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It is well documented that physical activity can induce a number of various stimuli which are able to enhance the strength and endurance performance of muscles. Moreover, regular physical activity can preserve or delay the appearance of several metabolic disorders in the human body. Physical exercise is also known to enhance the mood and cognitive functions of active people, although the physiological backgrounds of these effects remain unclear. In recent years, since the pioneering study in the past showed that physical activity increases the expression of the brain derived neurothophic factor (BDNF) in the rat brain, a number of studies were undertaken in order to establish the link between that neurothrophin and post-exercise enhancement of mood and cognitive functions in humans. It was recently demonstrated that physical exercise can increase plasma and/or serum BDNF concentration in humans. It was also reported that physical exercise or electrical stimulation can increase the BDNF expression in the skeletal muscles. In the present review, we report the current state of research concerning the effect of a single bout of exercise and training on the BDNF expression in the brain, in both the working muscles as well as on its concentrations in the blood. We have concluded that there may be potential benefits of the exercise-induced enhancement of the BDNF expression and release in the brain as well as in the peripheral tissues, resulting in the improvement of the functioning of the body, although this effect, especially in humans, requires more research.
Increasing body of evidence suggests a neuroprotective potential of metabotropic glutamatergic receptor group III (mGluR III) stimulation, however the role of particular subtypes of these receptors (mGluR4, mGluR7, mGluR8) in apoptotic processes is not fully recognized. Of special interest is the study on the role of mGluR7 which is widely expressed throughout the brain and recently developed selective positive allosteric modulator of this receptor, AMN082 (N,N=-dibenzhydrylethane-1,2-diamine dihydrochloride) enables investigation the biological role of mGluR7. In the present study, firstly we evaluated the possible neuroprotective effects of AMN082 (0.001–1 µM) on neurotoxicity induced by various apoptotic [stimuli staurosporine (St), doxorubicin (Dox) and low potassium (LP)] in 7 DIV cerebellar granule cells (CGC). The data showed that AMN082 (0.1–1 µM) partially attenuated the cell death induced by St and LP, but not by Dox. Next, we investigated the role of mGluR7 in neuronal cell death by testing the vulnerability of CGC from wild and mGluR7KO animals to toxic action of St, Dox and LP. No differences between groups under basal conditions have been found. However, after primary deprivation of CGC cells from potassium in culture medium and secondary application of proapoptotic stimuli we observed the higher vulnerability of mGluR7KO CGC to cell damaging effect of St and Dox but not LP. Further experiments performed on cortical glia cells demonstrated higher toxic action of St and Dox in mGluR7KO cells when compared to wild type one. Additionally, in mGluR7KO glia cells we found higher basal and stimulated by St or Dox caspase-3 activity when compared to wild type one. The obtained data suggest that specific stimulation of mGluR7 by AMN082 could be protective against staurosporine and low-potassium induced neuronal ell death. Moreover, the presence of mGluR7 could be particularly important for survival of glia cells under harmful conditions. The study was supported by statutory funds for Institute of Pharmacology PAS and grant No NN405611638 from the Ministry of Science and Higher Education, Warsaw, Poland.
Agonists of metabotropic glutamate receptors group II and III (mGluRs II/III) show neuroprotective effects in in vitro and in vivo models of excitotoxicity. However, their influence on neuronal apoptosis remains unknown. In this study the effect of agonists of mGluRs II/III on staurosporine (St)-evoked LDH release was estimated in undifferentiated (UN-) and retinoic acid (RA)-differentiated human neuroblastoma SH-SY5Y cells. It has been found that LY354740 (0.01-100 microM) and ACTP-I (0.01-100 microM), a nonspecific agonists of mGluRs group II and III, respectively when given alone had no effect on cell proliferation and cell viability. However, both of these compounds partially decreased the St-induced cell death in UN- and RA-SHSY5Y. The selective agonist of mGluR7, AMN082 in low concentrations (0.001-1 microM) had no effect on cell proliferation/viability and tended to attenuate the Stinduced toxicity only in UN-SHSY5Y. On the other hand, AMN082 in higher concentrations (>10 microM) had the cell damaging effect in both UN- and RA- SHSY5Y cells. This study indicates that agonists of mGluRs II/III have potential to attenuate cell death evoked by staurosporine - a well recognized inducer of apoptosis. Acknowledgment: The study was supported by grant No NN405611638 from the Ministry of Science and Higher Education, Warsaw, Poland.
A number of studies have shown neuroprotective effects of agonists of group-II metabotropic glutamate receptors (mGluR II) in various experimental models of excitotoxicity. However, an influence of these compounds on neuronal apoptosis is less recognized. We tested the effect of nonspecific agonist of mGluR II, LY354740 ((+)-2-aminobicyclo[3.1.0]hexane-2,6dicarboxylate) on staurosporine and doxorubicin evoked cell death in primary pure neuronal and neuronal-glial cortical cells, as well in cerebellar granule cells (CGC). We found that LY354740 (0.01-10 microM) was protective against staurosporine-evoked cell death in both, pure cortical neurons and CGC with higher efficacy in 12 DIV in comparison with the 7 DIV ones. Moreover, the neuroprotective effect of LY354470 in neuronal-glial cells did not differ from that found in pure neurons. The protective effect of mGluR II agonist was not connected with attenuation the St-induced caspase-3 activity and DNA fragmentation, but this agent decreased the St-evoked necrotic cell death as measured by propidium ioide staining. LY354470 had no influence on doxorubicin-evoked cell death, but attenuated the glutamate-mediated neuronal cell damage. Our data suggest that neuroprotective effects of the mGluR II ligand are stimuli- and development-dependent and are rather connected with attenuation of necrotic-, than the apoptotic cell death. The study was supported by grant No NN405611638 from the Ministry of Science and Higher Education, Warsaw, Poland.
W epoce Internetu wyewoluowały nowe formy przekazu informacji, które mogą zastać wykorzystane do diagnozy zaburzeń odżywiania. Od dziesięcioleci uznaną metodą diagnostyczną była analiza dokumentów osobistych. W dzisiejszych czasach jednym z takich dokumentów jest blog internetowy. W szeregu badań udowodniono zasadność analizowania postaw i preferencji w diagnostyce anoreksji. W tym badaniu zanalizowano 30 blogów internetowych, prowadzonych przez odchudzające się młode kobiety, minimum przez 2 miesiące. Wykazano, iż u dwóch z nich można było zdiagnozować anoreksję, 25 % miało objawy anoreksji, zaś ponad polowa miała syndrom gotowości anorektycznej.
Preclinical data indicated that antagonists of group I mGlu receptors, particularly antagonists of mGlu5 receptors, produced both anxiolytic-like and antidepressant-like effects. Clinical data also demonstrated that mGlu5 receptor antagonist, fenobam, was an active anxiolytic drug. The anxiolytic effects exerted by mGlu5 receptor antagonists are profound, comparable to or stronger than those of benzodiazepines. Among all mGlu receptor ligands, group II mGlu receptor agonists seem to be drugs with promising therapeutic potential and good safety profi le. Animal studies showed anxiolytic-like effects of group II mGlu receptor agonists. Currently, group II mGlu receptor agonists are in phase III clinical trials for potential treatment of anxiety disorders. On the other hand, data have been accumulated indicating that antagonists of group II mGlu receptors have an antidepressant potential. Group III mGlu receptor ligands represent the least investigated group of mGlu receptors. The preclinical data, however, indicate that a selective agonist of mGlu4 and Glu8 receptors- ACPT-I produced anxiolytic but not antidepressant effects after peripheral administration, while the selective positive allosteric modulator of Glu7 receptors, AMN082 produced both anxiolytic and antidepressantlike. The data show that the effects of group III mGlu receptor ligands may differ dependently of their receptor subtype specifi city
INTRODUCTION: A specific activation of metabotropic glutamatergic receptor subtype 7 (mGluR7) by its allosteric agonist AMN082 has been shown to protect neuronal cells against various detrimental factors. It is well established that some of subtypes of mGluRs (e.g., mGluR5 or mGluR3) engage glia cells to more efficiently protect neurons against various harmful stimuli. AIM(S): We aimed to study the role of mGluR7 in glia and neuronal cell survival. METHOD(S): We used primary cortical glia cell cultures and cerebellar granule neurons (CGNs)from mGluR7+/+ and mGluR7-/- C57Bl/6J mice which were exposed to various cell damaging factors (staurosporine (St), doxorubicin (Dox)and low potassium (LP)). MTT reduction, LDH release and caspase-3 activity biochemical assays were used for assessment of cell damage. The mRNA expression level of various subtypes of mGluRs was measured by qPCR. RESULTS: We showed the expression of mGluR7 in glia cell cultures and demonstrated the higher toxicity of St and Dox in mGluR7-/- glia cells when compared to wild type one. Moreover, we found a partial protection mediated by AMN082 against St and Dox in mGluR7+/+ glia cells. However, we did not find any differences in vulnerability of CGNs derived from mGluR7+/+ and mGluR7-/- animals to the cell damaging action of LP, St or Dox under standard treatment. Intriguingly, when we primed both types of CGNs by culturing them overnight in LP medium, we found significant higher toxic action of St and Dox in mGluR7‑/‑ CGNs. Finally, we confirmed neuroprotective properties of AMN082 in CGNs and showed that this effect is stimuli‑ and development-dependent. CONCLUSIONS: Our data obtained in isolated glia and neuronal cellular models showed a protective potential of mGluR7‑specific agonist AMN082 and pro‑survival role of mGluR7 in glia cells which together with its already known direct role on neuronal cells could suggest its higher efficacy under in vivo conditions. FINANCIAL SUPPORT: The study was supported by statutory funds for Institute of Pharmacology PAS and grant No NN405611638 from the Ministry of Science and Higher Education, Warsaw, Poland.
Previous findings show lack of proven biomarkers for predicting antidepressant drug response. Recent genome-wide expression study indicates CHL-1 gene as potential depression treatment biomarker. Aim of study is to examine possibility of applying CHL-1 gene with a group of Polish depressive patients as SSRI response biomarker. Peripheral blood samples were collected from well clinically characterized naïve (N), treatment resistant (TR) depressive patients and healthy (H) volunteers. Lymphocytes were isolated and cultured with two selected drugs – paroxetine and mirtazapine. Cell proliferation assay was done after 72 h of incubation. The total RNAs from lymphocytes without drugs were extracted and cDNAs were synthetized. Levels of CHL-1 gene expression were checked by real-time PCR method. There are significant differences between chosen phenotypes: high and low sensitivity to mirtazapine for H, TR and N; high and low sensitivity to paroxetine for H and N. There are significant differences between mirtazapine sensitivity for whole groups of H and TR. There are not significant differences of CHL-1 gene expression levels between groups. Findings indicate different phenotypes occurrence for SSRI mediated growth inhibition sensitivity. Conclusions about CHL-1 gene as a SSRI response biomarker are still unclear. Suported by Era-Net-Neuron “PADRE” grant.
Harmaline, a derivative of beta-carboline is a well-known tremorgenic compound which induces the action and postural tremor in animals. Oscillation frequency of this symptom is equal to 10–12 Hz in rats. A synchronous activation of the olivo-cerebellar pathway and release of glutamate in the cerebellum has been suggested to be a primary cause of the harmaline-induced tremor. Subtype 4 of metabotropic glutamate receptors (mGluR4) is mainly an autoreceptor and its stimulation decreases glutamate release. MGluR4 receptors are abundant in the cerebellum and therefore their influence on the harmaline-induced tremor might be expected. However, mechanisms underlying this symptom are more complex and seem to involve also other neurotransmitter systems, especially the noradrenergic neurotransmission in the cerebellum. The aim of the present study was to examine an influence of an orthosteric agonist of mGluR4 – AF22898:8 on the tremor induced by harmaline in rats. An antagonist of beta-adrenoceptors – propranolol was used as a reference compound. Tremor of animals was measured automatically by actimeters where four force tranducers measured the force exerted by an animal on the floor. The Power Spectra analysis which uses a Fourier transform generated power spectra for examination of the tremor. The average power over three specific frequency bands AP1 (0–8 Hz), AP2 (9–15 Hz), AP3 (16–25 Hz), and tremor indices, which quantified the differences in power between the AP2 and AP1 (T1) and AP3 and AP1 (T2) were used to quantify the tremor intensity. Harmaline in doses of 7.5–25 mg/kg i.p. induced the generalized tremor which was dose-dependent and lasted longer than 2 h. Propranolol in a dose of 20 mg/kg i.p. diminished the tremor (decreased T1 and AP2) induced by harmaline (15 mg/ kg i.p.). In contrast, AF22898:8 administered in doses of 2.5–20 mg/kg i.p. was ineffective. The present results indicate that the harmaline-induced tremor measured in the force plate actimeters consititute a good model for screening antitremorgenic compounds. However, in contrast to earlier expectations the agonist of mGluR4 had no influence on this symptom.The study was supported by the grant of the National Science Centre nr N N401 570638, and partly by Statutory Funds of the Department of Neuro-Psychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, Cracow, Poland.
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