Effects of the Novel High-affinity 5-HT(1B/1D)-receptor Ligand Frovatriptan on the Rat Carotid Artery.

BACKGROUND: In blood vessels 5-HT stimulates sympathetic nerves, the endothelium and vascular smooth muscle cells. Triptans are specific anti-migraine drugs and they activate the serotoninergic 5HT1b/d receptors causing vasoconstriction of the cerebral vessels. AIM: To evaluate the effect of frovatriptan on isolated rat carotid artery. METHODS: Contractile activity of the preparations was registered isometrically. Krebs solution (pH = 7.4) was used for washing smooth muscle (SM) preparations aerated with 95% O2 and 5% CO2 at 37°C. The 60-minute adaptation of tone level of preparations was taken as a starting tone and the changes such as contraction or relaxation were calculated using it. RESULTS: Frovatriptan (1×10-6 mol/l - 1×10-5 mol/l) induced a contraction, but at higher concentrations it caused relaxation of the carotid artery. The L-norepinephrine contractile reaction was enhanced in the presence of frovatriptan. In the presence of 5-HT2 receptor antagonist, methysergide, frovatriptan increased the relaxation. In the presence of the specific α-1 receptor antagonist, prazosin, the frovatriptan-induced relaxation decreased. CONCLUSION: The observed contractile effect of frovatriptan is probably associated with the main effect of the drug - activation of the serotoninergic 5HT1B /1D receptors causing vasoconstriction of the cerebral vessels and their anti-migraine effect. At higher concentrations, frovatriptan, most likely via some non-specific mechanism, could activate the following intracellular chain reaction: stimulation of α1D could activate eNOS which may increase in the concentration of NO which results in the final effect of relaxation.

Cognitive Impairment in Schizophrenia, Neurotransmitters and the New Atypical Antipsychotic Aripiprazole.

Cognition is a group of mental processes that includes the capacity to perceive, think, learn and to study, and the capacity of the brain to analyze information and program adaptive behaviour. Although there has been an appreciable evolution in the therapy of psychoses in the last twenty-five years, cognitive disturbances still persist in spite of antipsychotic treatment. The cognitive decay disrupts the ability of clinically diagnosed patients with psychoses, mainly schizophrenia, to learn and to memorize skills that are useful for their family and social relationships. Moreover, cognitive deficiency is often considered to be crucial for further rehabilitation. In atypical antipsychotics there are big differences in the effects on cognitive functions. Some clinical studies demonstrate the benefits of a third generation of antipsychotics on cognitive functions in patients treated for mental illnesses. In the present study we have reviewed many articles investigating the influence of aripiprazole on cognition in human and animal subjects. Aripiprazole is a third generation antipsychotic drug that possesses a unique pharmacodynamic profile, which in conjunction with recently published scientific data on the drugs' influence on antidepressant, anxiolytic and cognitive functions, suggests a highly positive future potential for restorative cognitive treatment and ongoing healthy function. The data included in the review will contribute to determining the potential benefits of aripiprazole on memory and training processes.

Rac1b increases with progressive tau pathology within cholinergic nucleus basalis neurons in Alzheimer's disease.

Cholinergic basal forebrain (CBF) nucleus basalis (NB) neurons display neurofibrillary tangles (NFTs) during Alzheimer's disease (AD) progression, yet the mechanisms underlying this selective vulnerability are currently unclear. Rac1, a member of the Rho family of GTPases, may interact with the proapoptotic pan-neurotrophin receptor p75(NTR) to induce neuronal cytoskeletal abnormalities in AD NB neurons. Herein, we examined the expression of Rac1b, a constitutively active splice variant of Rac1, in NB cholinergic neurons during AD progression. CBF tissues harvested from people who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment, or AD were immunolabeled for both p75(NTR) and Rac1b. Rac1b appeared as cytoplasmic diffuse granules, loosely aggregated filaments, or compact spheres in p75(NTR)-positive NB neurons. Although Rac1b colocalized with tau cytoskeletal markers, the percentage of p75(NTR)-immunoreactive neurons expressing Rac1b was significantly increased only in AD compared with both mild cognitive impairment and NCI. Furthermore, single-cell gene expression profiling with custom-designed microarrays showed down-regulation of caveolin 2, GNB4, and lipase A in AD Rac1b-positive/p75(NTR)-labeled NB neurons compared with Rac1b-negative/p75(NTR)-positive perikarya in NCI. These proteins are involved in Rac1 pathway/cell cycle progression and lipid metabolism. These data suggest that Rac1b expression acts as a modulator or transducer of various signaling pathways that lead to NFT formation and membrane dysfunction in a subgroup of CBF NB neurons in AD.

Antinociceptive and anti-inflammatory effects of Rhodiola rosea L. extract in rats.

BACKGROUND: Rhodiola rosea (golden root) is a unique phytoadaptagen with immunomodulatory, antioxidant, anti-inflammatory and antinociceptive activity. AIM: The aim of this study was to evaluate the antinociceptive and anti-inflammatory effects of the alcohol/water extract of Rhodiola rosea roots in rats. MATERIALS AND METHODS: Thirty male Wistar rats were used in the study. They were divided in 3 groups (n = 10), treated respectively with saline (controls), Rhodiola rosea extract 50 mg/kg bw and 100 mg/kg bw orally. The antinociceptive effect was evaluated using the hot-plate test, Randall-Sellito test and the formalin test. The hot-plate test evaluates the reaction time of rats which are dropped on a heated surface. The analgesy-meter test exerts a force increased at constant rate. In the formalin test we measured the total time spent in licking the injected paw during the early (0-10 min) and late phase (20-30 min) of test. To study anti-inflammatory effect the carrageenan-induced paw edema was used. The paw volume was measured plethysmometrically at 2, 3 and 4 hours. RESULTS: In the hot-plate test Rhodiola rosea increased in both doses the latency reaction compared with that in the controls. In analgesy-meter test Rhodiola rosea in a dose of 50 mg/kg showed a significant increase of pressure reaction compared with the controls. In the formalin test Rhodiola rosea in a dose of 100 mg/kg significantly decreased the paw licking time during the first phase. In the plethysmometer test Rhodiola rosea extract significantly reduced carrageenan-induced paw edema when compared with the saline-induced edema. CONCLUSION: The studied extract of Rhodiola rosea exhibited significant analgesic activity in all the pain models used--inhibition of thermal pain, mechanical hyperalgesia and formalin-induced pain behavior. Significant anti-inflammatory activity was observed from Rhodiola rosea extract in carrageenan induced paw edema in rats.

Effects of ketamine on memory and nociception in rats.

BACKGROUND: Ketamine is intravenous anaesthetic with NMDA-glutamate receptors mechanism of action. MATERIAL AND METHODS: Male Wistar rats were treated with saline (group A) or 10, 15 or 20 mg/kg of ketamine (groups B, C and D, respectively). For active avoidance test an automatic reflex conditioner was used. The observed variables were number of avoidances, escapes and intertrial crossings. Step-through and step-down passive avoidance tests were done with learning and memory retention test. Criteria for step-through test were latency of reactions of 180 sec in the light chamber. Criteria for step-down test were latency of reaction of 60 sec on the platform. The hot-plate test evaluates the reaction time of the rats dropped on a heated surface. The analgesy-meter test exerts a force increased at constant rate. RESULTS: In active avoidance test the controls increased the number of avoidances during learning and memory tests. Ketamine in all doses used increased the number of avoidances during learning and in memory test. Controls did not change the number of escapes, but the ketamine treated animals decreased it. The number of intertrial crossings was not changed by controls or ketamine-treated rats during learning and memory tests. In passive avoidance tests the controls and ketamine-treated rats increased the latency time during learning and memory retention tests. In hot-plate analgesic test and in analgesy-meter test the controls and ketamine-treated rats did not change the latency of reaction. CONCLUSION: The results suggest that ketamine improves learning and memory processes and has no analgesic effect in the doses applied.

A study of the effects of lamotrigine on mice using two convulsive tests.

UNLABELLED: The AIM was to study the effects of lamotrigine on bicuculline and pentylenetetrazol models of epilepsy. MATERIAL AND METHODS: Mice divided in 8 groups (n = 6) were pretreated intraperitoneally 30 min before pentylenetetrazol (50 mg/kg) or bicuculline (1 mg/kg) with saline 0.1 ml/10 g body weight or lamotrigine 10 mg/kg, 15 mg/kg or 20 mg/kg, respectively. The seizure intensity and latency to the seizures 60 min after bicuculline or pentylenetetrazol injection were observed. The following scale for seizure intensity was used: 1 - excitation; 2 - body tremor; 3 - clonic seizures of forelimbs; 4 - heavy clonic seizures with rotations; 5 - tonic seizures of forelimbs; 6 - tonic seizures of limbs. RESULTS: The controls showed bicuculline-induced seizure intensity up to 5. Lamotrigine in the higher doses used decreased the seizure intensity (p <0.05). Lamotrigine in all doses studied did not change the latency period of the first bicuculline seizure compared with the control. Controls treated with pentylenetetrazol showed seizure intensity up to 4. Lamotrigine in the highest dose decreased the pentylenetetrazol-induced seizure intensity (p < 0.05). Lamotrigine in all studied doses increased the latency to the first pentylenetetrazol-induced seizure compared with the controls (p < 0.05). Both convulsing drugs influence the brain GABA-ergic transmitter system by competitively blocking GABAA receptors. Lamotrigine inhibits glutamate transmission and sodium channels. Both neurotransmissions - glutamate and GABA are closely related in seizure control. The CONCLUSION is that lamotrigine has an anticonvulsive effect on both bicuculline and pentylenetetrazol seizure models, suppressing seizure intensity and influencing the latency to the first seizure.

Adverse drug reactions and reactive oxygen species.

Adverse drug reactions represent a major source of morbidity in hospitalized- and outpatients. Adverse drug reactions may affect the function of any organ or system. Due to their clinical nonspecificity adverse drug reactions are often difficult to be recognized. The clinical manifestation, the type and severity of adverse drug reactions vary a great deal depending on patient- and drug-related factors. In recent years growing evidence has emerged implicating involvement of free radicals and reactive oxygen species in chronic degenerative diseases and in acute conditions, such as stroke and infection. The review focuses on the role of reactive oxygen species in the pathogenesis of drug-induced disease with special reference to hepatotoxicity, nephrotoxicity and allergic disease. The participation of reactive oxygen species in the development of adverse drug reactions induced by special drug classes (non-steroidal anti-inflammatory drugs, anti-infective agents, cytostatics) is described. Results from studies on animals and humans reveal the putative implication of oxidative stress in drug-induced disease states.

Beneficial effect of commercial Rhodiola extract in rats with scopolamine-induced memory impairment on active avoidance.

Rhodiola rosea L., family Crassulaceae also known as Golden Root or Arctic root is one of the most widely used medicinal plants with effect on cognitive dysfunction, psychological stress and depression. The aim of the study was to examine the effect of a standardized commercial Rhodiola extract on learning and memory processes in naive rats as well as its effects in rats with scopolamine-induced memory impairment. MATERIALS AND METHODS: Sixty male Wistar rats were used in the study. The experiment was conducted in two series - on naive rats and on rats with scopolamine-induced model of impaired memory. The active avoidance test was performed in an automatic conventional shuttle box set-up. The criteria used were the number of conditional stimuli (avoidances), the number of unconditioned stimuli (escapes) as well as the number of intertrial crossings. RESULTS: The chemical fingerprinting of the standardized commercial Rhodiola extract was performed by means of nuclear magnetic resonance (NMR). Naive rats treated with standardized Rhodiola extract increased the number of avoidances during the learning session and memory retention test compared to the controls. Rats with scopolamine-induced memory impairment treated with Rhodiola extract showed an increase in the number of avoidances during the learning session and on the memory tests compared to the scopolamine group. The other two parameters were not changed in rats treated with the extract of Rhodiola in the two series. CONCLUSION: It was found that the studied Rhodiola extract exerts a beneficial effect on learning and memory processes in naive rats and rats with scopolamine-induced memory impairment. The observed effect is probably due to multiple underlying mechanisms including its modulating effect on acetylcholine levels in the brain and MAO-inhibitory activity leading to stimulation of the monoamines' neurotransmission. In addition the pronounced stress-protective properties of Rhodiola rosea L. could also play a role in the improvement of cognitive functions.

In vivo and in vitro study of the influence of the anticholinesterase drug galantamine on motor and evacuative functions of rat gastrointestinal tract.

Galantamine is efficacious for vascular dementia and Alzheimer's disease. Its application leads to some negative gastrointestinal side effects. The present study observes galantamine-induced influence on gastrointestinal motility of rats and its effects on isolated gastrointestinal smooth muscles. The gastrointestinal tract was studied by X-ray contrast examination. Functional disturbances were observed: hypertonia, increased stomach and ileal peristalsis activity, accelerated intestinal passage. In vitro, the drug caused tonic contractions in smooth muscle preparations and increased the gastric and ileal phasic amplitude. The jejunal smooth muscle strips demonstrated an opposite tendency. The reactions were a result of the interaction of galantamine-accumulated endogenic acetycholine with M- and N-acetylcholine receptors. The tonic effects were influenced in varying degree by atropine and ipratropium, whereas the phasic by atropine, ipratropium, hexametonium and methysergide. In conclusion, the in vitro effects registered satisfactorily explain in vivo examined galantamine-induced changes in the gastrointestinal tract of the treated rats and can be considered as main cause for development of such changes.

Calcium-independent tacrine-induced relaxation of rat gastric corpus smooth muscles.

Tacrine, a non-competitive reversible acetylcholinesterase and butyrylcholineserase inhibitor, caused a concentration-dependent tonic contraction of gastric smooth muscle preparations in the concentration range 1 x 10(-7) mol/L - 1 x 10(-5) mol/L, whereas concentrations higher than 2 x 10(-5) mol/L induced a biphasic effect; a short-time contraction was followed by a prolonged relaxation. To shed some light on the mechanism underlying this untypical relaxation, the amplitude of mechanical reactions caused by tacrine were compared with those of tacrine in the presence of atropine, ipratropium, metrifonate, TTX, nifedipine, D-600, caffeine, apamin, and charybdotoxin. The results obtained revealed that the relaxation was neither cholinergic in nature, nor mediated by the influence of the drug on intramural neuronal structures. It was not influenced by processes inducing changes in cytosolic Ca2+ levels. This assumption was confirmed by experiments with permeabilized muscle preparations that were pre-contracted in a solution with pCa 5.5. Tacrine relaxed the smooth muscles in spite of the constant intracellular Ca2+ concentration resulting from the permeabilization. These findings argue that tacrine at concentrations higher than 2 x 10(-5) mol/L has a desensitizing effect on the contractile apparatus of gastric corpus smooth muscle preparations towards Ca2+.