Current Pharmaceutical Design - Volume 17, Issue 2, 2011

The glutamatergic system is involved in a wide range of physiological processes in the brain, and its dysfunction plays an important role in the etiology and pathophysiology of psychiatric disorders, including schizophrenia. Among the glutamate receptors, metabotropic glutamate receptors (mGlu receptors) have emerged as attractive therapeutic targets for the development of novel interventions for psychiatric disorders. Among them, group II mGlu receptors, such as mGlu2 and mGlu3 receptors, are of particular interest because of their unique distribution and the regulatory roles they have in neurotransmission. Recently, potent agonists for mGlu2/3 receptor have been synthesized, and their pharmacological roles have been intensively investigated in animal models. The efficacy for the treatment of schizophrenia has also been proven in a clinical trial. Recently, much attention has been paid to mGlu2 receptor potentiators, which potentiate the glutamate response without affecting the actual activity of the mGlu2 receptor. In addition, mGlu1 receptor antagonists have recently been proposed as an attractive approach to developing novel antipsychotics in animal models. This review describes the potential of both mGlu2/3 receptor agonists/potentiators and mGlu1 receptor antagonists for the treatment of schizophrenia.

D-Amino acid oxidase (DAAO) catalyzes the oxidative metabolism of D-amino acids including D-serine, a full agonist at the allosteric glycine binding site of the NMDA receptor. D-serine was reported to improve negative and cognitive symptoms of schizophrenia, symptoms poorly addressed by the standard D2 antagonist therapies. Therefore, inhibition of DAAO has gained substantial interest as an effective way to increase D-serine levels in the brain. During the last several years, a growing number of structurally diverse DAAO inhibitors have been identified with significantly higher inhibitory potency compared to the conventional DAAO inhibitors. Some of these new generation of DAAO inhibitors are being evaluated for their ability to enhance D-serine levels in rodents and efficacy in animal models of schizophrenia. This article highlights the progress that has been made toward the discovery of DAAO inhibitors and recent efforts to exploit their therapeutic utility in schizophrenia.

The hypofunction hypothesis of glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) receptors in the pathophysiology of schizophrenia suggests that increasing NMDA receptor function via pharmacological manipulation could provide a new therapeutic strategy for schizophrenia. The glycine modulatory site on NMDA receptor complex is the one of the most attractive therapeutic targets for schizophrenia. One means of enhancing NMDA receptor neurotransmission is to increase the availability of the obligatory co-agonist glycine at modulatory site on the NMDA receptors through the inhibition of glycine transporter-1 (GlyT-1) on glial cells. Some clinical studies have demonstrated that the GlyT-1 inhibitor sarcosine (N-methylglycine) shows antipsychotic activity in patients with schizophrenia. Currently, a number of pharmaceutical companies have been developing novel and selective GlyT-1 inhibitors for the treatment of schizophrenia. A recent double blind phase II study demonstrated that the novel GlyT-1 inhibitor RG1678 has a robust and clinically meaningful effect in patients with schizophrenia. In this article, the author reviews the recent findings on the GlyT-1 as a potential therapeutic target of schizophrenia.

Accumulating evidence suggests that the α7 subtype of nicotinic acetylcholine receptors (nAChRs) plays a role in the pathophysiology of schizophrenia. Deficits in auditory P50 evoked potential suppression in patients with schizophrenia are associated with decreased density of α7 nAChRs in the brain. Some agonists (e.g., DMXB-A and tropisetron) at α7 nAChRs can improve P50 deficits in patients with schizophrenia. Together, these findings indicate that α7 nAChRs are a potential therapeutic target for schizophrenia. Currently, a number of agonists and allosteric modulators at α7 nAChRs are under development as potential therapeutic drugs. In this article, we review recent topics on α7 nAChR agonists and α7 nAChR allosteric modulators as therapeutic drugs for schizophrenia.

The disturbance of the dopaminergic neurotransmission is a key-feature in the neurobiology of schizophrenia. The interaction between the dopaminergic and the glutamatergic neurotransmission, however, attracted more notice to the glutamatergic system. Recent research focussed on factors influencing the glutamatergic neurotransmission. A pro-inflammatory immune state influences the glutamatergic neurotransmission indirectly by its effects on the tryptophan/kynurenine metabolism. The immune response in schizophrenia seems to be associated with the activation of the enzyme indoleamine 2,3-dioxygenase (IDO) and imbalance in the tryptophan/kynurenine metabolism resulting in increased production of kynurenic acid in the brain. This is associated with an imbalance in the glutamatergic neurotransmission, leading to an NMDA antagonism in schizophrenia. The immunological effects of antipsychotics reverse partly the immune imbalance and the unphysiologically enhanced production of the kynurenic acid. These immunological and neurochemical imbalances result in a chronic pro-inflammatory state in association with increased prostaglandin E2 (PGE2) production, increased cyclo-oxygenase-2 (COX-2) expression and increased pro-inflammatory cytokines production and NMDA receptor hypofunctioning. Substances acting directly on the kynurenine metabolism are still in very early stages of development, anti-inflammatory drugs acting indirectly on this metabolism are discussed as therapeutic or preventive agents in schizophrenia. Most of the existing data are related to COX-2 inhibitors, which have been tested in animal experiments and in clinical trials, pointing to favourable effects in schizophrenia.

Schizophrenia is a chronic, severe, and disabling brain disorder that affects about 1 percent of people worldwide. The manifestations of this disorder are positive symptoms (e.g., hallucinations, delusions, racing thoughts), negative symptoms (e.g., apathy, lack of emotion, poor or nonexistent social functioning), and cognitive deficits (e.g., poor executive functioning, trouble focusing or paying attention, problems with working memory). Although current treatments with antipsychotic drugs can eliminate some these symptoms in patients with schizophrenia, these drugs are not effective against negative symptoms and cognitive deficits. Although the precise causes of schizophrenia have not been determined, a number of pharmaceutical companies have been developing novel therapeutic drugs to treat this disorder. In this special issue, a multidisciplinary team of international experts discusses all the most relevant topics on novel therapeutic targets for schizophrenia. Multiple lines of evidence have implicated abnormalities in both glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) and metabotropic glutamate receptors (mGluRs) in the pathophysiology of schizophrenia. In this issue, Chaki and Hikichi (Taisho Pharmaceutical Co., Ltd., Japan) review recent topics in novel mGluR agonists/antagonists as novel potential therapeutic drugs for schizophrenia [1]. Considering the NMDA receptor hypofunction hypothesis for schizophrenia, the NMDA receptor glycine modulatory site is the most attractive therapeutic target for this disorder. Currently, D-serine (an endogenous co-agonist at the glycine modulatory site) and glycine transporter-1 (GlyT-1) inhibitors are considered potential therapeutic drugs for schizophrenia. Although D-amino acids including D-serine and D-alanine have been shown to be effective in the treatment of schizophrenia, these D-amino acids are metabolized by D-amino acid oxidase (DAAO) in the peripheral organs, reducing their bioavailability in the brain. In this issue, Ferraris and Tsukamoto (The Johns Hopkins University, USA) review recent topics in novel DAAO inhibitors as potential therapeutic drugs for schizophrenia [2]. Furthermore, Hashimoto (Chiba University, Japan) reviews recent findings on novel GlyT-1 inhibitors as potential therapeutic drugs [3]. Accumulating evidence suggests that the α7 subtype of nicotinic acetylcholine receptors (α7 nAChRs) plays an important role in the P50 auditory evoked-potential deficits in patients with schizophrenia, and that α7 nAChR agonists would be potential therapeutic drugs for cognitive deficits associated with P50 deficits in schizophrenia. In this issue, Ishikawa and Hashimoto (Chiba University, Japan) review recent topics in ??7 nAChRs in the pathophysiology of schizophrenia and on novel α7 nAChR agonists as potential therapeutic drugs [4]. In contrast, kynurenic acid, a product of the normal metabolism of the amino acid L-tryptophan, is the endogenous antagonist at NMDA receptors as well as at α7 nAChRs. Müller et al. (Ludwig-Maximilians University, Germany) review recent topics in the kynurenic acid pathway in the pathophysiology of schizophrenia [5]. Phosphodiesterase 10A (PDE10A) is a basal ganglia-specific hydrolase that plays an essential role in regulating cAMP/PKA and cGMP/PKG signaling cascades in the brain. Biochemical and behavioral data indicate that PDE10A inhibition activates cAMP/PKA signaling in the basal ganglia, leading to the potentiation of dopamine D1- and adenosine A2A-receptor signaling, with concomitant inhibition of dopamine D2- and adenosine A1-receptor signaling. In this issue, Kehler (Lundbeck A/S, Denmark) reviews novel PDE10A inhibitors as new treatments for schizophrenia [6]....

Disturbances of the basal ganglia processes is heavily involved in schizophrenia. Phosphodiesterase 10A (PDE10A) is a basal ganglia specific hydrolase, which plays an essential role in regulating cAMP/PKA and cGMP/PKG signalling cascades by controlling the magnitude, duration and cellular location of cAMP/cGMP elevation. Biochemical and behavioral data indicate that PDE10A inhibition activates cAMP/PKA signalling in the basal ganglia, leading to the potentiation of dopamine D1 receptor signalling, and concomitant inhibition of dopamine D2 receptor signalling. Preclinical evidence in a range of animal models suggests that a PDE10A inhibitor could provide efficacy on positive, cognitive and negative symptoms of schizophrenia and PDE10A inhibitors are currently being evaluated in clinical trials for the treatment of schizophrenia.

The enzyme steroid 5α-reductase (S5αR) catalyzes the conversion of Δ4-3-ketosteroid precursors - such as testosterone, progesterone and androstenedione - into their 5α-reduced metabolites. Although the current nomenclature assigns five enzymes to the S5αR family, only the types 1 and 2 appear to play an important role in steroidogenesis, mediating an overlapping set of reactions, albeit with distinct chemical characteristics and anatomical distribution. The discovery that the 5α-reduced metabolite of testosterone, 5α- dihydrotestosterone (DHT), is the most potent androgen and stimulates prostatic growth led to the development of S5αR inhibitors with high efficacy and tolerability. Two of these agents, finasteride and dutasteride, have received official approval for the treatment of benign prostatic hyperplasia and are being tested for prevention of prostate cancer. Finasteride is also approved for male-pattern alopecia and has been shown to induce very limited side effects. Over the last decade, converging lines of evidence have highlighted the role of 5α- reduced steroids and their precursors in brain neurotransmission and behavioral regulation. Capitalizing on these premises, we and other groups have recently investigated the role of S5αR in neuropsychiatric disorders. Our preliminary data suggest that S5αR inhibitors may elicit therapeutic effects in a number of disorders associated with dopaminergic hyperreactivity, including psychotic disorders, Tourette syndrome and impulse control disorders. In the present article, we review emerging preclinical and clinical evidence related to these effects, and discuss some of the potential mechanisms underlying the role of S5αR in the pathophysiology of mental disorders.

Schizophrenia is a debilitating mental disorder that afflicts about 1% of the population worldwide. Despite intensive, multifaceted research, its exact etiology remains elusive. Epidemiological data shows that when pregnant mothers experienced malnutrition or famine (e.g. the Dutch Hunger Winter of 1994-1945 and the Chinese famine of 1959-1961), the risk of schizophrenia in their children increased by two fold. This fact could be considered in the context of Developmental Origins of Health and Disease (DOHaD) or fetal programming. The concept of DOHaD is well referenced in the understanding of adult metabolic diseases, but less so in the field of mental disorders. We will attempt to show how the mechanisms of DOHaD could contribute at least in part to schizophrenia pathogenesis. Resonating with this concept, we introduce mainly our data showing increased expression of genes for fatty acid binding proteins (FABPs) in the postmortem brains from patients with schizophrenia and the beneficial effect conferred by the administration of polyunsaturated fatty acids (PUFAs) during the early developmental period of rats.

Schizophrenia is one of the most disabling psychiatric conditions. Current treatments target monoamine receptors but this approach does not address the full complexity of the disorder. Here we explore the possibility of developing new anti-psychotics by targeting microRNAs (miRNAs), single stranded RNA molecules, 21-23 nucleotides in length that are not translated into proteins and regulate gene expression. The present review reveals that research involving schizophrenia and miRNA is very recent (the earliest report from 2007) and miRNAs add a significant layer of complexity to the pathophysiology of the disorder. However, miRNAs offer an exciting potential not only to understand the underlying mechanisms of schizophrenia, but also for the future development of antipsychotics, as the human miRNA system provides a rich and diverse opportunity for pharmacological targeting. However, technology is still developing in order to produce effective strategies to modulate specific and localized changes in miRNA, particularly in relation to the central nervous system and schizophrenia.