Catechol-o-methyltransferase inhibitor tolcapone improves learning and memory in naïve but not in haloperidol challenged rats

Objective(s): Dopamine plays an important role in cognitive functions. Inhibition of the dopamine-degrading enzyme catechol-O-methyltransferase (COMT) may have beneficial effects. Our aim was to assess the effect of COMT inhibitor tolcapone (TCP) on learning and memory in naïve and haloperidol-challenged rats.Materials and Methods: Male Wistar rats were divided into 9 groups (n=8):  naïve-saline, tolcapone 5; 15 and 30 mg/kg BW; haloperidol (HP) challenged-saline, haloperidol, haloperidol+tolcapone 5; 15 and 30 mg/kg BW. Two-way active avoidance test (TWAA), elevated T-maze, and activity cage were performed. Observed parameters were: number of conditioned responses (CR) and unconditioned responses (UCR), working memory index, and vertical and horizontal movements. Results: Naïve rats with 30 mg/kg BW TCP had a significantly increased number of CR  and  UCR during the long-term memory test. The animals with 5 mg/kg BW TCP significantly increased the number of UCR during the two retention tests. In haloperidol-challenged rats, the three experimental groups decreased the number of CR and UCR during the learning session and the two memory tests, compared to the saline group.  There was no significant difference between the HP-challenged rats treated with TCP and the haloperidol control group. All experimental naïve groups had significantly increased working memory index whereas none of the HP-challenged groups showed significant increase in this parameter. Conclusion: Our results demonstrate that in naïve rats tolcapone improves memory in the hippocampal-dependent TWAA task and spatial working memory in T-maze

Vitamin D3 exerts immunomodulatory and memory improving properties in rats with lipopolysaccharide-induced inflammation

Introduction: Vitamin D is a fat-soluble secosteroid, its primary function being regulation of calcium-phosphate homeostasis and maintenance of bone integrity and mineralization. Recently, pleotropic effects of this vitamin have been recognized, including an immunomodulatory role and involvement in normal brain development and functioning. Aim: The aim of the present study was to investigate the influence of cholecalciferol on serum inflammatory markers and memory functions in lipopolysaccharide (LPS) model of inflammation. Materials and methods: Male Wistar rats were randomly divided into 4 groups (n=8): control group, LPS control group, LPS + cholecalciferol (vitamin D3) 500 UI group, and 1000 IU/kg bw group. Step-down passive avoidance test, novel object recognition test (NORT), Y- and T-maze were performed to assess the memory functions. Latency, recognition index (RI), % spontaneous alteration (SA), and working memory index were registered. Tumor necrosis factor-alpha (TNF-α), IL-1β, transforming growth factor-β1 (TGF-β1), and brain derived neurotrophic factor (BDNF) serum levels were measured by ELISA. Results: LPS administration caused significant impairment in memory functions in all memory tasks. Cholecalciferol treatment caused significant increase in % SA, RI, and working memory index. In the step-down passive avoidance test, cholecalciferol-treated groups showed statistically significant increase in latency in the long-term memory test. Vitamin D3-treated rats showed decreased TNF-α and IL-1β serum levels whereas the concentration of TGF-β1 and BDNF increased. Conclusions: Cholecalciferol improves spatial working and episodic memory, which can at least partially be explained with its effect on systemic inflammatory response that is closely related with the development of neuroinflammation

Cannabidiol improves memory and decreases IL-1β 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. Materials and methods: Male Wistar rats were randomly divided into 4 groups: control, LPS control, LPS + CBD 5 mg/kg bw, and LPS + CBD 10 mg/kg bw. Animals were treated with CBD 14 days before LPS administration and throughout the experiment. Step-through passive avoidance task, Y-maze, and novel object recognition test (NORT) were used to assess the memory functions. The following parameters were recorded: latency time, spontaneous alternations percentage (SA%) and recognition index (RI). IL-10, IL-6, TNF-α, and IL-1β serum levels were measured to evaluate the immunomodulatory properties of CBD. Results: LPS led to significant decrease of the recorded parameters in all memory tasks. This demonstrated the memory-impairing effect of LPS-induced inflammation. In the Y-maze and NORT tests, both doses of CBD increased SA% and RI, respectively. Significant difference was found in comparison with the LPS controls. Rats from the CBD treated groups showed increased latency in the step-through passive avoidance task. In the short-term memory test, both CBD doses significantly increased this parameter when compared with both control groups (p<0.05 and p<0.001, respectively), whereas in the long-term memory test, statistical significance was reached only in comparison with the LPS controls (p<0.01). CBD treatment failed to reduce TNF-α and IL-6 serum levels. The lower studied dose significantly decreased IL-10 and IL-1β concentrations compared to LPS controls (p<0.01 and p<0.05, respectively). Conclusions: CBD improved spatial working and recognition memory in rats with LPS-induced inflammation. Suppression of IL-1β production could be attributed to the observed effect

Pramipexole and tolcapone alleviate thermal and mechanical nociception in naive rats.

Introduction: Parkinson’s disease (PD) is а neurodegenerative disorder characterized mainly by its motor symptoms. The non-motor symptoms including pain are increasingly recognized in the last few decades. Existing evidence suggests that the dopaminergic neurotransmission has an essential role in pain control.Aim: The aim of the present study was to investigate the antinociceptive effect of dopaminergic drugs pramipexole and tolcapone against chemical and thermal stimuli in naive rats.Materials and methods: Male Wistar rats divided into 8 groups (n=8): saline; diclofenac 25 mg/kg body weight (bw) (positive control); pramipexole 0.5; 1 and 3 mg/kg bw; tolacapone 5; 15 and 30 mg/kg bw. Paw pressure and plantar tests were performed. Paw withdrawal pressure and latent time were measured. Statistical analysis was done by SPSS 19.Results: In the paw pressure test, pramipexole, in a dose of 1 and 3 mg/kg bw and tolcapone in a dose of 30 mg/kg bw, increased significantly the latency at 1, 2, and 3 hours compared to saline (p<0.05). In the plantar test, only the highest dose of pramipexole reached significance at 3 hours compared to the control rats (p<0.05). In contrast to pramipexole the three experimental groups with tolcapone markedly increased the latent time at 1 and 3 hours compared to saline (p<0.05).Conclusions: Pramipexole and tolcapone reduce mechanical and thermal nociception in naïve rats by enhancing dopaminergic neurotransmission at both spinal and supraspinal levels. In addition, tolcapone stimulates noradrenergic mediation which may contribute to its antinociceptive effect

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

An experimental study on phytochemical composition and memory enhancing effect of Ginkgo biloba seed extract

Introduction: The Ginkgo biloba L. tree is considered as one of the oldest species on Earth. It is known as a “living fossil” dating back approximately 200 million years. Both the leaves and seeds of this tree have been used for millennia in traditional Chinese medicine.Aim: To study the phytochemical profile of Gingko biloba seed extract (GBSE) and its memory enhancing effects.Materials and methods: Liquid chromatography with mass detection (LC-MS) was performed for phytochemical analyses of the extracts. For the in vivo experiments, male Wistar rats were divided randomly into 5 groups (n=8): saline; piracetam;  GBSE 50; 100, and 200 mg/kg b.w. Y-maze, T-maze, step-down passive avoidance and novel object recognition test (NORT) were performed. The observed parameters were: percentage of spontaneous alternations (% SA), working memory index, latency of reaction and recognition index, respectively. Statistical analysis was done using SPSS 19.Results: LC-MS analysis showed the presence of the flavonoids quercetin, kaempferol and isorhamnetin (as aglycones), the ginkgolides A, B, C, J, and bilobalide. In Y-maze task, the groups treated with 50 and 100 mg/kg of GBSE significantly increased the % SA during the memory test compared to saline (p<0.05). In T-maze test, the three experimental groups with GBSE significantly increased the working memory index in comparison with that of the control group (p<0.05). In step-down test, the animals receiving 100 mg/kg b.w. GBSE, notably increased the latency during both retention tests (p<0.05 and p<0.01, respectively). In NORT, only the animals with the middle dose of GBSE ameliorated the recognition index when compared to saline (p<0.05).Conclusions: GBSE enhances spatial working memory, recognition memory, and short- and long-term recall in naïve rats due to the synergic effects of detected flavonoids and terpene lactones on brain functions. The brain structures involved are probably the hippocampus and prefrontal cortex

Simulated microgravity affects carrageenan-induced inflammation process in rats

Weightlessness significantly impacts physiological systems. In the current study, we investigate the effects of 7 days exposure of rats to simulated microgravity (using a modified rat-modeled random positioning machine, working with four experimental animals simultaneously) on local carrageenan-induced inflammation and serum levels of liver enzymes, metabolites (glucose, urea, creatinine), and metabolic hormones (thyroid-stimulating hormone – TSH, aldosterone, cortisol). Male Wistar rats (n=12, m=200 ± 20 g) were evenly divided into RPM (experimental) and RPM-K (control) groups. The RPM rats showed a notable mass decrease compared to the controls. A significant increase in the carrageenan-induced inflammatory response was reached on the 24th hour in the RPM group compared to the RPM-K. Simulated microgravity resulted in lower serum glucose, creatinine, cortisol, and elevated urea levels. In conclusion, 7 days of exposure to random positioning machine-simulated microgravity promotes a pro-inflammatory state, potentially affecting insulin sensitivity, glucose utilization, and muscle catabolism

Immunomodulatory properties of cholecalciferol in rats with experimentally induced inflammation

The study aimed to investigate anti-inflammatory and immunomodulatory effects of cholecalciferol (vitamin D3) in rats with complete Freund’s adjuvant-induced arthritis (AIA) and lipopolysaccharide (LPS)-induced inflammation. In the first experiment, rats were treated with cholecalciferol 14 days before or from the day of induction of arthritis. In the second set-up, animals received cholecalciferol for 14 days which was followed by LPS injection. TNF (tumour necrosis factor)-alpha, IL (interleukin)-1β, TGF (transforming growth factor)-β1 levels were measured by enzyme linked immunosorbent assay (ELISA). Cholecalciferol treatment reduced paw oedema and ankle joint diameter in AIA. Significantly lower IL-1β concentrations were found in cholecalciferol-treated arthritic rats. In LPS-challenged rats, cholecalciferol markedly lowered serum TNF-α, whereas an elevation in IL-1β concentrations was observed. Cholecalciferol slightly increased TGF-β1 serum concentration in arthritic rats and non-significantly reduced its level in LPS-challenged animals. Our findings showed that cholecalciferol exerts immunomodulatory properties which probably contribute to its anti-inflammatory effect

Study on anti-inflammatory and immunomodulatory effects of fluoxetine in rat models of inflammation

The aim of the present study was to evaluate the anti-inflammatory effect of fluoxetine in carrageenan- and lipoplysaccharide-induced models of inflammation by investigating the changes in serum levels of pro-inflammatory cytokine TNF-α and anti-inflammatory cytokines IL-10 and TGF-β after single and repeated administration of the drug. To study the effect of a single and repeated dose fluoxetine on carrageenan-induced paw edema male Wistar rats were divided into five groups (n = 8): control group; positive control group; and three experimental groups treated with 5, 10, and 20 mg/kg bodyweight (bw) fluoxetine, respectively. To study the effect of a single and repeated dose of fluoxetine on serum cytokine levels, the animals were divided in four groups (n = 8): two control groups treated with saline and two experimental groups treated with fluoxetine 20 mg/kg bw. Carrageenan and LPS were injected immediately after fluoxetine or saline injection. Serum cytokine concentrations were tested by enzyme immunoassay. In single administration only the highest dose used inhibited carrageenan-induced inflammation. Edema inhibition was seen with 10 and 20 mg/kg bw fluoxetine after repeated administration. At 24 h a statistically significant effect on inhibition of carrageenan edema was found only in rats treated with 20 mg/kg bw fluoxetine In carrageenan-induced inflammation, fluoxetine significantly increased Il-10 and decreased TNF-α after repeated administration. Surprisingly, in single-dose treated animals an increase in TNF-α values upon fluoxetine administration was observed in this model of inflammation. In LPS-induced inflammation, fluoxetine significantly decreased TNF-α after single and repeated treatment. Fluoxetine has anti-inflammatory and immunomodulatory effect in the carrageenan-induced model of exudative inflammation. In LPS-induced inflammation it showed an immunomodulatory effect manifested with a decrease in pro-inflammatory cytokine TNF-α

Experimental Study of the Analgesic Effect of the Antidepressant Escitalopram

Background: Antidepressants have been found to possess antinociceptive and analgesic properties and are prescribed in the treatment of chronic pain