25 Hydroxyvitamin D and Cytokine Profile in Patients With Relapsing-Remitting Multiple Sclerosis.

In experimental allergic encephalomyelitis, the severity of the deficiency is associated with the loss of axons, and it is likely that cytotoxic T-cells 8 (CD8 T) play an important role. In relapsing-remitting multiple sclerosis, there is a correlation between the inflammatory activity in the lesion and the transection of axons. To understand the pathological mechanisms, it is important to evaluate the changes in serum concentrations of pro- and anti-inflammatory cytokines during the disease course. A total of 46 patients and 40 healthy individuals participated in an open-label, prospective, case-control study from 2012 to 2014. The serum concentrations of cytokines were measured using enzyme-linked immunosorbent assay (ELISA). An immune imbalance was observed during relapse and remission phases compared to the control group. During relapse, the levels of interferon-gamma (IFN-γ) were significantly higher compared to those in remission (p=0.017). During remission, there was an improvement in the deficiency (p<0.001), and the anti-inflammatory cytokines transforming growth factor-beta (TGF-ß) and interleukin 4 (IL4) increased compared to those in relapse (p=0.006; p=0.009). A correlation was found between the serum concentrations of tumor necrosis factor-alpha (TNF-α) and Expanded Disability Status Scale (EDSS) during relapse (correlation coefficient: 0.301; significance (Sig.) (2-tailed 0.042). During the exacerbation, there was a moderate relationship between interleukin 17 (IL17) and 25-hydroxyvitamin D (25(OH)D) (P (p-value (probability value) = 0.02)). TNF-α, IFN-γ, IL17, and TGF-ß serum levels are criteria for evaluating immune inflammatory activity during relapse and remission periods.

Anti-inflammatory and in vitro antioxidant activities of Satureja montana dry extract.

INTRODUCTION: Many chronic somatic and psychiatric diseases are associated with oxidative stress and inflammation, both of which have detrimental effects on human health.

Effect of Plant Extracts Combinations on TNF-α, IL-6 and IL-10 Levels in Serum of Rats Exposed to Acute and Chronic Stress.

Oxydative stress, anxiety and depression are associated with changes in cytokine levels. Natural products, including individual and combined plant extracts, have the potential to be used in the treatment of neuropsychiatric disorders. The goal of this study is to investigate the effects of two combined plant extracts, rich in flavonoids, on the levels of the cytokines TNF-α, IL-6, and IL-10 in rats subjected to models of acute cold stress and chronic unpredictable stress. The study utilized common medicinal plants such as Valeriana officinalis, Melissa officinalis, Crataegus monogyna, Hypericum perforatum, and Serratula coronata, which were combined in two unique combinations-Antistress I and Antistress II. The compositions of the used extracts were determined by HPLC methods. Pro- and anti-inflammatory cytokines in rats' serum were measured with Enzyme-linked immunosorbent assay. The results from the acute stress model revealed that the individual extract of Crataegus monogyna decreased levels of TNF-α, while Serratula coronata, Hypericum perforatum, and Valeriana officinalis effectively reduced IL-6 levels. Both combinations, Antistress I and Antistress II, were effective in reducing TNF-α and IL-6 levels, with Antistress II also increasing IL-10 levels. In the chronic stress model, Hypericum perforatum extract decreased the levels of the pro-inflammatory cytokines TNF-α and IL-6, whereas extracts of Serratula coronata and Valeriana officinalis only reduced TNF-α levels. The two combined extracts, Antistress I and Antistress II, decreased TNF-α and IL-6 levels, while Antistress I also reduced the levels of the anti-inflammatory cytokine IL-10. The combinations of plant extracts used in our experiment have not been previously studied or documented in the available literature. However, based on our own experimental results, we can draw the conclusion that the combinations exhibit a more pronounced effect in reducing cytokine levels compared to the individual plant extracts.

Phytochemical Profiling, Antioxidant and Cognitive-Enhancing Effect of Helichrysum italicum ssp. italicum (Roth) G. Don (Asteraceae).

This study aimed at the evaluation of the antioxidant and cognitive-enhancing effect of methanol-aqueous extract from Helichrysum italicum ssp. italicum aerial parts. Significant radical scavenging activity (110.33 ± 3.47 and 234.70 ± 5.21 mg TE/g for DPPH and ABTS) and reducing power (354.23 ± 17.51 and 210.24 ± 8.68 mg TE/g for CUPRAC and FRAP) were observed. The extract showed average acetylcholinesterase and low butyrylcholinesterase inhibitory potential. H. italicum extract (200 mg/kg/po) administered in combination with galantamine (3 mg/kg/po) for 12 days significantly improved the memory and learning process compared with galantamine alone in the passive avoidance test. The effect was comparable to that of Ginkgo biloba extract (100 mg/kg/po). In deep secondary metabolite annotation of the extract by UHPLC-HRMS, more than 90 hydroxybenzoic and hydroxicinnamic acid-glycosides, phenylethanoid glycosides, a series of acylquinic and caffeoylhexaric acids, methoxylated derivatives of scutellarein, quercetagetin and 6-hydroxyluteolin, and prenylated phloroglucinol-α-pyrones were reported for the first time in H. italicum. Fragmentation patterns of four subclasses of heterodimer-pyrones were proposed. In-depth profiling of the pyrones revealed 23 compounds undescribed in the literature. Pyrones and acylphloroglucinols together with acylquinic acids could account for memory improvement. The presented research advanced our knowledge of H. italicum, highlighting the species as a rich source of secondary metabolites with cognitive-enhancing potential.

Synthesis and Biological Study of 4-Aminopyridine-Peptide Derivatives Designed for the Treatment of Neurodegenerative Disorders.

BACKGROUND: Alzheimer's disease (AD) and Multiple sclerosis (MS) lead to neurodegenerative processes negatively affecting millions of people worldwide. Their treatment is still difficult and practically incomplete. One of the most commonly used drugs against these neurodegenerative diseases is 4-aminopyridine. However, its use is confined by the high toxicity. OBJECTIVES: The aim of this work is to obtain new peptide derivatives of 4-aminopyridine with decreased toxicity compared to 4-aminopyridine. METHODS: Synthesis was conducted in solution using a consecutive condensation approach. The new derivatives were characterized by melting points, NMR, and Mass spectra. Important ADME (absorption, distribution, metabolism, and excretion) properties have been studied in silico using ACD/Percepta v.2020.2.0 software. Acute toxicity was determined in mice according to a Standard protocol. All new derivatives were tested in vitro for cytotoxic activity in a panel of human (HEP-G2, BV-173) and murine (NEURO 2A) tumor cell lines via a standard MTT-based colorimetric method. ß-secretase inhibitory activity was determined by applying the fluorescent method. RESULTS: New derivatives of 4-aminopyridine containing analogues of the ß-secretase inhibitory peptide (Boc-Val-Asn-Leu-Ala-OH) were obtained. The in vivo toxicity of the tested compounds was found to be as high as 1500 mg/kg. Cell toxicity screening against tumor cell lines of different origins showed negligible growth-inhibitory effects of all investigated 4-aminopyridine analogues. CONCLUSION: Synthesis of new peptide derivatives of 4-aminopyridine is reported. Acute toxicity studies revealed a ca. 150 times lower toxicity of the new compounds as compared to 4-aminopyridine that may be ascribed to their peptide fragment.

Newly Synthesized Creatine Derivatives as Potential Neuroprotective and Antioxidant Agents on In Vitro Models of Parkinson's Disease.

Oxidative stress is one of the key factors responsible for many diseases-neurodegenerative (Parkinson and Alzheimer) diseases, diabetes, atherosclerosis, etc. Creatine, a natural amino acid derivative, is capable of exerting mild, direct antioxidant activity in cultured mammalian cells acutely injured with an array of different reactive oxygen species (ROS) generating compounds. The aim of the study was in vitro (on isolated rat brain sub-cellular fractions-synaptosomes, mitochondria and microsomes) evaluation of newly synthetized creatine derivatives for possible antioxidant and neuroprotective activity. The synaptosomes and mitochondria were obtained by multiple centrifugations with Percoll, while microsomes-only by multiple centrifugations. Varying models of oxidative stress were used to study the possible antioxidant and neuroprotective effects of the respective compounds: on synaptosomes-6-hydroxydopamine; on mitochondria-tert-butyl hydroperoxide; and on microsomes-iron/ascorbate (non-enzyme-induced lipid peroxidation). Administered alone, creatine derivatives and creatine (at concentration 38 µM) revealed neurotoxic and pro-oxidant effects on isolated rat brain subcellular fractions (synaptosomes, mitochondria and microsomes). In models of 6-hydroxydopamine (on synaptosomes), tert-butyl hydroperoxide (on mitochondria) and iron/ascorbate (on microsomes)-induced oxidative stress, the derivatives showed neuroprotective and antioxidant effects. These effects may be due to the preservation of the reduced glutathione level, ROS scavenging and membranes' stabilizers against free radicals. Thus, they play a role in the antioxidative defense system and have a promising potential as therapeutic neuroprotective agents for the treatment of neurodegenerative disorders, connected with oxidative stress, such as Parkinson's disease.

Cannabidiol improves memory and decreases IL-1ß serum levels in rats with lipopolysaccharide-induced inflammation.

AIM: Memory improving and anti-inflammatory properties of cannabidiol (CBD) were investigated in an experimental model of lipopolysaccharide (LPS)-induced inflammation.

Composition and chronic toxicity of dry methanol-aqueous extract of wild-growing Satureja montana.

INTRODUCTION: Saturejamontana is a wild growing medicinal plant, part of the Lamiaceae family. This herb is well known as a source of phenolic compounds, which can vary in a broad range depending on different factors and exert many pharmacological activities.

Anxiolytic Effect of Satureja montana Dry Extract and its Active Compounds Rosmarinic Acid and Carvacrol in Acute Stress Experimental Model.

BACKGROUND: Anxiety disorders are an important not only medical, but also social problem, affecting approx. 300 million people worldwide in 2019. Medications used in the treatment of anxiety are associated with many adverse reactions, which explains the increased use of herbal products as anxiolytics. METHODS: An anxiolytic activity of Satureja montana, rosmarinic acid and carvacrol after 14-day long administration on an animal model of acute stress was studied. For measurement of anxiolytic effect elevated plus maze, social interaction and Vogel tests were provided as well as examination of locomotor activity. RESULTS: The dry extract of Satureja montana at both tested doses significantly increased locomotor activity as well as the time spent in the social recognition, compared to the control groups. The extract reduced the time in the closed arms and the proportion of entries into open arms to total entries and increased the time in the open arms of elevated plus maze compared to the positive control group. Likewise, rosmarinic acid and carvacrol increased significantly the time spent with a new congener in the social interaction test. Both compounds reduced the ratio of entries into open arms to total entries similarly to the dry extract of Satureja montana. Only rosmarinic acid increased the time in the open arms and reduced the time in the closed arms. CONCLUSIONS: Satureja montana at both experimental doses exerted a significant anxiolytic activity in almost all the tests employed for evaluating anxious behavior. Carvacrol and rosmarinic acid showed a moderate anxiolytic effect.

Neuroprotective effect of newly synthesized 4-aminopyridine derivatives on cuprizone-induced demyelination in mice-a behavioral and immunohistochemical study.

The aim of this study was to assess the effect of newly synthesized derivatives of 4-aminopyridine (4-AP) on cuprizone-induced model of brain demyelination in mice. 4-AP is already approved for the treatment of walking difficulties in patients with multiple sclerosis. The model of demyelination was carried out by the administration of cuprizone to the drinking water of the experimental mice. Besides cuprizone, 4-AP derivatives and 4-AP were administered to the groups in order to assess their protective effect on the demyelination. We used immunohistochemistry for visualization of changes in corpus callosum. Memory storage processes were also assessed with the passive avoidance test on the last two days of the experiment. The experimental mice treated with compounds 4b and 4c increased significantly their latency time on the second day in comparison to the control group which indicated an improved memory process. The number of mature oligodendrocytes in the groups treated with compounds 4b, 4c and 4-AP is closer to those in the control group. The results of our studies showed that the newly synthesized compounds 4b and 4c reverse the effect of cuprizone. These groups also showed increased latency time in the passive avoidance test in comparison to the control group.

Biological Screening of Novel Structural Analog of Celecoxib as Potential Anti-Inflammatory and Analgesic Agent.

Background and objectives: The clinical use of non-steroidal anti-inflammatory drugs is limited due to high incidence of adverse drug reactions. The pyrrole heterocycle is included in the chemical structure of a number of drugs with various activities and shows relatively good tolerability and safety. The objectives of our study were to evaluate the analgesic and anti-inflammatory activity, as well as possible organ toxicity, of 2-[3-acetyl-5-(4-chloro-phenyl)-2-methyl-pyrrol-1-yl]-3-(1H-indol-3-yl)-propionic acid (compound 3g), a novel N-pyrrolylcarboxylic acid structurally similar to celecoxib. Materials and methods: All experiments were performed on 6-week-old male Wistar rats divided into parallel groups (n = 8). Antinociception was assessed using animal pain models with thermal and chemical stimuli (paw withdrawal, tail-flick, and formalin tests). Criteria for the analgesic effect were increased latency in the paw withdrawal and tail-flick tests and decreased paw licking time in the formalin test compared to animals treated with saline (control). Anti-inflammatory activity was measured using a carrageenan-induced paw edema model; the criterion for anti-inflammatory effect was decreased edema compared to control. Blood samples were obtained after animals were sacrificed to assess possible organ toxicity. Statistical analysis was performed with IBM SPSS 20.0. Results: 2-[3-Acetyl-5-(4-chloro-phenyl)-2-methyl-pyrrol-1-yl]-3-(1H-indol-3-yl)-propionic acid had analgesic action against chemical stimulus after single and multiple administration and against thermal stimulus after single administration. Compound 3g significantly suppressed carrageenan-induced paw edema after both single and continuous administration. After continuous administration, hematological tests showed that compound 3g decreased leukocyte and platelet levels and elevated serum creatinine levels. Conclusions: Antinociception with the tested compound is most likely mediated by spinal, peripheral, and anti-inflammatory mechanisms. Possible tolerance of the analgesic action at the spinal level develops after continuous administration. Anti-inflammatory activity is significant and probably the leading cause of antinociception. After multiple administration, compound 3g showed signs of potential nephrotoxicity and antiplatelet activity, as well as suppression of leukocyte levels.

Synthesis of New Galanthamine-Peptide Derivatives Designed for Prevention and Treatment of Alzheimer's Disease.

BACKGROUND: Although no effective treatment for the Alzheimer's disease currently exist, some drugs acting as Acetylcholinesterase inhibitors, like galanthamine have positively affected such patients. ß- and/or γ-secretase inhibitors are another type of potential drugs. Here we report synthesis of new peptide-galanthamine derivatives, with expected inhibitory activity against both Acetylcholinesterase and ß-secretase. OBJECTIVES: The aim of this work is obtaining new peptide derivatives of galanthamine with decreased toxicity compared to galanthamine. METHODS: Syntheses were conducted in solution using fragment condensation approach. The new derivatives were characterized by melting points, angle of optical rotation, NMR and Mass spectra. Acute toxicity was determined on mice, according to a Standard protocol. All new compounds were tested in vitro for cytotoxic activity in a panel of human (HEP-G2, BV-173) and murine (Neuro-2a) tumor cell lines via a standard MTT-based colorimetric method. RESULTS: New derivatives of galanthamine containing shortened analogues of ß-secretase inhibitor (Boc- Asn-Leu-Ala-Val-OH) and either nicotinic or isonicotinic residue, both connected with a linker (L-Asp) to position 11 of galanthamine were obtained. In vivo toxicity of some new compounds was found up to 1000 mg/kg. Cell toxicity screening against the tumor cell lines showed negligible growth-inhibiting properties of the galanthamine derivatives. CONCLUSION: Synthesis of new galanthamine derivatives comprising peptide moiety and nicotinic acid or isonicotinic acid is reported. Acute toxicity studies reveal they are about 100 times less toxic than galanthamine. This effect is due to the peptide fragment. Cytotoxicity studies show good correlation with low toxicity results. These results are encouraging for the application of this class compounds as medicines.

Antidepressant Effect and Recognition Memory Improvement of Two Novel Plant Extract Combinations - Antistress I and Anti-stress II on Rats Subjected to a Model of Mild Chronic Stress.

BACKGROUND: Chronic stress is one of the main factors which lead to depression - a psychiatric disorder affecting millions of people and predicted to be the second ranked cause of premature death in 2020. Depression is often associated with cognitive disturbances and memory deficit. Plant based therapy could be effective in the treatment of mild to moderate depression due to its low level of adverse reaction, its good tolerability and compliance. MATERIALS AND METHODS: 72 male Wistar rats, divided in 9 groups were given orally for 8 weeks two combinations of dry plant extracts - Antistress I and Antistress II and five individual dry extracts obtained from Serratula coronata, Hypericum perforatum, Valeriana officinalis, Crataegus monogyna and Melissa officinalis. The animals were exposed to a chronic unpredictable mild stress for 8 weeks. The depression-like symptoms were evaluated with Forced swim test while the assessment of the memory deficit was performed with Novel object recognition test. RESULTS: Antistress II demonstrates antidepressant effect while Antistress I doesn't improve the depressive-like symptoms. The individual extracts of Hypericum perforatum and Valeriana officinalis also possess antidepressant properties. Antistress II improves the cognition as well as the individual extracts of Hypericum perforatum, Valeriana officinalis and especially Serratula coronata. Dry extract from Serratula tend to have the best effect regarding the recognition memory. The effect of Antistress I on memory deficit is negligible. CONCLUSIONS: Antistress II possesses antidepressant effect and improves the recognition memory while Antistress I doesn't demonstrate any of the above-described effects.

25 Hydroxyvitamin D and Cytokines in Multiple Sclerosis.

INTRODUCTION: Clinical trials of patients with multiple sclerosis (MS) have produced inconsistent results for the profile of cytokine secretion in serum and cerebrospinal fluid in patients with multiple sclerosis during periods of relapse and remission. Epidemiological and clinical observations data reveal an association of the changes in vitamin D serum concentration with the risk of developing MS. AIM: To evaluate changes in serum concentrations of 25(OH)D, IL17, IFN-gamma, TGFß1, IL4, IL10 in relapse and remission and their correlation with the severity of disability. PATIENTS AND METHODS: Fifty-three persons (30 clinically healthy controls and 23 patients with relapsing-remitting multiple sclerosis) living between 41° and 42° northern latitude were registered during the astronomical winter period (October 2012- May 2013). -Patients were diagnosed according to Mc Donald 2010 criteria. The degree of neurological deficit was assessed by EDSS. Serum concentrations of 25(OH)D (nmol/l) and cytokines (pg/ml) were tested by ELISA - once for controls and twice for patients (during relapse and remission). RESULTS: In the studied population average levels of 25(OH)D were close to insufficiency, most pronounced in patients in relapse, as differences were not statistically significant. A reverse correlation was found between the levels of 25(OH)D and the deficit in relapse and remission. Concentrations of TGFß1 significantly increased in remission compared with exacerbation and controls. Serum level of IL4 was significantly lower in relapse compared with controls. In remission there was a marked tendency of increase compared with exacerbation. During clinical improvement IL17 and IFN-gamma tended to decrease compared to the average levels in relapse. In both periods, the average concentrations of IFN-gamma in patients were significantly lower compared with controls. No statistically significant differences were found comparing cytokine changes with those of 25(OH)D and deficit. CONCLUSION: Persistent cytokine imbalance in patients compared with controls is a marker for Th1-mediated CNS demyelination. Anti-inflammatory TGFß1, IL4 are indicators of immune response intensity. The deficit severity does not depend on changes of the tested cytokines, but correlates with 25(OH)D levels during periods of relapse and remission.

Cytokines and disability in interferon-ß-1b treated and untreated women with multiple sclerosis.

BACKGROUND AND AIMS: T-helper (Th) cells involved in the pathogenesis of multiple sclerosis (MS) represent a functionally heterogeneous population defined by their cytokine secretion profile. The effects of immunotherapeutic drugs on the cytokine network are still not fully clarified. This study aimed to investigate serum levels of IFN-γ, TNF-α, IL-4, IL-10 in interferon-ß-1b-treated and untreated women with relapsing-remitting MS (RRMS) in comparison with healthy controls and the relationship between cytokine concentrations and the degree of disability. METHODS: The study included 35 women with RRMS and 35 age-matched healthy controls. The patients were divided in two groups: Group A-without disease modifying treatment; Group B-treated with interferon-ß-1b. Degree of disability was assessed by the Expanded Disability Status Scale (EDSS). Serum cytokine concentrations were measured by ELISA during relapse and remission. RESULTS: Group A showed higher IFN-γ in remission (p = 0.0239) than the controls; Group B had lower IFN-γ during relapse (p = 0.0226) than controls. EDSS in relapse correlated with the levels of IL-10 for Group A (p = 0.015) and with the concentration of IFN-γ for Group B (p = 0.039). Nontreated patients showed higher EDSS in relapse compared to the interferon-ß-1b-treated group (p = 0.005). CONCLUSIONS: We found an imbalance in the patients' cytokine profile, which may be seen as supportive of the hypothesis that demyelination in the central nervous system is mediated by Th1 lymphocytes. IFN-γ is probably one of the important indicators for intensity of the immune reaction and shows promise as a potential biomarker for the therapeutic effect of interferon-ß-1b. The role of IL-10 in the autoimmune process needs further investigation.

Experimental study on the role of 5-HT2 serotonin receptors in the mechanism of anti-inflammatory and antihyperalgesic action of antidepressant fluoxetine.

INTRODUCTION: Fluoxetine is an antidepressant that has anti-inflammatory and antihyperalgesic effects in experimental models of pain and inflammation. The AIM of the present study was to determine the role of 5-HT2 receptors in the mechanism of anti-inflammatory and antihyperalgesic action of fluoxetine after single and repeated administration of the drug. MATERIALS AND METHODS: 40 male Wistar rats were randomly divided in five groups (n = 8) treated for 14 days with saline (control), diclofenac (positive control), fluoxetine, cyproheptadine (5-HT2 antagonist), and fluoxetine + cyproheptadine, respectively. We used the experimental model of inflammation induced by intraplantar injection of carrageenan and nociceptive test with mechanical pressure on the inflamed hind paw. RESULTS: Single and repeated administration of fluoxetine showed that it had significant anti-inflammatory and antihyperalgesic effects when compared with the control (p < 0.05). Cyproheptadine did not change significantly the anti-inflammatory effect of fluoxetine in the first 4 hours, after a single administration. At 24 hours the combination did not differ statistically when compared with the control. Cyproheptadin did not change significantly the anti-inflammatory effect of fluoxetine after repeated administration. After prolonged treatment the group that received fluoxetine + cyproheptadine showed a statistically significant increase in paw pressure to withdraw the hind paw compared with that treated with fluoxetine alone (p < 0.05). CONCLUSIONS: Fluoxetine has anti-inflammatory and antihyperalgesic effects in the carrageenan model of inflammation. 5-HT2 receptor mediated its anti-inflammatory effect in single dose treated animals. Spinal 5-HT2 receptors are involved in the antihyperalgesic effect of fluoxetine after repeated administration.

Study on anti-inflammatory and immunomodulatory effects of clomipramine in carrageenan- and lipopolysaccharide-induced rat models of inflammation.

The aim of the present study was to evaluate the anti-inflammatory effect of clomipramine in carrageenan- and lipopolysaccharide-induced (LPS-induced) models of inflammation by investigating the changes in serum levels of the pro-inflammatory cytokine TNF-α and the anti-inflammatory cytokines IL-10 and TGF-ß after single and repeated administration of the drug. In order to study the effect of single and repeated doses of clomipramine on carrageenan-induced paw oedema, male Wistar rats were divided in five groups (n = 8): control, positive control group and three experimental groups treated with 5, 10 and 20 mg/kg bw clomipramine, respectively. The effect of single and repeated doses of clomipramine on serum cytokine levels was studied as animals were divided in four groups: two control groups treated with saline and two experimental groups treated with clomipramine 20 mg/kg bw. Carrageenan and LPS were injected immediately after clomipramine or saline injection. Serum cytokine concentrations were tested by enzyme immunoassay. Following acute administration only the highest dose that was used inhibited the carrageenan-induced inflammation. Oedema inhibition was observed with 5, 10 and 20 mg/kg bw clomipramine after repeated administration. Single and repeated administration of clomipramine at a dose of 20 mg/kg bw did not significantly change the serum levels of TGF-1ß, IL-10 and TNF-α when compared to the controls in carrageenan-induced inflammation. Following LPS-induced inflammation clomipramine significantly increased the serum levels of TGF-1ß after repeated administration and decreased TNF-α in rats after single-dose and repeated pretreatment with 20 mg/kg bw clomipramine. A significant increase in the levels of IL-10 in relation to this inflammatory model was observed only in single dose treated animals. Clomipramine possesses an anti-inflammatory effect in the carrageenan-induced model of exudative inflammation. In LPS-induced inflammation, clomipramine showed an immunomodulatory effect, decreasing TNF-α and increasing TGF-1ß after repeated administration, and increasing IL-10 after a single dose.

Vitamin D immunomodulatory potential in multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of unknown etiology whose treatment is of limited efficiency and therefore has a high social burden. As it has been suggested that myelin destruction model, the clinical manifestation and the potential of therapeutic response in MS are correlated, it is quite justifiable that we study various factors (genetic, hormonal, environmental) that take part in the autoimmune process in order to improve the control over the disrupted immune regulation. Results from epidemiological and clinical studies clearly suggest that changes in vitamin D serum concentrations are correlated with the magnitude of the risk of developing MS, the phases of relapse and remittance and with gender differences in vitamin D metabolism. Experimental and clinical studies also have established that 25-hydroxy vitamin D (25(OH)D) and 1,25-dihydroxy vitamin D (1,25(OH)2D) exert an immunomodulatory effect in the central nervous system and peripheral organs of the immune system. The standard reference range of vitamin D concentration in serum is 50-80 nmol/l--it provides normal calcium metabolism. Issues that are discussed include the vitamin D serum concentration needed to suppress the aberrant immune response in MS patients; a subgroup of MS patients suitable for vitamin D treatment, the vitamin D being applied in optimally effective and safe dosage. MS prevalence rate in Bulgaria has increased two-fold in 17 years but this is a rather short interval to be able to assume that the gene pool of the population changes. Thus further studies on possible interactions between different environmental factors and these factors' role in the disease pathogenesis are justified and necessary.

Effect of atorvastatin and rosuvastatin on learning and memory in rats with diazepam-induced amnesia.

UNLABELLED: During the past decade, evidence has emerged that statins have neuroprotective effects. AIM: The aim of this study was to investigate the effects of atorvastatin and rosuvastatin on learning and memory in rats with diazepam-induced amnesia. MATERIAL AND METHODS: Experiments were carried out on 48 white male Wistar rats, divided into 6 groups, each of 8 rats. The experimental animals were treated per os for 14 days with atorvastatin and rosuvastatin in doses of 10 mg/kg and 20 mg/kg body weight, respectively. To induce amnesia diazepam was administered intraperitoneally in a dose of 2.5 mg/kg bw. Cognitive skills of the animals were examined after the induction of amnesia with active avoidance test using autonomic reflex conditioner (shuttle box) and passive avoidance tests (step-through and step down) (Ugo Basile, Italy). The following parameters were assessed: number of conditioned responses (avoidances), number of unconditioned responses (escapes) and number of intertrial crossings in the active avoidance test; latency of reactions was measured in the passive avoidance tests. RESULTS: We found a significant increase of conditioned responses in atorvastatin treated animals (in a dose of 10 mg/kg bw) in active avoidance training. In the animals treated with rosuvastatin in both doses there was a statistically significant increase of unconditioned responses. In the step-through passive avoidance test there was significant improvement of short-term and long-term memory following administration of atorvastatin (10 mg/kg bw). Rosuvastatin (10 mg/kg bw) preserves long-term memory. In the step-down passive avoidance test, atorvastatin (10 mg/kg bw) and rosuvastatin (10 mg/kg bw and 20 mg/kg bw) preserve long-term memory. CONCLUSIONS: Atorvastatin (10 mg/kg bw) and rosuvastatin (10 mg/kg and 20 mg/kg bw) improve cognitive functions in rats with diazepam-induced amnesia and preserve long-term memory.

Effect of testosterone propionate on erythropoiesis after experimental orchiectomy.

INTRODUCTION: Androgen deficiency anemia occurs most frequently in pharmacogenic suppression of androgen synthesis or with advancing age in men. Bilateral orchiectomy is a surgical modality used in the treatment of metastatic prostate carcinoma. It is accompanied by marked decrease in circulating serum levels of androgens. AIM: The aim of the experimental study was to determine the effect of substitution therapy with testosterone propionate (TP) on some haematological parameters of erythropoiesis in male rats after orchiectomy. MATERIAL AND METHODS: Eighty Wistar male rats with mean weight of 252.3 g were used in the study. The animals were allocated into 2 control orchidectomized groups, 2 sham-operated groups and 4 experimental orchidectomized groups. Testosterone propionate was administered intramuscularly, once a week at a dose of 4 mg and 8 mg per kilogram of body weight for 15 days and for 15 weeks. Erythrocyte count was performed and hemoglobin and hematocrit levels were measured. RESULTS: In the chronic experiment there was a significant decrease in red blood cells and hemoglobin, and a tendency of decrease in hematocrit after orchiectomy. The effect of TP on erythropoiesis in orchiectomised rats is dose-dependent. CONCLUSION: TP replacement therapy in doses of 4 mg/kg and 8 mg/kg has a stimulating effect on erythropoiesis only in chronic administration.