Comparative effectiveness of abatacept, apremilast, secukinumab and ustekinumab treatment of psoriatic arthritis: a systematic review and network meta-analysis.

To assess the comparative effectiveness and safety of novel biologic therapies in psoriatic arthritis (PsA) and to establish the position of the non-anti-tumor necrosis factor α (TNF-α) biologic drugs in the treatment regimen of the disease. A systematic review and network meta-analysis (NMA) was conducted according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) requirements. Two investigators identified the studies, abstracted data, and assessed the risk of bias independently. The NMA was conducted for efficacy [American College of Rheumatology (ACR) criteria, ACR20 and ACR50; psoriasis area and severity index (PASI), PASI75] and safety outcomes [any adverse events (AEs) and serious adverse events (SAEs)]; treatments were ranked using the P score for each outcome. The PROSPERO registration number was 42017072200. MEDLINE/PubMed, Embase, Cochrane Library, and ClinicalTrials.gov were searched from the inception of each database to July 10, 2017. Randomized controlled trials (RCTs) for abatacept, apremilast, secukinumab or ustekinumab in adults with moderate and severe PsA were included. The overall PsA population and anti-TNF-α-naive, anti-TNF-α-failure, or anti-TNF-α-experienced subpopulations were considered. We identified eight eligible RCTs and included them in the systematic review and NMA. Significant differences in ACR20 response rate were revealed between secukinumab 150 mg and apremilast 20 mg [relative risk; RR = 2.55 (CI-confidence interval; 1.24, 5.23)] and between secukinumab 300 mg and apremilast 20 or 30 mg [RR = 3.57 CI (1.48, 8.64) and RR = 2.84 CI (1.18, 6.86), respectively]. Any AEs occurred more often in apremilast 20 and 30 mg compared with placebo [RR = 0.58 CI (0.45, 0.74) and RR = 0.58 CI (0.45, 0.75), respectively] but also compared with secukinumab 150 mg [RR = 0.54 CI (0.35, 0.81) and RR = 0.45 CI (0.35, 0.82), respectively]. No significant differences were revealed for SAEs among biologics and between biologics and placebo. In the overall population, as well as in the anti-TNF-α-naive subpopulation, secukinumab at a dose of 300 and 150 mg was ranked the highest for the ACR20 endpoint, while in the anti-TNF-α-experienced subpopulation, secukinumab 300 mg and apremilast 30 mg revealed the highest rank. Secukinumab 75 mg was the safest drug in terms of any AEs, but for SEAs the safest was ustekinumab 90 mg. Our study revealed no significant differences among non-anti-TNF-α biologics in the treatment of PsA in the comparisons performed with regards to the highest efficacy and safety. Both in the overall population and in the analyzed subpopulations, secukinumab 300 mg was ranked the highest for the ACR20 response rate. Secukinumab 300 mg was the safest drug in terms of any AEs, and ustekinumab 90 mg presented the lowest overall risk of SAEs. Head-to-head trials and evaluation of comparative efficacy and safety between non-TNF-α biologics are warranted to inform clinical decision making with a relevant treatment paradigm.

The involvement of NMDA and AMPA receptors in the mechanism of antidepressant-like action of zinc in the forced swim test.

Antidepressant-like activity of zinc in the forced swim test (FST) was demonstrated previously. Enhancement of such activity by joint administration of zinc and antidepressants was also shown. However, mechanisms involved in this activity have not yet been established. The present study examined the involvement of the NMDA and AMPA receptors in zinc activity in the FST in mice and rats. Additionally, the influence of zinc on both glutamate and aspartate release in the rat brain was also determined. Zinc-induced antidepressant-like activity in the FST in both mice and rats was antagonized by N-methyl-D-aspartic acid (NMDA, 75 mg/kg, i.p.) administration. Moreover, low and ineffective doses of NMDA antagonists (CGP 37849, L-701,324, D-cycloserine, and MK-801) administered together with ineffective doses of zinc exhibit a significant reduction of immobility time in the FST. Additionally, we have demonstrated the reduction of immobility time by AMPA receptor potentiator, CX 614. The antidepressant-like activity of both CX 614 and zinc in the FST was abolished by NBQX (an antagonist of AMPA receptor, 10 mg/kg, i.p.), while the combined treatment of sub-effective doses of zinc and CX 614 significantly reduces the immobility time in the FST. The present study also demonstrated that zinc administration potentiated a veratridine-evoked glutamate and aspartate release in the rat's prefrontal cortex and hippocampus. The present study further suggests the antidepressant properties of zinc and indicates the involvement of the NMDA and AMPA glutamatergic receptors in this activity.

Breast cancer surgery decreases serum brain-derived neurotrophic factor concentrations in middle aged women: relationship to the serum C-reactive protein concentration.

The aim of this study was to establish the effect of breast cancer surgery in middle aged women on the serum (s) and plasma (p) brain-derived neurotrophic factor concentrations [BDNF]s and [BDNF]p, respectively, in relation to the serum C-reactive protein [CRP]s concentration measured before and at 24 hours after surgery. Eighteen patients with recently diagnosed breast cancer (mean ± SE): age 49.1 ± 1.6 years, body mass 69.8 ± 2.2 kg, BMI 25.8 ± 0.8 kg m-2, participated in this study. The [BDNF]s before the surgery amounted to 25 523 ± 1 416 pg ml-1. At 24 h after the surgery it decreased to 21 551 ± 998 pg ml-1 (P = 0.004). This decrease was accompanied by a significant (P = 0.001) decrease in the platelet count (PLT) from 254.7 ± 12.2 k µl-1 before, to 228.8 ± 9.7 k µl-1 after the surgery. The [CRP]s increased from 3.59 ± 0.79 mg l-1 before to 25.04 ± 4.65 mg l-1 after the surgery (P = 0.002). A significant positive correlation was found between the [BDNF]s and the PLT both before (P = 0.003) as well as after the surgery (P = 0.027). Moreover, a significant positive correlation (P = 0.046) was found between [BDNF]s and the [CRP] s before the surgery. At 24 h after the surgery the [BDNF]s and the [CRP]s still correlated positively (P = 0.044), despite the fact that the surgery significantlly decresed the [BDNF]s and increased [CRP]s. No significant effect of the surgery on the [BDNF]p was found. We have concluded that serum BDNF concentration in breast cancer patients positively correlates with serum CRP both before and at 24 h after the surgery. Moreover, breast cancer surgery decreases serum BDNF concentration at 24 h after operation and increases [CRP]s.

Peripheral administration of group III mGlu receptor agonist ACPT-I exerts potential antipsychotic effects in rodents.

Several lines of evidence implicate dysfunction of glutamatergic neurotransmission in the pathophysiology of schizophrenia. Previous behavioral studies have indicated that metabotropic glutamate (mGlu) receptors may be useful targets for the treatment of psychosis. It has been shown that agonists and positive allosteric modulators of group II mGlu receptors produce potential antipsychotic effects in behavioral models of schizophrenia in rodents. Group III mGlu receptors seem to be also promising targets for a variety of neuropsychiatric and neurodegenerative disorders. However, despite encouraging data in animal models, most ligands of group III mGlu receptors still suffer from weak affinities, incapacity to cross the blood-brain barrier or absence of full pharmacological characterization. These limitations slow down the validation process of group III mGlu receptors as therapeutic targets. In this work, we choose to study an agonist of group III mGlu receptors (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-I) using intraperitoneal administration in three animal behavioral models predictive of psychosis or hallucinations. The results of the present study show that ACPT-I, given at doses of 10 or 30mg/kg, decreased MK-801-induced hyperlocomotion and at a dose of 100mg/kg decreased amphetamine-induced hyperlocomotion in rats. Furthermore, ACPT-I dose-dependently decreased DOI-induced head twitches in mice and suppresses DOI-induced frequency and amplitude of spontaneous EPSPs in slices from mouse brain frontal cortices. These data demonstrate that ACPT-I is a brain-penetrating compound and illustrates its promising therapeutic role for the treatment of schizophrenia.

Anxiolytic-like effect of group III mGlu receptor antagonist is serotonin-dependent.

Literature data have provided evidence that antagonists of group I metabotropic glutamate receptors (mGluRs) and agonists of group II/III mGluRs show anxiolytic-like properties in preclinical studies. However data reporting anxiolytic-like action of group III mGlu receptor antagonists were also published. In the present paper we investigated the anxiolytic-like activity of the group III mGlu receptor antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG). To examine its anxiolytic-like effects, the basolateral amygdala was chosen as an injection site, as this brain region is involved in the regulation of anxiety-related behavior. To detect anxiolytic-like activity, the Vogel conflict-drinking test in rats was used. Intra-amygdalar injections of CPPG exhibited dose-dependent, potent anxiolytic-like action at a dose of 75 nmol, which was blocked by a concomitant administration of the group III mGlu receptor agonist CI (S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-I) at a dose of 7.5 nmol. The benzodiazepine receptor antagonist flumazenil (given intraperitoneally, 10 mg/kg) did not change the anxiolytic-like effect of CPPG, but that effect was abolished by the non-selective antagonist of 5-HT receptors metergoline and the antagonist of 5-HT2A/C receptors ritanserin (both given intraperitoneally at doses of 2 and 0.5 mg/kg, respectively). These findings suggest that the blockade of group III mGlu receptors in the amygdala is responsible for anxiolysis and that serotonergic, but not the benzodiazepine recognition site of the GABA-ergic system are involved in the anxiolytic-like response induced by group III mGlu antagonist.

Anxiolytic-like action of MTEP expressed in the conflict drinking Vogel test in rats is serotonin dependent.

The purpose of the present study was to investigate whether the anxiolytic-like action of a selective and brain penetrable group I metabotropic glutamate (mGlu5) receptor antagonist 3-[(2-methyl-1,3-tiazol-4-yl)ethynyl]-pyridine (MTEP) is dependent upon the serotonergic system. Experiments were performed on male Wistar rats. The Vogel conflict drinking test was used to detect anxiolytic-like activity. MTEP administered intraperitoneally at doses of 1, 3 and 6 mg/kg induced anxiolytic-like effect. The potential anxiolytic effect of MTEP (1 mg/kg) was inhibited by a nonselective 5-HT receptor antagonist metergoline (2 mg/kg i.p.) and 5-HT2A/2C receptor antagonist ritanserin (0.5 mg/kg i.p.), but not by a 5-HT1A receptor antagonist N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridynyl)cyclohexane-carboxamide (WAY 100635) (0.1 mg/kg i.p). The anxiolytic effect of MTEP (6 mg/kg) was attenuated by ritanserin (1 mg/kg i.p.). Moreover, MTEP-induced a dose-dependent release of serotonin in the frontal cortex. The obtained results suggest that the potential anxiolytic effect of the mGlu5 receptor antagonist MTEP is due to the increased serotonin release with subsequent activation of 5-HT2A/2C receptors, most probably located postsynaptically, but not by the 5-HT1A receptors.

The influence of group III metabotropic glutamate receptor stimulation by (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid on the parkinsonian-like akinesia and striatal proenkephalin and prodynorphin mRNA expression in rats.

Group III metabotropic glutamate receptors (mGluRs) are widely distributed in the basal ganglia, especially on the terminals of pathways which seem to be overactive in Parkinson's disease. The aim of the present study was to determine whether (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-1), an agonist of group III mGluRs, injected bilaterally into the globus pallidus (GP), striatum or substantia nigra pars reticulata (SNr), can attenuate the haloperidol-induced catalepsy in rats, and whether that effect was related to modulation of proenkephalin (PENK) or prodynorphin (PDYN) mRNA expression in the striatum. Administration of ACPT-1 (0.05-1.6 microg/0.5 microl/side) caused a dose-and-structure-dependent decrease in the haloperidol (0.5 mg/kg i.p. or 1.5 mg/kg s.c.)-induced catalepsy whose order was as follows: GP>striatum>SNr. ACPT-1, given alone to any of those structures, induced no catalepsy in rats. Haloperidol (3 x 1.5 mg/kg s.c.) significantly increased PENK mRNA expression in the striatum, while PDYN mRNA levels were not affected by that treatment. ACPT-1 (3 x 1.6 microg/0.5 microl/side) injected into the striatum significantly attenuated the haloperidol-increased PENK mRNA expression, whereas administration of that compound into the GP or SNr did not influence the haloperidol-increased striatal PENK mRNA levels. Our results demonstrate that stimulation of group III mGluRs in the striatum, GP or SNr exerts antiparkinsonian-like effects in rats. The anticataleptic effect of intrastriatally injected ACPT-1 seems to correlate with diminished striatal PENK mRNA expression. However, since the anticataleptic effect produced by intrapallidal and intranigral injection of ACPT-1 is not related to a simultaneous decrease in striatal PENK mRNA levels, it is likely that a decrease in enkephalin biosynthesis is not a necessary condition to obtain an antiparkinsonian effect.

Antidepressant-like activity of CGP 36742 and CGP 51176, selective GABAB receptor antagonists, in rodents.

BACKGROUND AND PURPOSE: A crucial role for the GABAB receptor in depression was proposed several years ago, but there are limited data to support this proposition. Therefore we decided to investigate the antidepressant-like activity of the selective GABAB receptor antagonists CGP 36742 and CGP 51176, and a selective agonist CGP 44532 in models of depression in rats and mice. EXPERIMENTAL APPROACH: Effects of CGP 36742 and CGP 51176 as well as the agonist CGP 44532 were assessed in the forced swim test in mice. Both antagonists were also investigated in an olfactory bulbectomy (OB) model of depression in rats, while CGP 51176 was also investigated in the chronic mild stress (CMS) rat model of depression. The density of GABAB receptors in the mouse hippocampus after chronic administration of CGP 51176 was also investigated. KEY RESULTS: The GABAB receptor antagonists CGP 36742 and CGP 51176 exhibited antidepressant-like activity in the forced swim test in mice. The GABAB receptor agonist CGP 44532 was not effective in this test, however, it counteracted the antidepressant-like effects of CGP 51176. The antagonists CGP 36742 and CGP 51176 were effective in an OB model of depression in rats. CGP 51176 was also effective in the CMS rat model of depression. Administration of CGP 51176 increased the density of GABAB receptors in the mouse hippocampus. CONCLUSIONS AND IMPLICATIONS: These data suggest that selective GABAB receptor antagonists may be useful in treatment of depression, and support an important role for GABA-ergic transmission in this disorder.

Decreased sensitivity to paroxetine-induced inhibition of peripheral blood mononuclear cell growth in depressed and antidepressant treatment-resistant patients.

Major depression disorder (MDD) is the most widespread mental disorder. Selective serotonin reuptake inhibitors (SSRIs) are used as first-line MDD treatment but are effective in <70% of patients. Thus, biomarkers for the early identification of treatment-resistant (TR) MDD patients are needed for prioritizing them for alternative therapeutics. SSRI-induced inhibition of the growth of peripheral blood mononuclear cells (PBMCs) is mediated via their target, the serotonin transporter (SERT). Here, we examined whether antidepressant drug-induced inhibition of the growth of PBMCs differed between MDD patients and healthy controls. PBMCs from well-characterized 33 treatment-sensitive (TS) and 33 TR MDD patients, and 24 healthy volunteers were studied. Dose-dependent inhibition of PBMCs growth was observed for both the non-SSRI antidepressant mirtazapine and the SSRI antidepressant paroxetine. Significantly lower sensitivities to 20 µm paroxetine were observed in MDD compared with control PBMCs prior to treatment onset (13% and 46%, respectively; P<0.05). Following antidepressant drug treatment for 4 or 7 weeks, the ex vivo paroxetine sensitivity increased to control levels in PBMCs from TS but not from TR MDD patients. This suggests that the low ex vivo paroxetine sensitivity phenotype reflects a state marker of depression. A significantly lower expression of integrin beta-3 (ITGB3), a co-factor of the SERT, was observed in the PBMCs of MDD patients prior to treatment onset compared with healthy controls, and may explain their lower paroxetine sensitivity. Further studies with larger cohorts are required for clarifying the potential of reduced PBMCs paroxetine sensitivity and lower ITGB3 expression as MDD biomarkers.

MTEP, a new selective antagonist of the metabotropic glutamate receptor subtype 5 (mGluR5), produces antiparkinsonian-like effects in rats.

The aim of the present study was to examine a potential antiparkinsonian-like action of 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), a new non-competitive antagonist of mGluR5, in the rat models. This compound has affinity for mGluR5 in a nanomolar concentration range and seems to be superior to the earlier known antagonists in terms of its specificity and bioavailability. Catalepsy and muscle rigidity induced by haloperidol administered at doses of 0.5 and 1 mg/kg were regarded as models of parkinsonian akinesia and muscle rigidity, respectively. MTEP at doses between 0.5 and 3 mg/kg i.p. decreased the haloperidol-induced muscle rigidity measured as an increased muscle resistance of the rat's hind leg in response to passive extension and flexion at the ankle joint. The strongest and the longest effect was observed after the dose of 1 mg/kg. MTEP (0.5-3 mg/kg i.p.) also reduced the haloperidol-induced increase in electromyographic (EMG) activity recorded in the gastrocnemius and tibialis anterior muscles. MTEP (3 and 5 mg/kg i.p.) inhibited the catalepsy induced by haloperidol. The present study confirms earlier suggestions that the antagonists of mGluR5 may possess antiparkinsonian properties. However, selective mGluR5 antagonists may be more effective in inhibiting parkinsonian muscle rigidity than parkinsonian akinesia.

The involvement of glutamate in the pathophysiology of depression.

In spite of more than 40 years of thorough studies, conventional antidepressants still have many limitations that hinder the effective treatment of depression. It seems that a breakthrough in the therapy of depression will require going beyond a monoamine-based theory of depression. Converging lines of evidence indicate that the glutamatergic system might be a promising target for a novel antidepressant therapy. Both ionotropic glutamate receptor ligands (functional NMDA receptor antagonists and AMPA receptor potentiators) and compounds acting at metabotropic glutamate receptors (mGluRs; group I mGluR antagonists, group II antagonists and group III agonists) produce antidepressant-like activity in several preclinical and some clinical studies. In this review, current knowledge and crucial hypotheses concerning the role of glutamate in the pathophysiology of depression are discussed.

Neuroprotective effects of mGluR II and III activators against staurosporine- and doxorubicin-induced cellular injury in SH-SY5Y cells: New evidence for a mechanism involving inhibition of AIF translocation.

There are several experimental data sets demonstrating the neuroprotective effects of activation of group II and III metabotropic glutamate receptors (mGluR II/III), however, their effect on neuronal apoptotic processes has yet to be fully recognized. Thus, the comparison of the neuroprotective potency of the mGluR II agonist LY354740, mGluR III agonist ACPT-I, mGluR4 PAM VU0361737, mGluR8 PAM AZ12216052 and allosteric mGluR7 agonist AMN082 against staurosporine (St-) and doxorubicin (Dox)-induced cell death has been performed in undifferentiated (UN-) and retinoic acid differentiated (RA-) human neuroblastoma SH-SY5Y cells. The highest neuroprotection in UN-SH-SY5Y cells was noted for AZ12216052 (0.01-1 µM) and VU0361737 (1-10 µM), with both agents partially attenuating the St- and Dox-evoked cell death. LY354740 (0.01-10 µM) and ACPT-I (10 µM) were protective only against the St-evoked cell damage, whereas AMN082 (0.001-0.01 µM) attenuated only the Dox-induced cell death. In RA-SH-SY5Y, a moderate neuroprotective response of mGluR II/III activators was observed for LY354740 (10 µM) and AZ12216052 (0.01 and 10 µM), which afforded protection only against the St-induced cell damage. The protection mediated by mGluR II/III activators against the St- and Dox-evoked cell death in UN-SH-SY5Y cells was not related to attenuation of caspase-3 activity, however, a decrease in the number of TUNEL-positive nuclei was found. Moreover, mGluR II/III activators attenuated the cytosolic level of the apoptosis inducing factor (AIF), which was increased after St and Dox exposure. Our data point to differential neuroprotective efficacy of various mGluR II/III activators in attenuating St- and Dox-evoked cell damage in SH-SY5Y cells, and dependence of the effects on the cellular differentiation state, as well on the type of the pro-apoptotic agent that is employed. Moreover, the neuroprotection mediated by mGluR II/III activators is accompanied by inhibition of caspase-3-independent DNA fragmentation evoked by AIF translocation.

Pretreatment with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline accelerates the electroshock-induced decrease in density of beta-adrenoceptors but not functional downregulation.

Intrapritoneal injection of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) to rats significantly reduced the density of alpha 1- and alpha 2-adrenoceptors in the cerebral cortex, without affecting beta-adrenoceptors. A single dose of EEDQ markedly accelerated the development of downregulation of beta-adrenoceptors induced by a short series of electroshocks. The accumulation of cAMP, induced by isoproterenol, was unchanged in rats treated with EEDQ, while the effect of noradrenaline was reduced, to the level observed after isoproterenol alone, indicating the attenuation of alpha-adrenoceptor function. The isoproterenol-induced accumulation of cAMP was not changed by EEDQ nor electroshock, not by the combined treatment. The stimulatory action of noradrenaline was reduced after EEDQ alone or in combination with electroshock, but the effect of electroshock alone was insignificant. The results suggest that the acceleration of downregulation of beta-adrenoceptors after combined treatment with an alpha-adrenoceptor blocking agent is related to elimination of the alpha-adrenergic potentiation of accumulation of cAMP mediated by beta-adrenoceptors.

Histidine-induced bizarre behaviour in rats: the possible involvement of central cholinergic system.

Histidine injected intraperitoneally into rats in doses from 400 to 800 mg/kg induced a dose-dependent bizarre behaviour. The behaviour after histidine was similar to that observed after L-DOPA and peripheral decarboxylase inhibition. The bizarre behaviour was antagonized by chloropyramine, ketotifen, clemastine and promethazine, antagonists of histamine H1 receptors, with ED50's of 13.9, 14.2, 21.6 and 22.2 mg/kg, respectively. Cimetidine, an antagonist of histamine H2 receptors, injected intraventricularly at a dose of 100 micrograms, was without effect. The bizarre behaviour after histidine was not changed by antagonists of dopamine, noradrenaline and serotonin receptors, but it was blocked by atropine, indicating involvement of central cholinergic systems.

Differential effects of NMDA-receptor antagonists on long-term potentiation and hypoxic/hypoglycaemic excitotoxicity in hippocampal slices.

Whole-cell patch clamp recording from cultured hippocampal neurones was used to investigate the NMDA antagonistic effects of the glycineB antagonist 5,7-DCKA and the competitive antagonist CGP 37849. Extracellular field potential recording from area CA1 of hippocampal slices was used to investigate their effects on the induction of LTP and hypoxia/hypoglycaemia-induced suppression of fEPSPs. Additionally, memantine and (+)MK-801 were tested in the later model. 5,7-DCKA inhibited NMDA-induced plateau currents (IC50=0.24+/-0.02 microM) with around nine times higher potency than against peak (IC50=2.14+/-0.17 microM). In contrast, CGP 37849 slowed the onset of NMDA-induced currents considerably and antagonized currents at the time point when the peak component occurred in control responses (IC50=0.18+/-0.01 microM) with around seven times higher potency than against plateau (IC50=1.26+/-0.19 microM). Both 5,7-DCKA and CGP 37849 inhibited the induction of LTP (IC50s=2.53+/-0.13 and 0.37+/-0.04 microM respectively) with potencies close to those inhibiting peak currents in patch clamp studies. 5,7-DCKA and CGP 37849 also blocked the hypoxia/hypoglycaemia-induced suppression of fEPSPs but CGP 37849 (EC50=4.3+/-0.33 microM) was far less potent than against the induction of LTP whilst 5,7-DCKA (EC50=1.47+/-0.04 microM) had similar potency in these two models. Memantine and (+)MK-801 also blocked hypoxia/hypoglycaemia-induced suppression of fEPSPs with EC50s of 14.1+/-0.52 and 0.53+/-0.02 microM respectively. Whereas memantine blocked this effect with similar potency as we previously reported for LTP, (+)MK-801 was four time less potent in this model. The calculated relative therapeutic indices (IC50 LTP over EC50 hypoxia/hypoglycaemia) for 5,7-DCKA, CGP 37849, memantine and (+)MK-801 were 1.72, 0.09, 0.82 and 0.24 respectively. These results show that even in a severe model of hypoxia/hypoglycaemia, glycineB site antagonists and moderate affinity channel blockers exhibit a better therapeutic index than competitive antagonists and high affinity channel blockers. It is likely that in milder forms of pathology the observed differences in therapeutic indices remain the same but the absolute values are expected to be higher.

The effect of prolonged imipramine and electroconvulsive shock treatment on calcium/calmodulin-dependent protein kinase II in the hippocampus of rat brain.

The phosphorylation of substrate proteins by protein kinases plays a key role in signal transduction and function of neurons. Protein kinases have been associated with several physiological and pathological states including depression. The aim of the present study was to investigate the effect of imipramine and electroconvulsive treatment (ECS), both clinically effective treatments of depression, on the activity of calcium/calmodulin dependent protein kinase II (CaM-KII) in the hippocampus. Our results indicate that repeated (but not acute) imipramine and ECS administration significantly decreased CaM-KII activity by 65 and 70%, respectively, in the soluble fractions from hippocampus. This decreased enzyme activity was accompanied by a proportional decrease (60-70%) of the amount of a-CaM-KII in the same fraction. A single and repeated administration of imipramine produced a significant increase in the activity of CaM-KII (50 and 337%, respectively) in the particulate fraction from hippocampus. Similarly, a single and repeated ECS produced an increase in the enzyme activity by 22 and 240%, respectively. The amount of a-CaM-KII in the particulate fraction was not significantly affected by repeated antidepressant administration. It is postulated that changes in CaM-KII activity following chronic antidepressant treatment might represent and important step in expression of its antidepressive action.

Blockade of the metabotropic glutamate receptor subtype 5 (mGluR5) produces antiparkinsonian-like effects in rats.

The aim of the present study was to examine a potential beneficial effect of the blockade of metabotropic glutamate receptor subtype 5 (mGluR5) by the selective non-competitive antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP), in models of parkinsonian symptoms in rats. Haloperidol, 0.25, 0.5 and 1mg/kg ip, was used to induce hypolocomotion, catalepsy and muscle rigidity, respectively. The locomotor activity was estimated by an open-field test, the catalepsy -- by a 9-cm cork test. The muscle rigidity was measured as an increased resistance of a hind leg to passive extension and flexion at the ankle joint. Additionally, increases in the electromyographic activity were recorded in the gastrocnemius and tibialis anterior muscles. MPEP (1.0-10mg/kg ip) inhibited the muscle rigidity, electromyographic activity, hypolocomotion and catalepsy induced by haloperidol. MPEP administered alone (5mg/kg ip) did not induce catalepsy, nor did it influence the muscle tone or locomotor activity in rats. The present results suggest that blockade of mGluR5 receptors may be important to amelioration of both parkinsonian akinesia and muscle rigidity.

Effect of chronic imipramine or electroconvulsive shock on the expression of mGluR1a and mGluR5a immunoreactivity in rat brain hippocampus.

Previous studies showed that chronic electroconvulsive shock (ECS) or imipramine treatment induced a subsensitivity of group I metabotropic glutamate receptors (mGluR) in hippocampus. In the present study effects of antidepressant treatment on the expression of mGluR1a and mGluR5a, belonging to the group I mGluR, were investigated in rat brain hippocampus using immunohistochemical and Western blot methods, respectively. Male Wistar rats were treated singly or chronically for 21 days with imipramine, 10 mg/kg, twice daily; with ECS (90 mA, 50 Hz, 0.5 s) every second day; or with haloperidol, 1.2 mg/kg, once daily. Appropriate controls were injected with saline. Rats were sacrificed 24 h after the last treatment and their hippocampi were taken out for analysis. It was found that the mGluR1a-immunoreactivity expression increased significantly in Ammon's horn (CA) regions after chronic ECS. The most pronounced effect was observed in the CA3. No significant effects were found after single treatment or after haloperidol. The expression of mGluR5a increased significantly after chronic imipramine in the CA1 and after chronic ECS in the CA3 region. The results obtained indicate an influence of antidepressant treatment on group I mGluR. This increase in the receptor protein level may be a compensatory mechanism developing after chronic treatment.

Potential anti-anxiety, anti-addictive effects of LY 354740, a selective group II glutamate metabotropic receptors agonist in animal models.

Despite there being a lot of biochemical data about metabotropic glutamate (mGlu) receptors, our knowledge of the behavioural effects of mGlu receptor agonists/antagonists is still inadequate. LY 354740 is a systemically active agonist of group II mGlu receptors. After peripheral administration, LY 354740 produced anxiolytic-like effects in the conflict drinking test in rats and a four-plate test in mice. It was also found that LY 354740 decreased spontaneous locomotor activity in mice, but did not disturb motor coordination. In behavioural models of depression including the despair test and a tail suspension test, LY 354740 did not produce antidepressant-like effects. LY 354740 inhibited the naloxone-induced symptoms of morphine withdrawal in morphine-dependent mice. The above results indicate that agonists of group II mGlu receptors may play a role in the therapy of anxiety and/or drug-dependence states. The brain sites of action of LY 354740 need to be identified and the mechanism of both the above described effects remains to be elucidated.

Multiple MPEP administrations evoke anxiolytic- and antidepressant-like effects in rats.

Several lines of evidence suggest a crucial involvement of glutamate in the mechanism of action of anxiolytic and antidepressant drugs. The involvement of group I mGlu receptors in anxiety and depression has also been proposed. In view of the recent discovery of anxiolytic- or antidepressant-like effects of acute injections of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective and brain penetrable mGlu5 receptor antagonist, we designed the present study to examine anxiolytic- and/or antidepressant-like effects of multiple administrations of this drug. The anxiolytic-like effects of MPEP were evaluated in rats using the conflict drinking test. The antidepressant-like effect was estimated using the rat olfactory bulbectomy model of depression. Seven subsequent injections of MPEP (1 mg/kg) significantly (by 320%) increased the number of shocks accepted during the experimental session in the Vogel test. MPEP given once daily at a dose of 10 mg/kg, restored the learning deficit of bulbectomized rats after 14 days of treatment, remaining without any effect in the sham-operated animals. N-methyl-D-aspartic acid (NMDA)-induced convulsions in mice were not affected by a single injection of MPEP (30 mg/kg) indicating that at this dose MPEP did not block NMDA receptors. The results indicate that the prolonged blockade of mGlu5 receptors exerts anxiolytic- and antidepressant-like effects in rats. No tolerance to anxiolytic-like action occurs. The previously mentioned results further indicate that antagonists of group I mGlu receptors may play a role in the therapy of both anxiety and depression.