Cyclooxygenase (COX) is a heme-containing enzyme that produces prostaglandins (PGs) via a pathway known as the arachidonic acid (AA) cascade. Two isoforms of COX enzyme (COX-1 and COX-2) and splice variant (COX-3) have been described so far. COX-2 is a neuronal enzyme that is intensively produced during activation of the synapse and glutamate (Glu) release. The end product of COX-2 action, prostaglandin E2 (PGE2), regulates Glu level in a retrograde manner. At the same time, the level of Glu, the primary excitatory neurotransmitter, is regulated in the excitatory synapse via Glu receptors, both ionotropic and metabotropic ones. Glu receptors are known modulators of behavior, engaged in cognition and mood. So far, the interaction between ionotropic N-methyl-D-aspartate (NMDA) receptors or metabotropic glutamate (mGluRs) receptors and COX-2 was found. Here, based on literature data and own research, a new mechanism of action of COX-2 in an excitatory synapse will be presented.

Multiple N-methyl-d-aspartate (NMDA)-receptor-enhancing agents have demonstrated promising effects for cognition in schizophrenia. However, the results of studies have been conflicting. This updated meta-analysis explored the effect of NMDA-receptor-enhancing agents on cognitive function.
We searched PubMed, the Cochrane Collaboration Central Register of Controlled Clinical Trials and Cochrane Systematic Reviews for studies on the effect of NMDA-receptor-enhancing agents on cognitive function in patients with schizophrenia up to September 2018. Double-blind randomised placebo trials with cognition rating scales were included. We pooled studies by using a random-effect model for comparisons with add-on NMDA-receptor-enhancing agents. Cognitive function scores were compared between baseline and subsequent levels, and NMDA-receptor-positive modulators were assessed using the standardised mean difference (SMD) with 95% confidence intervals (CIs). We evaluated statistical heterogeneity through visual inspection of funnel plots and by using the I2 statistic.
We identified 25 trials with 1951 participants meeting the inclusion criteria. NMDA-receptor-enhancing agents had a small but nonsignificant effect compared with the placebo on overall cognitive function (SMD = 0.068, CI = -0.056 to 0.193, P = 0.283). We identified trials enrolling patients aged between 30 and 39 years old, which reported significant positive effects (SMD: 0.163, 95% CI: 0.016-0.310, P = 0.030). Men were associated with a smaller effect of NMDA-receptor-positive modulators on overall cognitive function. Moreover, subgroup meta-analysis of cognitive domains revealed that N-acetyl cysteine (NAC) had a significant effect on working memory ( P-value for interaction = 0.038; SMD = 0.679, CI = 0.397-0.961, P < 0.001).
Our meta-analysis revealed no significant effect of NMDA-enhancing agents on overall cognition. However, subgroup analysis suggested that NMDAR-enhancing agents may benefit young patients with schizophrenia, and NAC may have an effect on working memory. Additional trials with larger samples are suggested to evaluate these cognitive domains and ascertain the possible mechanisms.

Whether and under which conditions D-cycloserine (DCS) augments the effects of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders is unclear.
To clarify whether DCS is superior to placebo in augmenting the effects of cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders and to evaluate whether antidepressants interact with DCS and the effect of potential moderating variables.
PubMed, EMBASE, and PsycINFO were searched from inception to February 10, 2016. Reference lists of previous reviews and meta-analyses and reports of randomized clinical trials were also checked.
Studies were eligible for inclusion if they were (1) double-blind randomized clinical trials of DCS as an augmentation strategy for exposure-based cognitive behavior therapy and (2) conducted in humans diagnosed as having specific phobia, social anxiety disorder, panic disorder with or without agoraphobia, obsessive-compulsive disorder, or posttraumatic stress disorder.
Raw data were obtained from the authors and quality controlled. Data were ranked to ensure a consistent metric across studies (score range, 0-100). We used a 3-level multilevel model nesting repeated measures of outcomes within participants, who were nested within studies.
Individual participant data were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants. When controlling for antidepressant use, participants receiving DCS showed greater improvement from pretreatment to posttreatment (mean difference, -3.62; 95% CI, -0.81 to -6.43; P = .01; d = -0.25) but not from pretreatment to midtreatment (mean difference, -1.66; 95% CI, -4.92 to 1.60; P = .32; d = -0.14) or from pretreatment to follow-up (mean difference, -2.98, 95% CI, -5.99 to 0.03; P = .05; d = -0.19). Additional analyses showed that participants assigned to DCS were associated with lower symptom severity than those assigned to placebo at posttreatment and at follow-up. Antidepressants did not moderate the effects of DCS. None of the prespecified patient-level or study-level moderators was associated with outcomes.
D-cycloserine is associated with a small augmentation effect on exposure-based therapy. This effect is not moderated by the concurrent use of antidepressants. Further research is needed to identify patient and/or therapy characteristics associated with DCS response.

D-Cycloserine, known from tuberculosis therapy, has been widely introduced to neuropsychiatric studies, since its central active mechanism as a partial NMDA-agonist has been found. In this review, we evaluate its therapeutic potential in neuropsychological disorders and discuss its pitfalls in terms of dosing and application frequency as well as its safety in low-dose therapy. Therefore, we identified 91 clinical trials by performing a Medline search. We demonstrate in part preliminary but increasing evidence that D-cycloserine may be effective in various psychiatric diseases, including schizophrenia, anxiety disorders, addiction, eating disorders, major depression, and autism as well as in neurological diseases, including dementia, Alzheimer\'s disease, and spinocerebellar degeneration. D-Cycloserine in low-dose therapy is safe, but there is still a need for new drugs with higher specificity to the different N-methyl-D-aspartate-receptor subunits.

Motor complications (dyskinesias and motor fluctuations) are a common and disabling problem of dopaminergic therapy in Parkinson\'s disease, which are often difficult to treat with the current therapeutic strategies. It has been proposed that continuous dopaminergic delivery could reduce the emergence of motor complications, which has been tried with levodopa intestinal infusion or subcutaneous apomorphine infusion. In selected refractory cases, surgical approaches such as deep brain stimulation should be considered. Ongoing clinical and preclinical research tried to lead the field into the discovery of other therapeutic targets and strategies that might prevent or reduce motor complications. These include drugs targeting non-dopaminergic systems (e.g. glutamatergic, serotonergic, noradrenergic, adenosinergic and cholinergic systems), gene therapy for delivering neurotrophic factors or critical enzymes for dopamine synthesis, and cell therapy. These studies found variable results, some of them promising, with the possibility of new therapeutic armamentarium in the management of Parkinson\'s disease in the near future.

BACKGROUND: Metabotropic glutamate receptor 4 (mGlu(4)) is a group III GPCR and has been demonstrated to play a major role in a number of therapeutic areas within the CNS. As the orthosteric site of all glutamate receptors is highly conserved, modulating mGlu(4) via allosteric modulation has emerged as a very attractive mode-of-action and has been validated preclinically in a number of animal models for Parkinson\'s disease, anxiety, pain, and neuroinflammation.
METHODS: In this review, the patent literature for mGlu(4)-positive allosteric modulators over the past 4 years will be provided. Patents from all companies are discussed and an overview of the chemical matter and relevant biological properties will be given.
CONCLUSIONS: Although there has yet to be an mGlu(4)-positive allosteric modulator progressed into clinical trials, there is a wealth of preclinical data from the primary literature that shows the promise of this emerging target. A number of academic and industry laboratories have recently published exciting patent data covering a multitude of chemical matter. Positive allosteric modulation of mGlu(4) remains one of the more attractive non-dopaminergic therapies for Parkinson\'s disease, as well as emerging data for other indications such as pain, neuroinflammation, schizophrenia and diabetes, which could potentially make mGlu(4) a significant therapeutic target going forward.

There is accumulating evidence to implicate the importance of N-methyl-D-aspartate (NMDA) receptors to the induction and maintenance of central sensitization during pain states. However, NMDA receptors may also mediate peripheral sensitization and visceral pain. NMDA receptors are composed of NR1, NR2 (A, B, C, and D), and NR3 (A and B) subunits, which determine the functional properties of native NMDA receptors. Among NMDA receptor subtypes, the NR2B subunit-containing receptors appear particularly important for nociception, thus leading to the possibility that NR2B-selective antagonists may be useful in the treatment of chronic pain.

Degeneration of dopaminergic nigrostriatal neurons is a primary cause of Parkinson\'s disease. Oxidative stress, excitotoxicity and mitochondrial failure are thought to be key mechanisms responsible for degeneration of dopaminergic cells. We found that the selective antagonist of the mGluR5 subtype MPEP in a dose of 5 mg/kg diminished basal and veratridine (100 microM)-stimulated dopamine release in rat striatum in an in vivo model of microdialysis. In contrast, MPEP given intrastriatally in a high concentration (500 microM) enhanced the striatal extracellular concentration of dopamine. DCG-IV (100 microM), a non-selective agonist of group II mGluRs, inhibited the veratridine-stimulated striatal dopamine release. In an animal model of neuroxicity in vivo, methamphetamine (5 x 10 mg/kg, injected at 2 h intervals) produced deficits in the striatal content of dopamine and its metabolites DOPAC and HVA 72 h after the treatment. MPEP (5 x 5 mg/kg) given before each methamphetamine injection reversed the decrease in the striatal content of dopamine and diminished the methamphetamine-induced dopamine outflow from nigrostriatal terminals. It is concluded that the MPEP-produced blockade of mGluR5 situated on dopaminergic cells, or the suppression of glutamate release in the subthalamic nucleus or substantia nigra pars reticulata may directly and indirectly cause a decrease in striatal dopamine release. However, inhibitory effect of DCG-IV on dopamine release can be induced by attenuation of excitatory input from corticostriatal terminals by activation of mGluR2/3. Regulation of dopamine carriers by MPEP, an antagonist of group I mGluRs may be responsible for the reversal of toxicity induced by methamphetamine.

3,5-dihydroxyphenylglycine (3,5-DHPG) was the first agonist shown to be group I metabotropic glutamate receptor selective with its agonist effects residing exclusively in the S-isomer. Some results suggest that (S)-3,5-DHPG may be a partial agonist of mGluR1a and mGluR5a in neurons and astrocytes. It has been reported that (S)-3,5-DHPG can, under certain conditions, interact with NMDA receptors. (S)-3,5-DHPG exerts different effects on second messengers in adult and neonatal tissues. It stimulates phosphoinositide hydrolysis in a dose-dependent manner in both the adult and neonate hippocampus, inhibits stimulated cAMP levels in the adult and enhances the cAMP in the neonate. It is an effective antagonist of mGluRs linked to phospholipase D (PLD) in the adult and an agonist in the neonate brain or astrocyte cultures. (S)-3,5-DHPG induces elevation of [Ca2+]i and regulates multiple subtypes of Ca2+ channels. This agonist of group I mGluRs may modulate neurotransmitters release, reflecting the diversity of mechanisms involved. Depending on the dose, (S)-3,5-DHPG enhances or decreases excitatory postsynaptic potentials (EPSPs) and under appropriate conditions it can induce long-term depression (LTD) and long-term potentiation (LTP). Some studies suggested a therapeutic role for (S)-3,5-DHPG in neuronal injury, regulation of intestinal motility and secretion, learning and memory processes and in cardiovascular system. (S)-3,5-DHPG may be useful as a cognitive enhancing agent in memory impairment associated with ischemia or hypoxia. Recent investigations suggested possible beneficial effects of (S)-3,5-DHPG in Alzheimer\'s disease.

Besides its fast excitatory properties, glutamate is known to have neurotoxic properties when released in large amounts or when incompletely recycled. This so-called excitotoxicity is involved in a number of acute and/or degenerative forms of neuropathology such as epilepsy, Alzheimer\'s, Parkinson\'s, stroke, and retinal ischemia. In the cochlea, excitotoxicity may occur in two pathological conditions: anoxia and noise trauma. It is characterized by a two-step mechanism: (1) An acute swelling, which primarily depends on the AMPA/kainate type of receptors, together with a disruption of the postsynaptic structures (type I afferent dendrites) resulting in a loss of function. Within the next 5 days, synaptic repair may be observed with a full or a partial (acoustic trauma) recovery of cochlear potentials. (2) The second phase of excitotoxicity, which may develop after strong and/or repetitive injury, consists of a cascade of metabolic events triggered by the entry of Ca2+, which leads to neuronal death in the spiral ganglion. Ongoing experiments in animals, tracking the molecular basis of both these processes, presages the development of new pharmacological strategies to help neurites to regrow and reconnect properly to the IHCs, and to prevent or delay neuronal death in the spiral ganglion. Human applications should follow, and a local (transtympanic) strategy against cochlear excitotoxicity may, in the near future, prove to be helpful in ischemic- or noise-induced sudden deafness, as well as in the related tinnitus.