„Drogi mistrz” czy „mistrz drogi”? Autorytet pedagogiczny w czasach postmoderny

Wielość stanowisk na temat potrzeby i roli autorytetu w edukacji można zredukować do dwóch poglądów: tradycyjnego i alternatywnego. Zgodnie z poglądem tradycyjnym autorytet („drogi mistrz”) przekazuje więzi i wartości, jest punktem odniesienia dla uczniów, którzy ufają mu i pragną naśladować. Pogląd alternatywny zaś głosi, że autorytet alternatywny („mistrz drogi”) nie przekazuje wiedzy, lecz ukazuje jej wieloznaczność, burząc zastane pewniki. Rozumienie autorytetu jako „mistrza drogi” można porównać do soczewki, w której ogniskują się różnorodne wątki myślowe kształtujące nie tylko to pojęcie, lecz także współczesne pojmowanie prawdy i dobra. Jeden z owych wątków myślowych to filozoficzna strategia dekonstrukcji. Jej celem jest ukazywanie wieloznaczności prawdy, która to wieloznaczność stała się specyficznym przymiotem czasów postmoderny. Efektem dekonstrukcji jest też alternatywne rozumienie autorytetu. Dekonstrukcję zaś można uznać za przejaw tzw. „myśli słabej”, która skutkuje „słabym” wychowaniem i kształceniem. Jej oznaką są negatywne zachowania uczniów świadczące o braku szacunku dla prawdy, cudzej własności, życia oraz zdrowia innych osób. Należy dodać, że tych wartości nie uczy „mistrz drogi”. Zadaniem autorytetu czasu postmoderny jest bowiem ukazywanie pluralistycznego świata różnic, nie zaś przekazywanie wiedzy, wartości czy norm postępowania. Przebywanie w przestrzeni oddziaływania „mistrza drogi” nie wpływa zatem korzystnie na integralny rozwój dzieci i młodzieży. Usuń zaznaczoneDorota Łażewsk

Dekonstrukcja logosu jako zagrożenie dla życia religijnego

Christianity understands itself as a religion of logos, that is, a religion in accord with reason. Therefore, a weakening of reason, which is the logos, indicates a weakening, and even the degeneration of Christian life. In order to understand the truths of faith, philosophical arguments have been used. Deconstruction is a contemporary style of philosophical thought, which prevents understanding, for it serves not in the formulation of reasonable answers nor in demonstrating a lack of sense. Therefore, deconstruction demolishes the logocentric mode of thought that is “meaning,” “understanding” and “certainty.” Hence, it constitutes a threat to a life of faith that seeks understanding (fides quaerens intellectum).Chrześcijaństwo rozumie siebie jako religię logosu, czyli religię według rozumu. Osłabienie rozumu, czyli logosu, oznacza zatem osłabienie, a nawet zanik, życia chrześcijańskiego. W celu zrozumienia prawd wiary posługiwano się argumentacją filozoficzną. Współczesnym stylem filozoficznego myślenia jest dekonstrukcja. Jednak dekonstrukcja uniemożliwia rozumienie. Nie służy bowiem do sformułowania sensownych odpowiedzi czy wykazania braku sensu, lecz uwalnia od sensu. Dekonstrukcja burzy zatem logocentryczny sposób myślenia, czyli „znaczenie”, „rozumienie”, „pewność”. Dlatego stanowi zagrożenie dla życia wiary poszukującej zrozumienia (fides quaerens intellectum)

Simultaneous blockade of histamine H3H_{3} receptors and inhibition of acetylcholine esterase alleviate autistic-like behaviors in BTBR T+ tf/J mouse model of autism

Autism spectrum disorder (ASD) is a heterogenous neurodevelopmental disorder defined by persistent deficits in social interaction and the presence of patterns of repetitive and restricted behaviors. The central neurotransmitters histamine (HA) and acetylcholine (ACh) play pleiotropic roles in physiological brain functions that include the maintenance of wakefulness, depression, schizophrenia, epilepsy, anxiety and narcolepsy, all of which are found to be comorbid with ASD. Therefore, the palliative effects of subchronic systemic treatment using the multiple-active test compound E100 with high H3R antagonist affinity and AChE inhibitory effect on ASD-like behaviors in male BTBR T+tf/J (BTBR) mice as an idiopathic ASD model were assessed. E100 (5, 10 and 15 mg/kg, i.p.) dose-dependently palliated social deficits of BTBR mice and significantly alleviated the repetitive/compulsive behaviors of tested animals. Moreover, E100 modulated disturbed anxiety levels, but failed to modulate hyperactivity parameters, whereas the reference AChE inhibitor donepezil (DOZ, one milligram per kilogram) significantly obliterated the increased hyperactivity measures of tested mice. Furthermore, E100 mitigated the increased levels of AChE activity in BTBR mice with observed effects comparable to that of DOZ and significantly reduced the number of activated microglial cells compared to the saline-treated BTBR mice. In addition, the E100-provided effects on ASD-like parameters, AChE activity, and activated microglial cells were entirely reversed by co-administration of the H3R agonist (R)-α-methylhistamine (RAM). These initial overall results observed in an idiopathic ASD mice model show that E100 (5 mg/kg) alleviated the assessed behavioral deficits and demonstrate that simultaneous targeting of brain histaminergic and cholinergic neurotransmissions is crucial for palliation of ASD-like features, albeit further in vivo assessments on its effects on brain levels of ACh as well as HA are still needed.Autism spectrum disorder (ASD) is a heterogenous neurodevelopmental disorder defined by persistent deficits in social interaction and the presence of patterns of repetitive and restricted behaviors. The central neurotransmitters histamine (HA) and acetylcholine (ACh) play pleiotropic roles in physiological brain functions that include the maintenance of wakefulness, depression, schizophrenia, epilepsy, anxiety and narcolepsy, all of which are found to be comorbid with ASD. Therefore, the palliative effects of subchronic systemic treatment using the multiple-active test compound E100 with high H3R antagonist affinity and AChE inhibitory effect on ASD-like behaviors in male BTBR T+tf/J (BTBR) mice as an idiopathic ASD model were assessed. E100 (5, 10 and 15 mg/kg, i.p.) dose-dependently palliated social deficits of BTBR mice and significantly alleviated the repetitive/compulsive behaviors of tested animals. Moreover, E100 modulated disturbed anxiety levels, but failed to modulate hyperactivity parameters, whereas the reference AChE inhibitor donepezil (DOZ, one milligram per kilogram) significantly obliterated the increased hyperactivity measures of tested mice. Furthermore, E100 mitigated the increased levels of AChE activity in BTBR mice with observed effects comparable to that of DOZ and significantly reduced the number of activated microglial cells compared to the saline-treated BTBR mice. In addition, the E100-provided effects on ASD-like parameters, AChE activity, and activated microglial cells were entirely reversed by co-administration of the H3R agonist (R)-α-methylhistamine (RAM). These initial overall results observed in an idiopathic ASD mice model show that E100 (5 mg/kg) alleviated the assessed behavioral deficits and demonstrate that simultaneous targeting of brain histaminergic and cholinergic neurotransmissions is crucial for palliation of ASD-like features, albeit further in vivo assessments on its effects on brain levels of ACh as well as HA are still needed

Binding of 1-[3-(4-tert-butyl-phenoxy)propyl]piperidine, a new non imidazole histamine H3 receptor antagonist to bovine serum albumin

The degree of binding of a drug to plasma proteins has a significant effect on its distribution, elimination, and pharmacological effect since only the unbound fraction is available for distribution into extra-vascular space. The binding of DL76 (1-[3-(4-tert-butyl-phenoxy)propyl]piperidine) to bovine serum albumin (BSA) was studied in vitro by equilibrium dialysis at 37OC and pH 7.4 over the concentration range of 0.32ñ317.18 μM and at a physiological protein concentration of 602 μM. Drug concentrations were determined by validated LC/MS/MS method. Nonlinear regression analyses of the data pointed to a single class of binding sites (m = 1) with a dissociation constant of DL76 equal 49.20 μM. Scatchard plot concave-down curve might indicate positive cooperativity, which was confirmed by the Hill plot with the slope higher than one

The neuroprotective effects of histamine H3 receptor antagonist E177 on pilocarpine-induced status epilepticus in rats

Epilepsy is a multifaceted neurological disorder which severely a ects neuronal function. Some patients may experience status epilepticus (SE), a life-threatening state of ongoing seizure activity linked to cognitive dysfunction, necessitating an immediate intervention. The potential of histamine H3 receptors in several neuropsychiatric diseases including epilepsy is well recognized. In the current study, we aimed to explore the e ect of H3R antagonist E177 on prevention and termination of pilocarpine (PLC)-induced SE in rats as well as evaluating the e ects of E177 on the levels of oxidative stress in hippocampus tissues. The results showed that the survival rate of animals pretreated with E177 (5 and 10 mg/kg, intraperitoneal (i.p.)) was significantly increased during the first hour of observation, and animals were protected from SE incidence and showed a prolonged average of latency to the first seizure when compared with animals pretreated with PLC (400 mg/kg, i.p.). Moreover, the protective e ect of E177 (10 mg/kg) on SE was partially reversed when rats were co- administered with H3R agonist R-( )-methylhistamine (RAM) and with the H2R antagonist zolantidine (ZOL), but not with the H1R antagonist pyrilamine (PYR). Furthermore, pretreatment with E177 (5 and 10 mg/kg) significantly decreased the abnormal levels of malondialdehyde (MDA), and increased levels of glutathione (GSH) in the hippocampal tissues of the treated rats. However, E177 failed to modulate the levels of catalase (CAT), superoxide dismutase (SOD), or acetylcholine esterase activity (AChE). Our findings suggest that the newly developed H3R antagonist E177 provides neuroprotection in a preclinical PLC-induced SE in rats, highlighting the histaminergic system as a potential therapeutic target for the therapeutic management of SE

Determination of "in vitro" metabolism of a new non-imidazole histamine H3 receptor antagonist 1-[3-(4-tert-butylphenoxy) propyl]piperidine

Early understanding of the pharmacokinetics of drug candidates is essential during the evaluation of drug development process. DL76 1-[3-(4-tert-butylphenoxy)propyl]piperidine is a novel promising non-imidazole H3 receptor antagonist. The presented study was undertaken to compare with each other the predicted hepatic clearance values of DL76 calculated, using two most common mathematical models ìwell-stirredî and ìparallel tubeî, based on the data obtained in in vitro experiments. The metabolic intrinsic clearance of DL76 equaled to 0.4848 mL/min/mg protein was scaled up and the values of hepatic clearance estimated from ìwellstirredî and ìparallel tubeî models were 55.47 mL/min/kg and 58.80 mL/min/kg, respectively. They were further compared with pharmacokinetic parameters calculated based on the concentration-time profile obtained following intravenous administration of DL76 to rats at the dose of 6 mg/kg. The estimated systemic serum clearance value of 144.5 mL/h/kg and blood clearance value of 81.17 mL/min/kg indicate the potential extrahepatic metabolism of the investigated compound. This study demonstrates the utility of rat liver microsomes for the prediction of DL76 hepatic clearance

Antagonism of histamine H3 receptors alleviates pentylenetetrazole-induced kindling and associated memory deficits by mitigating oxidative stress, central neurotransmitters, and c-Fos protein expression in rats

Histamine H3 receptors (H3Rs) are involved in several neuropsychiatric diseases including epilepsy. Therefore, the e ects of H3R antagonist E177 (5 and 10 mg/kg, intraperitoneal (i.p.)) were evaluated on the course of kindling development, kindling-induced memory deficit, oxidative stress levels (glutathione (GSH), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD)), various brain neurotransmitters (histamine (HA), acetylcholine (ACh), -aminobutyric acid (GABA)), and glutamate (GLU), acetylcholine esterase (AChE) activity, and c-Fos protein expression in pentylenetetrazole (PTZ, 40 mg/kg) kindled rats. E177 (5 and 10 mg/kg, i.p.) significantly decreased seizure score, increased step-through latency (STL) time in inhibitory avoidance paradigm, and decreased transfer latency time (TLT) in elevated plus maze (all P < 0.05). Moreover, E177 mitigated oxidative stress by significantly increasing GSH, CAT, and SOD, and decreasing the abnormal level of MDA (all P < 0.05). Furthermore, E177 attenuated elevated levels of hippocampal AChE, GLU, and c-Fos protein expression, whereas the decreased hippocampal levels of HA and ACh were modulated in PTZ-kindled animals (all P < 0.05). The findings suggest the potential of H3R antagonist E177 as adjuvant to antiepileptic drugs with an added advantage of preventing cognitive impairment, highlighting the H3Rs as a potential target for the therapeutic management of epilepsy with accompanied memory deficits

Aryl-1,3,5-triazine ligands of histamine H4H_{4} receptor attenuate inflammatory and nociceptive response to carrageen, zymosan and lipopolysaccharide

Objective and design Histamine $H_{4}$ receptor ($H_{4}R$) offers a great potential for new therapeutic strategies for the treatment of inflammation-based diseases. The aim of this study is to present the pharmacological profile of two recently synthesized ligands of $H_{4}R$ with particular reference to their anti-inflammatory and analgesic activity. Materials and subjects We used mice and rats in the in vivo tests. We also used murine RAW 264.7 cells and isolated guinea-pig ileum in in vitro test. Treatments In the in vivo tests, animals were pre-treated with the increasing doses of investigated compounds (12.5, 25 and 50 mg/kg) and reference compounds: JNJ7777120 (25 mg/kg), indomethacin (10 mg/kg). Macrophages were pre-treated with two concentrations of tested compounds 100 and 10 $\mu$M. Methods We examined anti-inflammatory and analgesic effects of the new $H_{4}R$ antagonists in the in vivo models of inflammation induced by carrageenan or zymosan. We assessed the level of cAMP and release of cytokines, ROS and NO in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Moreover, we assessed the affinity of the investigated compounds for histamine $H_{1}$ receptor in functional studies. Results Both investigated compounds reduced paw edema, mechanical and thermal hyperalgesia in the carrageenaninduced acute inflammation. Moreover, administration of the investigated compounds resulted in decreased granulocyte influx and attenuated nociceptive reaction in the zymosan-induced peritonitis model. In the same model of inflammation, the investigated compounds reduced vascular permeability; however, this effect was observed only after the highest applied dose. Furthermore, the test compounds had no impact on cell viability in the experiments on RAW 264.7 macrophages. In these cells, stimulated with LPS, the test compounds decreased reactive oxygen species (ROS) production. They increased the cellular concentration of cAMP and attenuated the production of inflammatory cytokines such as $TNF\alpha$ and $IL-1\beta$. All results were comparable to those obtained for the reference compound JNJ7777120 with the exception of the impact on NO production. Nevertheless, this effect was similar to that obtained for the other reference compound rolipram, which is a phosphodiesterase 4 (PDE 4) inhibitor. Further experiments revealed that both of the investigated compounds possessed relatively low affinity for histamine H$_{1}$ receptor and do not inhibit the activity of the PDE 4B1 enzyme. In addition, all the effects of the investigated compounds in in vivo experiments were observed at doses that did not cause neurologic deficits in rotarod test and did not reduce spontaneous locomotor activity. Conclusions Our results demonstrate the anti-inflammatory and analgesic activity of the new aryl-1,3,5-triazine derivatives, which are primarily $H_{4}R$-dependent

The histamine H3R antagonist DL77 attenuates autistic behaviors in a prenatal valproic acid-induced mouse model of autism

Autistic spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in social communication and restricted/repetitive behavior patterns or interests. Antagonists targeting histamine H3 receptor (H3R) are considered potential therapeutic agents for the therapeutic management of diferent brain disorders, e.g., cognitive impairments. Therefore, the efects of subchronic treatment with the potent and selective H3R antagonist DL77 (5, 10, or 15mg/kg, i.p.) on sociability, social novelty, anxiety, and aggressive/repetitive behavior in male Tuck-Ordinary (TO) mice with ASD-like behaviors induced by prenatal exposure to valproic acid (VPA, 500mg/kg, i.p.) were evaluated using the three-chamber test (TCT), marble burying test (MBT), nestlet shredding test (NST), and elevated plus maze (EPM) test. The results showed that VPA-exposed mice exhibited signifcantly lower sociability and social novelty preference compared to VPA-exposed mice that were pretreated with DL77 (10 or 15mg/kg, i.p.). VPA-exposed mice presented a signifcantly higher percentage of buried marbles in MBT and shredded nestlet signifcantly more in NST compared to the control groups. However, VPA-exposed animals pretreated with DL77 (10 or 15mg/kg, i.p.) buried a reduced percentage of marbles in MBT and presented a signifcantly lower percentage of shredding behavior in NST. On the other hand, pretreatment with DL77 (5, 10, or 15mg/kg, i.p.) failed to restore the disturbed anxiety levels and hyperactivity observed in VPA-exposed animals in EPM, whereas the reference drug donepezil (DOZ, 1mg/kg, i.p.) signifcantly palliated the anxiety and reduced the hyperactivity measures of VPA-exposed mice. Furthermore, pretreatment with DL77 (10 or 15mg/kg, i.p.) modulated oxidative stress status by increasing GSH and decreasing MDA, and it attenuated the proinfammatory cytokines IL-1β, IL-6 and TNF-α exacerbated by lipopolysaccharide (LPS) challenge, in VPA-exposed mouse brain tissue. Taken together, these results provide evidence that modulation of brain histaminergic neurotransmission, such as by subchronic administration of the H3R antagonist DL77, may serve as an efective pharmacological therapeutic target to rescue ASD-like behaviors in VPA-exposed animals, although further investigations are necessary to corroborate and expand these initial data