuli to coordinated
activations of gene transcription-programs for ALAS1 and apo-cytochromes P450 (apo-CYPs), thus effecting the formation of xenobiotic-metabolizing cytochrome P450 enzymes. The potency of the CAR/PXR-transduction axis is enhanced by co-activators generated in
at least four other genomic circuits, each triggered by different external and internal stimuli clinically experienced to be porphyroge
nic, and each controlled by co-activating and co-repressing modulators. The expressions of the genes for CAR and PXR are thus augmented by binding glucocorticoid receptor (GR) activated by a steroid hormone, e.g, cortisol generated in fasting, infection or different forms of stress. The promotor regions of ALAS1 and apoCYPs contain binding sites for at least three co-activating transcription factors enhancing CAR/PXR transduction: i.e. the ligand-independent growth hormone (GH)-pulse controlled hepatocyte nuclear factor 4 (HNF4), the insulin-responsive forkhead box class O-(FOXO) protein pathway activated in stress and infection, and the proliferator-activated receptor gamma co-activator 1 al
pha (PGC-1alpha) circuit responding to glucagon liberated in fasting. Many interactions and cross-talk take place within the tangle of genomic circuits that control ALAS1-transcription, which may explain the extreme inter- and intra-individual variability in morbidity in acute porphyria. Reasons for gender-differences are found in sex-dependent control of HPA- and GH-activity as well as in direct, or GR-mediated effects on CAR/PCR activation. Constitutional differences in individual porphyric morbidity may be discussed along lines of mutations or duplications of genes for co-activating or co-repressing nuclear proteins active at different levels within the circuits.
The study deals with activity of three antioxidant enzymes, copper, zinc-superoxide dismutase (CuZnSOD), manganese superoxide dismutase (MnSOD), catalase (CAT) in hippocampus of rats, following the exposure to single chronic (individual housing or forced swimming) and acute (immobilization or cold) stress, as well as to combined chronic/acute stress. In addition, plasma noradrenaline (NA) and adrenaline (A) concentrations were measured in the same stress conditions, because their autooxidation can add to the oxidative stress. We observed that i) long-term social isolation and repeated forced swimming had minor effects on plasma catecholamines, but in the long-term pretreated groups, acute stressors caused profound elevation NA and A levels, ii) chronic stressors activate antioxidant enzymes, iii) acute stressors decrease catalase activity, their effects on CuZnSOD appear to be stressor-dependent, whereas MnSOD is not affected by acute stressors, and iv) pre-exposure to chronic stress affects the antioxidant-related effects of acute stressors, but this effect depends to a large extent on the type of the chronic stressor. Based on both metabolic and neuroendocrine data, long-term isolation appears to be a robust psychological stressor and to induce a “priming” effect specifically on the CuZnSOD and CAT activity.
Chaotic transitions likely emerge in a wide variety of cognitive phenomena and may be linked to specific changes during the development of mental disorders. They represent relatively short periods in the behavior of a system, which are extremely sensitive to very small changes. This increased sensitivity has been suggested to occur also during retrieval of stressful emotional experiences because of their fragmentary, temporally and spatially disorganized character. To test this hypothesis we recorded EEG during retrieval of fearful memories related to panic attack in 7 patients and retrieval of anxiety-related memories in 11 healthy controls. Nonlinear data analysis of EEG records showed a statistically significant increase in degree of chaotic dynamics after retrieval of stressful memories in majority of patients as well as in control subjects. This change correlated with subjective intensity of anxiety induced during the memory retrieval. The data suggest a role of nonlinear changes of neural dynamics in the processing of stressful
anxiety-related memories, which may play an important role in the pathophysiology of panic disorder.
According to recent findings activation of anterior cingulate co
rtex (ACC) is related to detecting cognitive conflict. This
conflict related activation elicits autonomic responses which can be assessed by psychophysiological measures such as
heart rate variability calculated as beat to beat R-R interv
als (RRI). Recent findings in neuroscience also suggest that
cognitive conflict is related to specific nonlinear chaotic changes of the signal generated by neural systems. The present
study used Stroop word-color test as an experimental approach to psychophysiological study of cognitive conflict in
connection with RRI measurement, psychometric measurement of limbic irritability (LSCL-33), depression (BDI-II)
and calculation of largest Lyapunov exponents in nonlinear data analysis of RRI time series. Significant correlation 0.61
between largest Lyapunov exponents and LSCL-33 found in this study indicate that a defect of neural inhibition during
conflicting Stroop task is closely related to
limbic irritability. Because limbic irritability is probably closely related to
epileptiform abnormalities in the temporolimbic structures, this result might represent useful instrument for indication
of anticonvulsant treatment in depressive patients who are resistant to antidepressant medication.
Glucocorticoids (GCs) are steroid hormones produced by the adrenal cortex in reaction to stress stimuli. GCs production is not stable over a 24-hour period; the plasma concentration peaks in the morning (approximately upon awakening) and then the plasma levels decrease, reaching the nadir in the evening. In our experiments, the levels of cortisol, cortisone, DHEA and DHEAS were tested in young female pigs (n=23) during heart catheterization at two different day times (in the morning and in the afternoon). The non-parametric Mann-Whitney test for statistical analysis was used. We found only minimal statistical differences in studied markers between the morning and afternoon group (p>0.05). The absence of circadian variation in GCs levels could originate either at an early age of our experimental pigs, or in stressful conditions on the experiment day, or most likely the day before (e.g. social isolation, fasting, transport, and catheterization), respectively. We can conclude there is no difference in the stress load between morning and afternoon experiments, and therefore we can assume the stress load is not a limiting factor for the timing when catheterization should be preferably performed., H. Skarlandtová ... [et al.]., and Obsahuje seznam literatury
Activation of the hypothalamic-pituitary-adrenal (HPA) axis is important for maintenance of homeostasis during stress. Recent studies have shown a connection between the HPA axis and adipose tissue. The present study investigated the effect of acute heterotypic stress on plasma levels of adrenocorticotropic hormone (ACTH), corticosterone (CORT), leptin, and ghrelin in adult male rats with respect to neonatal maternal social and physical stressors. Thirty rat mothers and sixty of their male progeny were used. Pups were divided into three groups:
unstressed control (C), stressed by maternal social stressor (S),
stressed by maternal social and physical stressors (SW). Levels of
hormones were measured in adult male progeny following an
acute swimming stress (10min) or no stress. ELISA immunoassay was used to measured hormones. The ACTH and CORT levels were significantly increased in all groups of adult progeny after acute stress; however, CORT levels were significantly lower in both neonatally stressed groups compared to controls. After acute stress, plasma leptin levels were decreased in the C and SW groups but increased in the S group. The data suggest that long-term neonatal stressors lead to lower sensitivity of ACTH receptors in the adrenal cortex, which could be a sign of stress adaptation in adulthood. Acute stress in adult
male rats changes plasma levels of leptin differently relative to social or physical neonatal stressors.
To achieve a better understanding of learning and declarative memory under mild transient stress, we investigated the effect of brief hypobaric hypoxia on spatial orientation in rats. Young male Wistar rats aged 30 days were exposed for 60 min to hypobaric hypoxia, simulating an altitude of 7000 m (23 000 ft) either shortly prior to attempting or after mastering an allothetic navigation task in the Morris water maze with a submerged platform. The post-hypoxic group performed significantly better in the navigation task than the control animals (the mean difference in escape latencies was 11 seconds; P= 0.0033, two-way ANOVA with repeated measures, group × session). The experimental group also achieved a remarkably higher search efficiency (calculated as a percentage of su
ccessful trials per session), especially during the first four days following hypoxic stress (P= 0.0018). During the subsequent training, the post-hypoxic group performed better than the control animals, whilst the efficiency levels of both groups progressively converged. Spatial memory retention and recall of well-trained rats were not affected by the transient hyp
obaric hypoxia. These results indicate that brief hypobaric hypoxia enhances rats’ spatial orientation. Our findings are consistent with several studies, which also suggested that mild transient stress improves learning.