Hypoxia is one of the major pathological factors affecting brain function. The aim of the present study was to describe the effect of neonatal hypobaric hypoxia on the behavior of rats and to analyze its effect on hippocampal neurodegeneration. Hypobaric hypoxia at a simulated altitude of 9000 m was induced for one hour in neonatal rat pups (PND7 and PND9) of both sexes. Subsequently, the rats underwent behavioral testing on PND25 and PND35 using a LABORAS apparatus to assess spontaneous behavior. Hypoxia did not cause any morphological damage in the hippocampus of rats. However, hypoxia on PND7 led to less horizontal locomotor activity both in males (on PND25) and females (on PND35). Hypoxia on PND9 led to higher rearing in females on PND25. Hypoxic males exhibited higher grooming activity, while females lower grooming activity on PND35 following hypoxia induced on PND7. In females, hypoxia on PND9 resulted in higher grooming activity on PND25. Sex differences in the effect of hypoxia were observed on PND35, when hypoxic males compared to hypoxic females displayed more locomotor, rearing and grooming activity. Our data suggest that hypoxia on PND7 versus PND9 differently affects locomotion and grooming later in adolescence and these effects are sex-dependent.
The study examined the morphological and long-term behavioral impacts of neonatal hypoxic-ischemic brain injury in a mouse model. We investigated the modification of different behavioral domains, such as spontaneous climbing, which represents fine motor skills. We also focused on sex-dependent differences during hypoxic-ischemic encephalopathy. The Rice-Vannucci model of hypoxia-ischemia was used, adjusted and adapted to 7-day-old C57BL/6NTac mice. The effects of induced hypoxia and ischemia were also studied separately. At postnatal day 60, mice underwent behavioral testing using the LABORAS apparatus. The perfusion for histological evaluation was performed one day after the behavioral analyses. In groups with separately induced hypoxia or ischemia, the observed alterations in behavior were not accompanied by morphological changes in the cortex or hippocampal formation. Female mice naturally climbed significantly more and hypoxic females reared less than hypoxic males (p<0.05). Male mice postnatally exposed to hypoxiaischemia exhibited significantly lower vertical activity and higher horizontal activity (p<0.05). Mild hypoxic damage may not be morphologically detectable but may induce substantial behavioral changes in adult mice. There were significant differences between horizontal and vertical activity in reaction to hypoxiaischemia. Our study indicates that the importance of behavioral testing is irreplaceable and may be reflected in neonatal medicine.
Neonatal hypoxic-ischemic encephalopathy is a disorder with heterogeneous manifestation due to asphyxia during perinatal period. It affects approximately 3-12 children per 1000 live births and cause death of 1 million neonates worldwide per year. Besides, motor disabilities, seizures, impaired muscle tone and epilepsy are few of the consequences of hypoxic-ischemic encephalopathy. Despite an extensive research effort regarding various treatment strategies, therapeutic hypothermia with intensive care unit supportive treatment remains the only approved method for neonates who have suffered from moderate to severe hypoxicischemic encephalopathy. However, these protocols are only partially effective given that many infants still suffer from severe brain damage. Thus, further research to systematically test promising neuroprotective treatments in combination with hypothermia is essential. In this review, we discussed the pathophysiology of hypoxic-ischemic encephalopathy and delved into different promising treatment modalities, such as melatonin and erythropoietin. However, preclinical studies and clinical trials are still needed to further elucidate the mechanisms of action of these modalities.
Extracellular DNA (ecDNA) activates immune cells and is involved in the pathogenesis of diseases associated with inflammation such as sepsis, rheumatoid arthritis or metabolic syndrome. DNA can be cleaved by deoxyribonucleases (DNases), some of which are secreted out of cells. The aim of this experiment was to describe plasma DNase activity in relation to extracellular DNA in adult rats, to analyse potential sex differences and to prove whether they are related to endogenous testosterone. Adult Lewis rats (n=28) of both sexes were included in the experiment. Male rats were gonadectomized or sham-operated and compared to intact female rats. Plasma ecDNA and DNase activity were measured using fluorometry and single radial enzyme diffusion assay, respectively. Concentrations of nuclear ecDNA and mitochondrial ecDNA were determined using real-time PCR. Females had 60% higher plasma DNase activity than males (p=0.03). Gonadectomy did not affect plasma DNase aktivity in males. Neither the concentration of total ecDNA, nor nuclear or mitochondrial DNA in plasma differed between the groups. No significant correlations between DNase aktivity and ecDNA were found. From previous studies on mice, it was expected, that male rats will have higher DNase activity. In contrast, our study in rats showed the opposite sex difference. This sex difference seems not to be caused by endogenous testosterone. Interestingly, no sex differences were observed in plasma ecDNA suggesting a complex or missing association between plasma ecDNA and DNase. The observed sex difference in plasma DNase aktivity should be taken into account in animal models of ecDNAassociated diseases.
The sex steroid hormones (SSHs) such as testosterone, estradiol, progesterone, and their metabolites have important organizational and activational impacts on the brain during critical periods of brain development and in adulthood. A variety of slow and rapid mechanisms mediate both organizational and activational processes via intracellular or membrane receptors for SSHs. Physiological concentrations and distribution of SSHs in the brain result in normal brain development. Nevertheless, dysregulation of hormonal equilibrium may result in several mood disorders, including depressive disorders, later in adolescence or adulthood. Gender differences in cognitive abilities, emotions as well as the 2-3 times higher prevalence of depressive disorders in females, were already described. This implies that SSHs may play a role in the development of depressive disorders. In this review, we discuss preclinical and clinical studies linked to SSHs and development of depressive disorders. Our secondary aim includes a review of up-to-date knowledge about molecular mechanisms in the pathogenesis of depressive disorders. Understanding these molecular mechanisms might lead to significant treatment adjustments for patients with depressive disorders and to an amelioration of clinical outcomes for these patients. Nevertheless, the impact of SSHs on the brain in the context of the development of depressive disorders, progression, and treatment responsiveness is complex in nature, and depends upon several factors in concert such as gender, age, comorbidities, and general health conditions.