Pyridoindole SMe1EC2 as cognition enhancer in ageing-related cognitive decline.

Synthetic pyridoindole-type substances derived from the lead compound stobadine represent promising agents in treatment of a range of pathologies including neurological disorders. The beneficial biological effects were suggested to be likely associated with their capacity to ameliorate oxidative damage. In our study, the effect of supplementation with the derivative of stobadine, SMe1EC2, on ageing-related cognitive decline in rats was investigated. The 20-months-old male Wistar rats were administered SMe1EC2 at a low dose, 0.5 mg/kg, daily during eight weeks. Morris water maze test was performed to assess the spatial memory performances. The cell-based assays of capacity of SMe1EC2 to modulate proinflammatory generation of oxidants by microglia were also performed. The rats treated with SMe1EC2 showed significantly increased path efficiency, significantly shorter time interval of successful trials and exerted also notably lower frequencies of clockwise rotations in the pool compared to non-supplemented aged animals. Mildly improved parameters included test durations, distances to reach the platform, time in periphery of the pool and overall rotations in the water maze. However, the pyridoindole SMe1EC2 did not show profound inhibitory effect on production of nitric oxide and superoxide by activated microglial cells. In conclusion, our study suggests that pyridoindole SMe1EC2, at low doses administered chronically, can act as cognition enhancing agent in aged rats. The protective mechanism less likely involves direct modulation of proinflammatory and prooxidant state of microglia, the prominent mediators of neurotoxicity in brain ageing and neurodegeneration.

Prenatal hypoxia in rats increased blood pressure and sympathetic drive of the adult offspring.

Decreased oxygenation during pregnancy and early periods of ontogeny can affect normal body development and result in diseases in adulthood. The aim of this study was to use the model of prenatal intermittent hypoxia (PIH) and evaluate the effects of short-term hypoxia at the end of gestation on blood pressure (BP) control in adulthood. Wistar rats were exposed daily to PIH for 4 h during gestational day 19 and 20. In adult male rats, heart rate (HR), systolic BP and pulse pressure (PP) were acquired by radiotelemetry during 1 week. On the basis of HR variability and BP variability, sympathovagal balance (LF/HF) and spontaneous baroreflex sensitivity (sBRS) were evaluated. Systolic BP and PP were significantly elevated in PIH rats in comparison with control rats during the light and dark phase of the day, while LF/HF increased only during the light phase of the day. In contrast, sBRS tended to decrease only during the dark phase in PIH rats. In all measured and calculated parameters, significant circadian rhythms were present and were not affected by PIH. In conclusion, our data suggest that short intermittent hypoxia at the end of gestation can increase BP and PP via significant changes in LF/HF, which occur especially during the passive phase of the day. Results suggest that minor changes in the autonomous nervous system activity induced by environmental conditions during the perinatal period may contribute to development of hypertension in adulthood.

Chronic unpredictable mild stress paradigm in male Wistar rats: effect on anxiety- and depressive-like behavior.

OBJECTIVES: There are several models of depression. Chronic unpredictable mild stress (CMS) appears to have the greatest validity, although it is often being criticized for low reliability. METHODS: Male Wistar/DV rats were used in this study to assess our modified 2-week model of CMS as a combination of psychosocial, physical and metabolic stressors and to compare the effect of acute administration of venlafaxine (VFX) and diazepam (DZP), either in stress or no stress conditions. The animals were exposed to one particular stressor each day. The time of day and duration of the stressor differed across the procedure to avoid animals to adapt to the stress stimulus. After cessation of stress, the animals underwent the following behavioral tests to assess motor activity, cognition, anxiety- and depression-like behavior: Open field test, Elevated plus maze, Forced swim test, Stress-iduced hyperthermia, Light/dark test and Y maze. To assess hypothalamic-pituitary-adrenal axis (HPA) reactivity in our CMS model, plasma corticosterone levels were measured 24 h after termination of stress. RESULTS: Corticosterone levels were significantly increased compared to control values (p<0.05) in our experimental schedule of CMS. Our paradigm produced delayed anxiety-like behavior observed in Open field (decreased time spent in central zone 3 weeks after CMS, p<0.05), with anxiolytic effect of CMS shortly after its cessation. Stressed animals spent more time in the open arms of Elevated plus maze (p<0.05) and travelled longer distance in the light zone of the Light/dark box (p<0.01). CMS did not increase the behavioral despair analyzed in Forced swim test yet it disrupted the capacity of the Stress-induced hyperthermia test (CMS rats failed to react to the stress by increasing the core temperature). CONCLUSIONS: Based on our results, we can conclude that our CMS protocol leads to increased corticosterone levels as a result of HPA axis hyperactivity and produces delayed onset of anxiogenic behavior. Moreover, CMS exerted a substantial effect on the behavioral outputs, interfering with drug testing.

Pyridoindole antioxidant-induced preservation of rat hippocampal pyramidal cell number linked with reduction of oxidative stress yet without influence on cognitive deterioration in Alzheimer-like neurodegeneration.

BACKGROUND: The idea of antioxidant therapy attenuating Alzheimer disease (AD) neuropathology starts to be attractive. Animal models are often used in these studies. An AD-like model of trimethyltin (TMT)-induced neurodegeneration, targeting the hippocampus, involves neuronal cell death and cognitive impairment. OBJECTIVES: Effect of the pyridoindole SMe1EC2 (3×50 mg/kg) and vitamin C (3×50mg/kg) was analyzed in the model of TMT-induced (8 mg/kg) neurodegeneration. METHODS: The study was focused on the effect of the antioxidants tested on learning performance in the Morris water maze (MWM) on days 21-25 after TMT administration, on biochemical variables - malondyaldehyde (MDA) and lysosomal enzyme NAGA in brain cortex and blood serum, and on pyramidal cell number in the CA1 area of the hippocampus on day 31 after TMT administration in adult male Wistar rats (n=32). RESULTS: Critical deterioration of learning performance was observed due to the TMT administration in the MWM. Further, apparent reduction of pyramidal cell number to 21% in the CA1 area of the hippocampus, increased MDA and NAGA activity in serum and increased NAGA activity in the cortex were determined contrary to controls. In serum, an increase of MDA level was prevented by both antioxidants tested without any effect on NAGA activity. SMe1EC2 apparently preserved pyramidal cell viability in the CA1 area. Both substances tested failed to ameliorate the detrimental effect of TMT on spatial memory. CONCLUSION: The biochemical and morphometrical findings suggest that reduction of oxidative stress may play a role in AD-like neurodegeneration. Different doses and timing of SMe1EC2 administration might bring improvement in next learning performance.

Subchronic perinatal asphyxia increased anxiety-and depression-like behaviors in the rat offspring.

OBJECTIVES: Perinatal asphyxia is one of the major cause of mortality in newborns and cause of neurological disorders in adulthood. Brain damage is of the most concern due to high sensitivity of nervous system to suboptimal intrauterine oxygen condition. The aim of this study was to assess effect of subchronic prenatal asphyxia (SPA) during sensitive stages of brain maturation on behavioral changes in rats, as a method of prenatal programming of anxiety and depression-like behavior. METHODS: Pregnant Wistar/DV females were exposed to environment containing lower oxygen (10.5% O2) during sensitive stages of brain maturation (day 19-20 of gestation) for 4h a day and anxiety- and depression-like behaviors in offspring were assessed using battery of behavioral tests--Open field (OF), Elevated plus maze (EPM), Light/dark test (L/D), Forced swim test (FST), and Stress induced hyperthermia (SIH). RESULTS: OF did not induced changes of locomotor and exploration activities. The anxiety-like behavior was induced by SPA in EPM and L/D. These results were significant in males SPA group only. The higher response to the stress stimulus in SIH was recorded in both males and females SPA group. The intensity of climbing on the walls of cylinder in FST in males SPA group was significantly decreased indicating depression-like behavior in adulthood. CONCLUSIONS: In conclusion, we found out that perinatal asphyxia on 19th and 20th day of gestation caused anxiety- and depression-like behaviors in the rat offspring. Our model of SPA has proved to be useful to study the conditions of asphyxia during pregnancy, and could be suitable model for studies uncovering the mechanisms of prenatal programming of psychiatric diseases.

Subchronic perinatal asphyxia in rats: embryo-foetal assessment of a new model of oxidative stress during critical period of development.

Approximately 3% of annual births suffer from birth asphyxia and one million of these newborns die. The aim of this study was to develop a model for studying subchronic perinatal asphyxia (SPA) in rats. Pregnant animals were exposed to 10.5% O2 during sensitive stages of brain development for 4h a day. Biochemical variables were analysed immediately and 24h after asphyxia. SPA caused significant reduction of foetal weight, produced abnormalities of distal parts of the skeleton, and anomalies in the development of brain ventricles. Time-dependent changes were observed in several parameters indicating adjustment of the developing organism to the delivery. Whereas lactate was elevated immediately after asphyxia, glucose mirrored high energy needs 24h after the insult. Immunohistochemical examination of the placentas revealed overgrowth of acidic glycoconjugates in the extracellular matrix of vascular walls in the animals exposed to asphyxia. We observed the presence of muscle fibres in chorionic plate arteries and also in intraplacental arteries. The present model proved to be useful for the study of asphyxial conditions during pregnancy. As it is non-invasive and allows to control asphyxial conditions, it appears suitable for the screening and investigation of indicators of asphyxia in the mother and foetus.

Anxiolytic activity of pyridoindole derivatives SMe1EC2 and SMe1M2: behavioral analysis using rat model.

Anxiety and mood disorders have become very significant affections in the last decades. According to WHO at least one mental disease occurred per year in 27% of EU inhabitants (more than 82 mil. people). It is estimated that by 2020, depression will be the main cause of morbidity in the developed countries. These circumstances call for research for new prospective drugs with anxiolytic and antidepressive properties exhibiting no toxicity and withdrawal effect and possessing beneficial properties, like antioxidant and/or neuroprotective effects. The aim of this study was to obtain information about psychopharmacological properties of pyridoindole derivatives SMe1EC2 and SMe1M2, using non-invasive behavioral methods in rats.The battery of ethological tests (open field, elevated plus-maze, light/dark box exploration, forced swim test) was used to obtain information about anxiolytic and antidepressant activity of the pyridoindole derivatives. The substances were administered intraperitoneally 30 minutes before the tests at doses of 1, 10 and 25 mg/kg.In the behavioral tests, SMe1EC2 was found to exert anxiolytic activity in elevated plus maze with no affection of locomotor activity. The highest dose of SMe1M2 increased the time spent in the lit part of the Light/Dark box, however this result was influenced by inhibition of motor activity of the rats. Similar findings were observed also in elevated plus-maze, although these results were not statistically significant.In conclusion, from the results of our study it is evident that both pyridoindoles acted on the CNS. In the highest dose, SMe1M2 was found to possess rather sedative than anxiolytic or antidepressant activity.