Experimental and Clinical Pharmacology

Angiotensin II receptor blockers (ARBs) are one of the most frequently recommended antihypertensive drugs. Apart from their activity towards the circulatory system, ARBs also penetrate the blood-brain barrier and display neuroprotective effects. Kynurenic acid (KYNA) is an endogenous metabolite of tryptophan produced by kynurenine aminotransferase II (KAT II) in the brain. Antagonism towards all ionotropic glutamate (GLU) receptors is the main mechanism of KYNA action. An elevated brain level of KYNA is linked with memory impairment and psychotic symptoms. The aim of this study was to examine the influence of three ARBs: irbesartan, losartan, and telmisartan on KYNA production and KAT II activity in rat brain. The effect of ARBs on KYNA production was analyzed in rat brain cortical slices and on isolated KAT II enzyme. Irbesartan, losartan, and telmisartan decreased KYNA production and KAT II activity in a dose-dependent manner in rat brain cortex in vitro. Molecular docking suggest...

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Significant body of evidence suggests that abnormal kynurenic acid (KYNA) level is involved in the pathophysiology of central nervous system disorders. In the brain, KYNA is synthesized from kynurenine (KYN) by kynurenine aminotransferases (KATs), predominantly by KAT II isoenzyme. Blockage of ionotropic glutamate (GLU) receptors is a main cellular effect of KYNA. High KYNA levels have been linked with psychotic symptoms and cognitive dysfunction in animals and humans. As immunological imbalance and impaired glutamatergic neurotransmission are one of the crucial processes in neurological pathologies, we aimed to analyze the effect of anti-inflammatory agents, inhibitors of cyclooxygenase-2 (COX-2): celecoxib, niflumic acid, and parecoxib, on KYNA synthesis and KAT II activity in rat brain in vitro. The influence of COX-2 inhibitors was examined in rat brain cortical slices and on isolated KAT II enzyme. Niflumic acid and parecoxib decreased in a dose-dependent manner KYNA production and KAT II activity in rat brain cortex in vitro, whereas celecoxib was ineffective. Molecular docking results suggested that niflumic acid and parecoxib interact with an active site of KAT II. In conclusion, niflumic acid and parecoxib are dual COX-2 and KAT II inhibitors.

Glutamate (GLU) mainly through N-methyl-D-aspartate (NMDA) receptors plays pivotal role in kidney function regulation. Kynurenic acid (KYNA), a GLU receptors antagonist, is synthesized from kynurenine by kynurenine aminotransferases (KATs). Previously, it was shown that angiotensin II type 1 receptor blockers (ARBs) decrease KYNA production in rat brain in vitro. The aim of this study was to examine the influence of six ARBs: candesartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan on KYNA production on rat kidney in vitro. The effect of ARBs was determined in kidney homogenates and on isolated KAT II enzyme. Among tested ARBs, irbesartan was the most effective KYNA synthesis inhibitor with IC 50 of 14.4 μM. Similar effects were observed after losartan (IC 50 45.9 μM) and olmesartan administration (IC 50 108.1 μM), whereas candesartan (IC 50 475.3 μM), valsartan (IC 50 513.9 μM), and telmisartan (IC 50 669.5 μM) displayed lower activity in KYNA synthesis inhibition in rat kidney homogenates in vitro. On the other hand, valsartan (IC 50 27.5 μM) was identified to be the strongest KAT II inhibitor in rat kidney in vitro. Candesartan, losartan, and telmisartan suppressed KAT II activity with IC 50 equal to 83.2, 83.3, and 108.3 μM, respectively. Olmesartan and irbesartan were the weakest KAT II inhibitors with IC 50 values of 237.4 and 809.9 μM, respectively. Moreover, molecular docking suggested that studied ARBs directly bind to an active site of KAT II. In conclusion, our results indicate that ARBs decrease KYNA synthesis in rat kidney through enzymatic inhibition of KAT II, which may have impact on kidney function.

The aims of the study were to determine the effectiveness of blebbistatin (BLEB) on detrusor overactivity (DO) in an animal model induced by retinyl acetate (RA) and, because of potential urothelial permeability, to evaluate the degenerative impact of BLEB on the urothelium. Three days after RA instillation into the urinary bladder, BLEB was administered into the bladder and immediately after cystometric assessment was performed. Furthermore, Evans Blue extravasation into bladder tissue and urothelium thickness were measured. Sixty female Wistar rats were used and randomly assigned to one of four groups (n = 15 in each group): (1) control, (2) RA, (3) BLEB, and (4) RA + BLEB. RA administration induced changes in cystometric parameters reflecting DO, as previously reported. Treatment with BLEB did not significantly alter cystometric parameters in rats which did not receive RA. Administration of BLEB to rats pretreated with RA reversed changes in cystometric parameters induced by RA in basal pressure, threshold pressure, detrusor overactivity index, amplitude of nonvoiding contractions, frequency of nonvoiding contractions, voided volume, volume threshold, intercontraction interval, bladder compliance, and volume threshold to elicit nonvoiding contractions. There were no significant differences in Evans Blue extravasation into bladder tissue or urothelium thickness between the groups. The current research provides new data on the possible utility of blebbistatin in the pharmacotherapy of DO, which is an important feature of overactive bladder (OAB). Further studies in human patients with DO/ OAB are warranted to confirm these preclinical results.

Histamine type 2 receptor antagonists are one of the most commonly used agents to treat peptic ulcer disease. Since patients with epilepsy may have many comorbidities, the aim of this study was to investigate the influence of one of the strongest second generation histamine type 2 receptor antagonist, famotidine, on the exploratory and spontaneous activity in mice after 1 or 7 days treatment. Additionally, the interaction between famotidine and antiepileptics: carbamazepine, phenytoin, phenobarbital or valproate and their effect on animals activity was also evaluated. Locomotor activity was monitored electronically using a Digiscan analyzer in relation to ambulatory and rearing activities, as well as total distance travelled by animals during 15 minute periods. Results of our study indicate that famotidine administered alone did not modulate three variables of exploratory motor activity (horizontal activity, total distance and vertical activity) in mice. On the other hand, famotidin...

throughput sequencing and the results were differentially analyzed. Finally, the correlation of the target genes corresponding to differently expressed microRNAs was analyzed by GO Ontology and KEGG pathway analysis. RESULTS: At the microRNA level, high-throughput sequencing showed that the TC group had 280 microRNAs. miR-146a-5p was a uniquely up-regulated microRNA and the most significantly down-regulated microRNA was miR-150-5p among the 279 microRNAs included. There were 180 differentially expressed microRNAs in the TE group, where miR-146-5p was one of 176 upregulated microRNAs and miR-203b-5p was one of 4 downregulated microRNAs. Coincidentally, bioinformatics analysis showed that IRAK1 was a critical target gene of miR-146-5p related to the TOLL-like receptor signaling pathway. CONCLUSIONS: In contrast with the control group, there were significantly differentially expressed microRNAs in both MSCs and exosomes. Interestingly, miR-146a-5p was up-regulated in both comparative groups, and its target gene IRAK1 plays a crucial part in the TOLL-like receptor signaling pathway according to KEGG pathway analysis. These investigations demonstrate a new direction for subsequent inflammation mechanistic studies.

We found previously that intravenous kynurenic acid (KYNA), a native broad spectrum glutamate antagonist, increases renal blood flow and induces natriuresis in anesthetized spontaneously hypertensive rats (SHR). Since such changes may affect systemic circulation and can potentially find therapeutic application, in this study we examined long term influence of orally administered KYNA on systemic and renal hemodynamics and renal excretion in conscious SHR. KYNA was administered in drinking water at a dose of 25 mg/kg/day for 3 weeks. Heart rate (HR), systolic (SBP), and mean arterial pressure (MAP) were measured through telemetry. The records were taken at the beginning of the study (control, day 0), and then on day 7, 14, and 21 of treatment. Diuresis (V), total solute excretion (U osm V), and sodium excretion (U Na V) were determined on days 0, 7, and 14. KYNA consistently decreased HR, from 319 ± 8 to 291 ± 5, 299 ± 9 and 284 ± 6 beats/min on day 7, 14, and 21, respectively, (− 9, − 6, and − 11%; p < 0.01-0.0001); HR was stable in the solvent group. SBP, MAP, V, and U Na V were not affected by KYNA, whereas U osm V increased modestly. Chronic oral administration of KYNA to conscious SHR decreased HR without affecting MAP. Since tachycardia is an independent risk factor for cardiovascular disorders, and most drugs used to decrease HR have strong inotropic negative or hypotensive effect, such selective action seems of therapeutic potential. Moreover, food supplementation with KYNA can be considered in the prevention of heart diseases.

Background The goal of our study was to examine the long-term effect of vigabatrin (VGB), a γ-aminobutyric acid aminotransferase (GABA-AT) inhibitor on clonazepam (CLO), ethosuximide (ETX) and valproate (VPA) anticonvulsive activity against pentylenetetrazole (PTZ)-induced seizures in mice. Methods VGB was administered for 3 and 7 days. Convulsions were evoked by PTZ at its CD97 (99 mg/kg). The influence of CLO, ETX and VPA alone or in combination with VGB on motor performance and long-term memory was analyzed. γ-aminobutyric acid (GABA) concentration in mice brain and plasma as well as glutamate decarboxylase (GAD) activity was measured. Results After 3 days of treatment, VGB in doses up to 500 mg/kg increased PTZ-induced seizure threshold, whereas after 7 days VGB (at the dose of 125 mg/kg) inhibited clonic seizures in experimental mice. 7 days of VGB administration did not change the protective effect of CLO, ETX and VPA against PTZ-induced seizures. 7 days of VGB treatment at a subthreshold dose of 75 mg/kg decreased TD50 of ETX and CLO in the chimney test, but did not affect TD50 value for VPA. 7 days of VGB administration in combination with AEDs did not affect long-term memory in mice. VGB after 3 days or 7 days of administration increased brain GABA concentration. GAD activity was decreased after 3 and 7 days of VGB administration. Conclusions The presented results confirm anticonvulsive activity of VGB through GABA metabolism alteration and suggest care when combining VGB with ETX or CLO in the therapy.

Kidney diseases have become one of the most common health care problems. Due to a growing number of advanced aged patients with concomitant disorders the prevalence of these diseases will increase over the coming decades. Despite available laboratory tests, accurate and rapid diagnosis of renal dysfunction has yet to be realized, and prognosis is uncertain. Moreover, data on diagnostic and prognostic markers in kidney diseases are lacking. The kynurenine (KYN) pathway is one of the routes of tryptophan (Trp) degradation, with biologically active substances presenting ambiguous properties. The KYN pathway is known to be highly dependent on immunological system activity. As the kidneys are one of the main organs involved in the formation, degradation and excretion of Trp end products, pathologies involving the kidneys result in KYN pathway activity disturbances. This review aims to summarize changes in the KYN pathway observed in the most common kidney disease, chronic kidney disease ...

Background Guillain-Barré syndrome (GBS) is an autoimmune polyneuropathy affecting the peripheral nervous system. This neurological disorder has been previously reported in bone marrow transplant recipients but is uncommon after kidney transplantation. Viral infections and calcineurin inhibitors are the main triggers of GBS in renal transplant recipients. Case presentation In this report, we present a case of a 47-year-old male patient 12 years after his second kidney transplantation who developed GBS due to papillary renal cell carcinoma. Infectious and drug-related origins of GBS were excluded. Despite intensive treatment, graftectomy was performed, after which neurological symptoms resolved. Conclusions In kidney transplant recipients, paraneoplastic aetiology should be considered in the differential diagnosis of GBS.

Drug interactions are major problems in polytherapy, especially in epilepsy, and inappropriate drug selection may result in increased frequency of seizures. In this study, the influence of histamine type 1 (H1) receptor antagonist ketotifen and four chosen antiepileptic drugs (AEDs) on mice activity was examined. We evaluated three parameters of locomotor activity in mice: horizontal total activity with total distance and vertical activity, as well as animal spontaneous activity. Experiments were divided into two 15-minutes studies. During the first 15 minutes, we examined exploratory activity in mice; in the second period, spontaneous activity was tested. In the experiment, Ketotifen or vehicle were administered once or for 7 days daily, whereas AEDs were given only once before test performance. Our results show that ketotifen given alone once or for 7 days significantly increased exploratory locomotor activity in mice without affecting their spontaneous activity. However, in combi...

Background Iron overload is inevitably related to chronic kidney disease (CKD) treatment. Haemochromatosis leads to multiorgan damage and is associated with increased mortality. Primary haemochromatosis is the most common autosomal recessive disease in white populations. In most cases, the classic form of hereditary haemochromatosis is caused by mutations, mainly C282Y and H63D, in the haemochromatosis gene (HFE). Secondary haemochromatosis can be triggered by iron administration and blood transfusions. Haemochromatosis is rarely reported in kidney transplant recipients. Atypical factors may evoke haemochromatosis in patients without HFE mutations or other standard risk factors. Case presentation In the current study, we present a patient who started to have haemochromatosis symptoms after kidney transplantation. A 37-year-old man after kidney transplantation from a deceased donor was admitted to the hospital due to high serum ferritin levels and impaired graft function. The patient...

Numerous reports have proven that dialysis patients experience disturbances in the levels of elements in biological fluids. Disturbances in the homeostasis of essential elements or the appearance of highly toxic elements are serious problems also in clinical ophthalmology. The purpose of this study was to investigate the influence of hemodialysis (HD) on the elemental composition of anterior chamber aqueous humor (AH) in patients undergoing cataract surgery. The study involved 22 patients. The control group enrolled 16 patients (age 75.68 ± 9.67, female 54.55%, male 45.45%) with cataract and normal kidney function (control), and the second group included six patients (age 70.33 ± 12.74, female 33.33%, male 66.67%) with cataract undergoing HD treatment. The elements quantification was established using an inductively coupled plasma optical emission spectrometer (ICP-MS). In the eye fluid of dialysis patients, there were increased levels of manganese (Mn) and mercury (Hg) and decrease...

Lit odkryty został na początku dziewiętnastego wieku. Pierwsze próby jego zastosowania w medycynie obejmowały dnę moczanową, kamicę nerkową, cukrzycę, choroby zakaźne oraz padaczkę. Nie uzyskano jednakże oczekiwanych wyników klinicznych. Przełom nastąpił dopiero w latach czterdziestych dwudziestego wieku dzięki obserwacjom australijskiego psychiatry Johna Cade’a, który wykazał uspokajające działanie litu bez towarzyszącej senności. Odkrycie to dało początek kolejnym badaniom, które potwierdziły skuteczność litu w leczeniu choroby afektywnej dwubiegunowej. Nadal szerokie zainteresowanie budzi wyjaśnienie mechanizmu działania soli litu, gdyż mimo tak długiego okresu potwierdzonej skuteczności klinicznej pozostaje niejasny. Zaproponowano kilka mechanizmów wyjaśniających jego efektywność w leczeniu zaburzeń psychicznych. Jednak istnieją doniesienia sugerujące, że lit może wykazywać szersze właściwości farmakologiczne. W niniejszej pracy zebrano aktualną wiedzę na temat mechanizmu i możl...