COVID-19 Disease and Vitamin D: A Mini-Review.

Novel coronavirus disease (COVID-19) pandemic caused by SARS-CoV-2, for which there is no effective treatment except employing prevention strategies, has already instituted significant number of deaths. In this review, we provide a scientific view on the potential role of vitamin D in SARS-CoV-2 virus/COVID-19 disease. Vitamin D is well-known to play a significant role in maintaining the immune health of an individual. Moreover, it induces antimicrobial peptide expression that can decrease viral replication and regulate the levels of pro-inflammatory/anti-inflammatory cytokines. Therefore, supplementation of vitamin D has the potential to reduce the incidence, severity and the risk of death from pneumonia resulting from the cytokine storm of many viral infections including COVID-19. We suggest that supplementation of subjects at high risk of COVID-19 with vitamin D (1.000 to 3.000 IU) to maintain its optimum serum concentrations may be of significant benefit for both in the prevention and treatment of the COVID-19.

Effects of Vitamin D3 in Long-Term Ovariectomized Rats Subjected to Chronic Unpredictable Mild Stress: BDNF, NT-3, and NT-4 Implications.

The purpose of this study was to explore the antidepressant-like effects of vitamin D3 at different doses (1.0, 2.5, and 5.0 mg/kg sc) on a model of depression produced by chronic unpredictable mild stress (CUMS) for 28 days in long-term (3 months) ovariectomized (OVX) adult rats. Sucrose preference (SPT), forced swimming (FST) and open-field (OFT) tests were conducted to examine the depression-like state. Serum corticosterone/adrenocorticotrophic hormone (ACTH) levels and hippocampal brain-derived neurotrophic factor (BDNF) and neurotrophin (NT)-3/NT-4 expressions by ELISA kits and/or western blotting were determined to assess the possible mechanisms of the vitamin D3 effects on the depression-like profile in long-term OVX rats subjected to CUMS. The results showed that vitamin D3 (5.0 mg/kg), as well as fluoxetine treatment, considerably reversed the depression-like state in the SPT and FST, decreased serum corticosterone/ACTH levels, and increased BDNF and NT-3/NT-4 levels in the hippocampus of long-term OVX rats compared to OVX rats with CUMS (p < 0.05). Thus, a high dose of vitamin D3 (5.0 mg/kg sc) could improve the depression-like profile in long-term OVX adult female rats subjected to the CUMS procedure, which might be mediated by the regulation of BDNF and the NT-3/NT-4 signaling pathways in the hippocampus, as well as the corticosterone/ACTH levels of the blood serum.

Vitamin D3 treatment differentially affects anxiety-like behavior in the old ovariectomized female rats and old ovariectomized female rats treated with low dose of 17ß-estradiol.

BACKGROUND: Estrogen deficiency effects on affective-related behavior are restricted to certain periods of age after ovary removal. Among other nutraceuticals, one of such «natural¼ substances for treatment of affective-related diseases could be vitamin D3. It is a great interest to evaluate the effects of repeated cholecalciferol administration on anxiety-related behavior in the old female rats with long-term estrogen deficiency. The present study was performed to determine the behavioral effects of cholecalciferol treatment at different doses as an adjunctive therapy alone or in a combination with low dose of 17ß-estradiol on anxiety-like behavior of the old (16-18 months) female rats at 12 weeks after ovariectomy. METHODS: Vitamin D3 supplementation individually (as cholecalciferol at doses of 1.0, 2.5 or 5.0 mg/kg/day, s.c.) or in co-administration with of 17ß-estradiol (17ß-E2, 0.5 µg/rat, s.c.) were given to the old ovariectomized (OVX) rats at 12 weeks after ovariectomy. Anxiety-related state was tested in the elevated plus maze (EPM) and light-dark test (LDT), as well behavioral reactivity was registered in the open field test (OFT). Moreover, 25-hydroxyvitamin D3 levels in the blood serum of these OVX rats treated with Vitamin D3 or Vitamin D3 plus 17ß-E2 were measured. RESULTS: The results of the present study indicated that Vitamin D3 supplementation at dose of 1.0 mg/kg/day decreased manifestations of anxiety-like profile in the old OVX rats. Treatment with Vitamin D3 (1.0 mg/kg/day) plus 17ß-E2 in resulted in more profound anxiolytic-like effects the old OVX rats than effects of both drugs administered alone. Moreover, treatment with cholecalciferol (1.0 mg/kg/day, s.c.) in the old ovariectomized rats after ovariectomy at 12 weeks produced elevated estradiol and 25-OH-VD3 levels for these rats as compared to the old OVX females treated with oil solvent. CONCLUSIONS: Using the preclinical study, chronic cholecalciferol, 17ß-E2 and their combination treatment were shown to be effective for anxiety-like treatment in the old subjects with long-term estrogen deficiency.

Therapeutical strategies for anxiety and anxiety-like disorders using plant-derived natural compounds and plant extracts.

Anxiety and anxiety-like disorders describe many mental disorders, yet fear is a common overwhelming symptom often leading to depression. Currently two basic strategies are discussed to treat anxiety: pharmacotherapy or psychotherapy. In the pharmacotherapeutical clinical approach, several conventional synthetic anxiolytic drugs are being used with several adverse effects. Therefore, studies to find suitable safe medicines from natural sources are being sought by researchers. The results of a plethora experimental studies demonstrated that dietary phytochemicals like alkaloids, terpenes, flavonoids, phenolic acids, lignans, cinnamates, and saponins or various plant extracts with the mixture of different phytochemicals possess anxiolytic effects in a wide range of animal models of anxiety. The involved mechanisms of anxiolytics action include interaction with γ-aminobutyric acid A receptors at benzodiazepine (BZD) and non-BZD sites with various affinity to different subunits, serotonergic 5-hydrodytryptamine receptors, noradrenergic and dopaminergic systems, glutamate receptors, and cannabinoid receptors. This review focuses on the use of both plant-derived natural compounds and plant extracts with anxiolytic effects, describing their biological effects and clinical application.

Modulating Effects of Cholecalciferol Treatment on Estrogen Deficiency-Induced Anxiety-Like Behavior of Adult Female Rats.

BACKGROUND: Vitamin D can be one of the candidate substances that are used as additional supplementation in the treatment of anxiety-related disorders in women with estrogen imbalance. MATERIALS AND METHODS: The aim of the present study was to examine the effects of chronic cholecalciferol administration (1.0, 2.5 or 5.0 mg/kg/day, s.c.) on the anxiety-like behavior and monoamines levels in the rat hippocampus following ovariectomy in female rats. Cholecalciferol was given to ovariectomized (OVX) rats and OVX rats treated with 17ß-estradiol (17ß-E2, 0.5 µg/rat, s.c.). The anxiety-like behavior was assessed in the elevated plus maze (EPM) and the light-dark tests (LDT), locomotor and grooming activities were assessed in the open-field test (OFT). RESULTS: Cholecalciferol in high doses alone or in combination with 17ß-E2-induced anxiolytic-like effects in OVX and OVX rats treated with 17ß-E2 as evidenced in the EPM and LDT tests, and increased grooming activity in the OFT test. We found that DA and 5-HT levels increased while 5-HT turnover in the hippocampus decreased in these groups of OVX rats. CONCLUSION: Our results indicate that cholecalciferol in high doses has a marked anxiolytic-like effect due to an increase in the monoamines levels in the experimental rat model of estrogen deficiency.

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.

Different effects of vitamin D hormone treatment on depression-like behavior in the adult ovariectomized female rats.

Vitamine D (VD) has important functions in the human brain and may play a role in affective-related disorders. VD receptors are expressed in multiple brain regions associated with depressive disorders. The aim of the preclinical study was to examine the effects of chronic cholecalciferol administration (1.0, 2.5 or 5.0mg/kg/day,s.c., once daily, for 14days) on the depression-like behavior and corticosterone levels in the blood samples following ovariectomy in female rats. Cholecalciferol was administered to the ovariectomized (OVX) rats and OVX rats treated with 17ß-estradiol (17ß-E2, 0.5µg/rat,s.c., once daily, for 14days). Depression-like behavior and spontaneous locomotor activity were assessed in the forced swimming test (FST) and the open field test (OFT), respectively. The corticosterone levels in the blood serum before and after FST were measured in all experimental groups. Treatment with cholecalciferol in high dose (5.0mg/kg/day,s.c.) significantly decreased the immobility time of OVX rats in the FST. Co-administration of cholecalciferol in high dose with 17ß-E2 exerted a markedly synergistic antidepressant-like effect in the OVX rats on the same model of depression-like behavior testing. Cholecalciferol in high dose (5.0mg/kg/day,s.c.) administered alone or together with 17ß-E2 significantly enhanced frequency of grooming for the OVX rats in the OFT. Moreover, cholecalciferol in high dose administered alone or together with 17ß-E2 significantly decreased the elevated corticosterone levels in the blood serum of OVX rats following the FST. These results indicate that Cholecalciferol in high dose has a marked antidepressant-like effect in the adult female rats with low levels of estrogen.

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.

Anxiolytic-like effect of quinpirole in combination with a low dose of 17ß-estradiol in ovariectomized rats.

The aim of this study was to explore effects on anxiety-like behavior of the D2 dopamine receptor agonist, quinpirole and of the D2 dopamine receptor antagonist, sulpiride given alone or in combination with a low dose of 17ß-estradiol (17ß-E2) to ovariectomized (OVX) rats. Two weeks after surgery, OVX rats began 14 days of treatment with the vehicle, a low dose of 17ß-E2 (5.0 µg/rat, s.c.), quinpirole (0.1 mg/kg, i.p.), sulpiride (10.0 mg/kg, i.p.), quinpirole plus 17ß-E2 or sulpiride plus 17ß-E2. The animals were then tested in the black and white model (BWM) and the open field test (OFT). Quinpirole (0.1 mg/kg, i.p.) administered alone or in a combination with a low dose of 17ß-E2 (5.0 µg/rat, s.c.) resulted in anxiolytic-like effect in OVX rats in the BWM. Repeated treatment of quinpirole and 17ß-E2 profoundly increased anxiolytic-like effect of the single substances they exert per se. Co-administration of quinpirole with 17ß-E2 increased frequency of rearing and grooming in OVX rats in the OFT. Sulpiride (10.0 mg/kg, i.p.) treatment failed to alter anxiety-like behavior in OVX rats in the BWM. In addition, sulpiride blocked the anxiolytic-like effect of 17ß-E2 in OVX rats. Application of neither sulpiride nor sulpiride plus 17ß-E2 led to any changes of rearing and grooming behavior in OVX rats in the OFT. The results of the present study suggest that 17ß-E2 and quinpirole interact to exert anxiolytic-like action and that each of these drugs can potentiate effects of each other. Further research is needed to elucidate detailed mechanisms by which quinpirole and 17ß-E2 exert synergistic effect on anxiety-related behavior.

Ropren(®) is a polyprenol preparation from coniferous plants that ameliorates cognitive deficiency in a rat model of beta-amyloid peptide-(25-35)-induced amnesia.

This study assesses the efficacy of a fixed dose of Ropren(®) (a plant preparation isolated from the neutral fraction of an extract of spruce needles) on cognitive impairment in rats with ß-amyloid peptide-(25-35)-induced amnesia. Ropren(®) was administered at a dose of 8.6mg/kg for 28 days, per os, to rats with ß-amyloid peptide-(25-35)-induced amnesia. Cognitive performance was assessed using the passive avoidance paradigm and the Morris water maze and behavior was assessed using the open field test. After four weeks, Ropren(®) treatment significantly improved non-spatial and spatial learning in rats with ß-amyloid peptide-(25-35)-induced amnesia. The results of the present study suggest that Ropren(®), a novel plant preparation, ameliorates cognitive deficiencies in an animal model relevant to Alzheimer's disease.

Behavioral effects of dehydroepiandrosterone in adult male rats.

It is well-documented that dehydroepiandrosterone (DHEA) exhibits various behavioral effects in rodents, at least one of which is modulation of learning/memory processes in several test paradigms. However, little is known about the influence of DHEA on cognitive performance in the adult rodents. This work was designed to determine whether chronic DHEA administration during 10 days in the high (0.7 mg/kg, s.c.) or low (0.1 mg/kg, s.c.) doses has any effect on learning/memory abilities and behavior in the adult male rats (5- to 6-month old). Effect of DHEA was estimated in active and passive avoidance tasks, behavior was registered in the elevated "plus" maze and the "open field" test. DHEA in the high dose significantly (p<0.05) increased time spent and the number of enterings in the "open" arms of the elevated "plus" maze in intact male rats as compared with the control rats. DHEA in the low dose significantly (p<0.05) decreased horizontal and vertical locomotor activity and grooming behavior, whereas DHEA in the high dose did not significantly modify behavior in intact rats as compared with control group. Results of the ANOVA on passive avoidance performance revealed no statistically significant differences among the groups receiving DHEA in the high or low doses as compared to the control. However, DHEA in the low dose significantly (p<0.05) reduced the number of correct avoidance responses in intact rats as compared to the control rats, while in rats treated with the high dose DHEA, the active avoidance performance did not differ significantly from the control. Thus, chronic DHEA administration has a modulatory action on the learning and behavior of the adult male rats.