Nonpharmacological treatments of stress-induced disorders are promising, since they enhance endogenous stress defense systems, are free of side effects, and have few contraindications. The present study tested the hypothesis that intermittent hypoxia conditioning (IHC) ameliorates behavioral, biochemical, and morphological signs of experimental posttraumatic stress disorder (PTSD) induced in rats with a model of predator stress (10-day exposure to cat urine scent, 15 min daily followed by 14 days of stress-free rest). After the last day of stress exposure, rats were conditioned in an altitude chamber for 14 days at a 1,000-m simulated altitude for 30 min on day 1 with altitude and duration progressively increasing to 4,000 m for 4 h on day 5. PTSD was associated with decreased time spent in open arms and increased time spent in closed arms of the elevated X-maze, increased anxiety index, and increased rate of freezing responses. Functional and structural signs of adrenal cortex degeneration were also observed, including decreased plasma concentration of corticosterone, decreased weight of adrenal glands, reduced thickness of the fasciculate zone, and hydropic degeneration of adrenal gland cells. The thickness of the adrenal fasciculate zone negatively correlated with the anxiety index. IHC alleviated both behavioral signs of PTSD and morphological evidence of adrenal cortex dystrophy. Also, IHC alone exerted an antistress effect, which was evident from the increased time spent in open arms of the elevated X-maze and a lower number of rats displaying freezing responses. Therefore, IHC of rats with experimental PTSD reduced behavioral signs of the condition and damage to the adrenal glands. NEW & NOTEWORTHY Intermittent hypoxia conditioning (IHC) has been shown to be cardio-, vaso-, and neuroprotective. For the first time, in a model of posttraumatic stress disorder (PTSD), this study showed that IHC alleviated both PTSD-induced behavioral disorders and functional and morphological damage to the adrenal glands. Also, IHC alone exerted an antistress effect. These results suggest that IHC may be a promising complementary treatment for PTSD-associated disorders.

Posttraumatic stress disorder (PTSD) causes mental and somatic diseases. Intermittent hypoxic conditioning (IHC) has cardio-, vaso-, and neuroprotective effects and alleviates experimental PTSD. IHC’s ability to alleviate harmful PTSD effects on rat heart, liver, and brain was examined. PTSD was induced by 10-day exposure to cat urine scent (PTSD rats). Some rats were then adapted to 14-day IHC (PTSD+IHC rats), while PTSD and untreated control rats were cage rested. PTSD rats had a higher anxiety index (AI, X-maze test), than control or PTSD+IHC rats. This higher AI was associated with reduced glycogen content and histological signs of metabolic and hypoxic damage and of impaired contractility. The livers of PTSD rats had reduced glycogen content. Liver and blood alanine and aspartate aminotransferase activities of PTSD rats were significantly increased. PTSD rats had increased norepinephrine concentration and decreased monoamine oxidase A activity in cerebral cortex. The PTSD-induced elevation of carbonylated proteins and lipid peroxidation products in these organs reflects oxidative stress, a known cause of organ pathology. IHC alleviated PTSD-induced metabolic and structural injury and reduced oxidative stress. Therefore, IHC is a promising preventive treatment for PTSD-related morphological and functional damage to organs, due, in part, to IHC’s reduction of oxidative stress.

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Traumatic stress causes post-traumatic stress disorder (PTSD). PTSD is associated with cardiovascular diseases and risk of sudden cardiac death in some subjects. We compared effects of predator stress (PS, cat urine scent, 10 days) on mechanisms of cardiac injury and protection in experimental PTSD-vulnerable (PTSD) and -resistant (PTSDr) rats. 14-days post-stress, rats were evaluated with an elevated plus-maze test, and assigned to PTSD and PTSDr groups according to an anxiety index calculated from the test results. Cardiac injury was evaluated by: 1) Exercise tolerance; 2) ECG; 3) Myocardial histomorphology; 4) Oxidative stress; 5) Pro- and anti-inflammatory cytokines. Myocardial heat shock protein 70 (HSP70) was also measured. Experimental PTSD developed in 40% of rats exposed to PS. Exercise tolerance of PTSD rats was 25% less than control rats and 21% less than PTSDr rats. ECG QRS, QT, and OTc intervals were longer in PTSD rats than in control and PTSDr rats. Only cardiomyocytes of PTSD rats had histomorphological signs of metabolic and hypoxic injury and impaired contractility. Oxidative stress markers were higher in PTSD than PTSDr rats. Pro-inflammatory IL-6 was higher in PTSD rats than in control and PTSDr rats, and anti-inflammatory IL-4 was lower in PTSD than in control and PTSDr rats. Myocardial HSP70 was lower in PTSD rats than PTSDr and control rats. Conclusion: Rats with PTSD developed multiple signs of cardiac injury. PTSDr rats were resistant also to cardiac injury. Factors that limit cardiac damage in PS rats include reduced inflammation and oxidative stress and increased protective HSP70.

Background: Rats exposed to chronic predator scent stress mimic the phenotype of complex post-traumatic stress disorder (PTSD) in humans, including altered adrenal morphology and function. High- and low-anxiety phenotypes have been described in rats exposed to predator scent stress (PSS). This study aimed to determine whether these high- and low-anxiety phenotypes correlate with changes in adrenal histomorphology and corticosteroid production. Methods: Rats were exposed to PSS for ten days. Thirty days later, the rats’ anxiety index (AI) was assessed with an elevated plus-maze test. Based on differences in AI, the rats were segregated into low- (AI ≤ 0.8, n = 9) and high- (AI > 0.8, n = 10) anxiety phenotypes. Plasma corticosterone (CORT) concentrations were measured by ELISA. Adrenal CORT, desoxyCORT, and 11-dehydroCORT were measured by high-performance liquid chromatography. After staining with hematoxylin and eosin, adrenal histomorphometric changes were evaluated by measuring the thickness of the functional zones of the adrenal cortex. Results: Decreased plasma CORT concentrations, as well as decreased adrenal CORT, desoxyCORT and 11-dehydroCORT concentrations, were observed in high- but not in low-anxiety phenotypes. These decreases were associated with increases in AI. PSS led to a significant decrease in the thickness of the zona fasciculata and an increase in the thickness of the zona intermedia. The increase in the thickness of the zona intermedia was more pronounced in low-anxiety than in high-anxiety rats. A decrease in the adrenal capsule thickness was observed only in low-anxiety rats. The nucleus diameter of cells in the zona fasciculata of high-anxiety rats was significantly smaller than that of control or low-anxiety rats. Conclusion: Phenotype-associated changes in adrenal function and histomorphology were observed in a rat model of complex post-traumatic stress disorder.

Mast cells (MC) are widely distributed throughout the body of animals and humans, mainly in barrier tissues. This review provides new information on the hematopoietic origin of MCs from early erythromyeloid progenitors (EMPs), late EMPs, and definitive hematopoietic stem cells. As well as information on the maturation of MSs and heparin synthesis already in the embryonic period. Many physiological functions of MCs are determined by the properties of heparin, which forms the basis of the matrix of granules, since the heparin molecule is a strong polyanion, capable to forming complexes with many biologically active substances and regulating their properties. In a new hypothesis about the participation of MCs in pathological processes, it is assumed that this is due to the depletion of the heparin pool. In such cases, injections of exogenous heparin can help replenish MCs heparin stores. As a result of the restoration of the physiological functions of MCs and the action of exogenous heparin, the pathological process will be converted into an adaptive one. In clinical practice, unfractionated heparin (UFH) obtained from natural sources and low molecular weight heparin (LMWH) obtained by the biochemical route are used. Most often, UFH and LMWH are used in the clinic only as anticoagulants. The worldwide spread of a disease named COVID-19 in 2020 showed that UFH and LMWH are multifunctional drugs that have saved many people. The pandemic caused by COVID-19 has been an unprecedented social and health emergency worldwide. Depression, anxiety and post-traumatic stress disorder (PTSD) have been reported in populations of many countries. This review provides new information on experimental studies on the successful treatment of pathology with low doses of UFH in modeling PTSD in animals. Consequently, heparin can be considered as a promising multifunctional drug for effective pharmacological correction of comorbid diseases under the influence of extreme factors.

Posttraumatic stress disorders were induced in Wistar rats by modeling predatory stress. Animals tested in elevated plus-maze demonstrated signs of high anxiety and difficulties in space orientation. Behavioral disorders were paralleled by degenerative changes in hepatocytes. A course of low-dose high-molecular heparin after stress exposure promoted effective adaptation and normalization of behavioral and morphofunctional disorders. Analysis of the results indicated good prospects of heparin as an effective drug under conditions of exposure to extreme factors of psychotraumatic type.

Stress-induced conditions are associated with impaired cerebral blood flow (CBF) and increased risk of dementia and stroke. However, these conditions do not develop in resilient humans and animals. Here the effects of predator stress (PS, cat urine scent, ten days) on CBF and mechanisms of CBF regulation were compared in PS-susceptible (PSs) and PS-resilient (PSr) rats. Fourteen days post-stress, the rats were segregated into PSs and PSr groups based on a behavior-related anxiety index (AI). CBF and its endothelium-dependent changes were measured in the parietal cortex by laser Doppler flowmetry. The major findings are: (1) PS susceptibility was associated with reduced basal CBF and endothelial dysfunction. In PSr rats, the basal CBF was higher, and endothelial dysfunction was attenuated. (2) CBF was inversely correlated with the AI of PS-exposed rats. (3) Endothelial dysfunction was associated with a decrease in eNOS mRNA in PSs rats compared to the PSr and control rats. (4) Brain dopamine was reduced in PSs rats and increased in PSr rats. (5) Plasma corticosterone of PSs was reduced compared to PSr and control rats. (6) A hypercoagulation state was present in PSs rats but not in PSr rats. Thus, potential stress resilience mechanisms that are protective for CBF were identified.