Antidepressant-Like Effect of Ropren® in ß-Amyloid-(25-35) Rat Model of Alzheimer's Disease with Altered Levels of Androgens.

This study elucidated the potential antidepressant-like effect of prolonged Ropren® administration (8.6 mg/kg, orally, once daily for 28 days) using a ß-amyloid (25-35) rat model of Alzheimer's disease following gonadectomy. The experimental model was created by intracerebroventricular injection of ß-amyloid (25-35) into gonadectomized (GDX) rats and GDX rats with testosterone propionate (TP, 0.5 mg/kg, subcutaneous, once daily, 28 days) supplementation. Ropren® was administered to the GDX rats and GDX rats treated with TP. Depression-like behavior was assessed in the forced swimming test, and the spontaneous locomotor activity was assessed using the open-field test. The corticosterone and testosterone levels in the blood serum before and after FST were measured in all experimental groups. Treatment with Ropren® significantly decreased the immobility time of GDX rats with ß-amyloid (25-35) in the forced swimming test. Coadministration of Ropren® with TP exerted a markedly synergistic antidepressant-like effect in the GDX rats with ß-amyloid (25-35 on the same model of depression-like behavior testing. Ropren® administered alone or together with TP significantly enhanced crossing, frequency of rearing, and grooming of the GDX rats with ß-amyloid (25-35) in the open-field test. Moreover, Ropren® administered alone or together with TP significantly decreased the elevated corticosterone levels in the blood serum of GDX rats with ß-amyloid (25-35) following the forced swimming test. These results indicate that Ropren® has a marked antidepressant-like effect in the experimental model of Alzheimer's disease in male rats with altered levels of androgens.

Ropren® treatment reverses anxiety-like behavior and monoamines levels in gonadectomized rat model of Alzheimer's disease.

Previous studies indicated that reduced androgen levels may contribute to both physical and cognitive disorders in men, including Alzheimer's disease. New drug candidates for Alzheimer's disease in patients with androgen deficiency should ideally be able to act not only on multiple brain targets but also to correct impaired endocrine functions in hypogonadal men with Alzheimer's disease. Ropren® is one such candidate for the treatment of Alzheimer's disease in men with an imbalance of androgens. Accordingly, the aim of the current study was to examine the effects of long-term Ropren® administration (8.6mg/kg, orally, once daily, for 28 days) on the anxiety-like behavior and monoamines levels in the rat hippocampus using a ß-amyloid (25-35) rat model of Alzheimer's disease following gonadectomy. Ropren® was administered to the gonadectomized (GDX) rats and GDX rats treated with testosterone propionate (TP, 0.5mg/kg, subcutaneous, once daily, for 28 days). Anxiety-like behavior was assessed in the elevated plus maze (EPM) and the light-dark test (LDT), locomotor and grooming activities were assessed in the open field test (OFT). Ropren® alone or in combination with TP-induced anxiolytic effects as evidenced in the EPM and in the LDT and increased locomotor activity in the OFT. Additionally, it was observed that dopamine (DA) and serotonin (5-HT) levels increased while 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratio in the hippocampus decreased. Our results indicate that Ropren® has a marked anxiolytic-like action due to an increase in the monoamines levels in the experimental rat model of Alzheimer's disease with altered levels of androgens.

Cognitive-enhancing activities of the polyprenol preparation Ropren® in gonadectomized ß-amyloid (25-35) rat model of Alzheimer's disease.

The present preclinical study was designed to examine the effects of prolonged Ropren® administration (8.6 mg/kg, orally, once daily, 28 days) in a ß-amyloid (25-35) rat model of Alzheimer's disease following gonadectomy. The experimental model was created by intracerebroventricular injection of ß-amyloid (25-35) into gonadectomized (GDX) rats and GDX rats with testosterone propionate (TP, 0.5mg/kg, subcutaneous, once daily, 28 days) supplementation. Ropren® was administered to the GDX rats and GDX rats treated with TP. Memory performance was assessed using the passive avoidance and the Morris water maze tests and the spontaneous locomotor activity was assessed using the open field test. Treatment with Ropren® significantly improved and restored the cognitive ability of GDX rats with ß-amyloid (25-35)-induced amnesia in the passive avoidance test and Morris water maze. Co-administration of Ropren® with TP exerted a markedly synergistic memory-enhancing effect in the GDX rats with ß-amyloid (25-35)-induced amnesia on the same models of memory testing. Ropren® administered alone or together with TP significantly enhanced crossing, frequency of rearing and grooming of the GDX rats with ß-amyloid (25-35)-induced amnesia in the open field test. These results indicate that Ropren® has a marked memory-enhancing action in the experimental model of Alzheimer's disease in male rats with altered levels of androgens.

Postnatal ontogeny of the glucocorticoid receptor in the hippocampus.

Corticosteroid hormones are important intrinsic factors that not only mediate the response to stress but also largely contribute to the main physiological processes. The biological actions of these steroids involve, first of all, the activation of specific receptors, namely mineralocorticoid (MR) and glucocorticoid (GR) receptors. These two receptor types govern a flexible and well-balanced mechanism that leads to the often opposing changes in the cell. The hippocampus is the central part of the extrahypothalamic feedback loop in the control of the hypothalamic-pituitary-adrenal (HPA) axis activity. The coexpression of both MR and GR in the hippocampus serves a coordinated response to corticosteroids in the hippocampal neurons, thereby mediating the neuronal excitability, stress response, and behavioral adaptation. Each receptor type reveals distinct ontogenetic pattern over the postnatal period. This review addresses the issues relating to postnatal development of the HPA axis and especially the hippocampal expression of the GR proteins in intact and prenatally stressed rats.

Involvement of the hypothalamic-pituitary-adrenal axis in the antidepressant-like effects of mild hypoxic preconditioning in rats.

The preconditioning (PC) by using mild intermittent hypobaric hypoxia (PC) increases a resistance of the brain to severe hypoxia/ischemia and various stresses. Recently, potent antidepressant-like effects of PC have been described in animal models of depression. In the present study, the impact of PC on the activity and feedback regulation of the hypothalamic-pituitary-adrenal axis (HPA) impaired in depression has been studied in the model of shock-induced depression in rats. PC completely prevented depressive-like behavior (54% reduction in ambulance, 59% reduction in rearing in the open field, 654% increase of the anxiety level in the elevated plus maze), the HPA hyperactivity and the impairment of HPA feedback regulation that appeared in response to the inescapable footshock. Not affecting basal HPA activity, PC remarkably enhanced the HPA reactivity to stresses and substantially up-regulated the expression of glucocorticoid receptors in the ventral hippocampus following footshock that apparently contributes to the mechanisms responsible for the antidepressant-like action of PC.

Antidepressant-like effects of mild hypoxia preconditioning in the learned helplessness model in rats.

The effects of preconditioning using mild repetitive hypobaric hypoxia (360 Torr for 2 h each of 3 days) have been studied in the learned helplessness model of depression in rats. Male Wistar rats displayed persistent depressive symptoms (depressive-like behaviour in open field, increased anxiety levels in elevated plus maze, ahedonia, elevated plasma glucocorticoids and impaired dexamethasone test) following the exposure to unpredictable and inescapable footshock in the learned helplessness paradigm. Antidepressant treatment (ludiomil, 5 mg/kg i.p.) augmented the development of the depressive state. The hypoxic preconditioning had a clear antidepressive action returning the behavioural and hormonal parameters to the control values and was equally effective in terms of our study as the antidepressant. The findings suggest hypoxic preconditioning as an effective tool for the prophylaxis of post-stress affective pathologies in humans.

Expression of glucocorticoid receptors in the hippocampal region of the rat brain during postnatal development.

Circulating glucocorticoids, of which their concentration is largely under the control of the hypothalamic-pituitary adrenal (HPA) axis, acting through the glucocorticoid receptors (GR) regulate a large variety of pivotal functions of the organism such as growth, development, immune- and stress-response. The main mechanism of regulation of the HPA axis activity is via negative feedback at all levels of the HPA axis itself as well as at the extra-hypothalamic level, a central part of which is the hippocampus. During neonatal development, the HPA axis of rats undergoes a period of hyporesponsiveness (SHRP)-when most stress stimuli fail to induce stress-response. Here, we describe the pattern of GR proteins expression in the hippocampal area of the rat brain during postnatal development and in adulthood. We demonstrated that the GR protein, of which its expression level is gradually enhanced in the hippocampus during postnatal life, exists in three different molecular sized forms. A larger molecular form was expressed at rather high levels at all studied time periods. A second smaller variant of GR was transiently expressed during the first one and a half weeks that corresponds with SHRP and then appeared again only in the adulthood. By the end of SHRP on PD 13, third smallest protein form of GR started to be detected in the hippocampal area. Thus, it remains to be disclosed in the nearest future, how the hippocampal GR isoforms may be involved in regulation of the neonatal HPA axis hyporesponsiveness as well as in functions of this system during the ensuing period of the brain maturation.