1,3,8-Triazaspiro[4.5]decane-2,4-diones as efficacious pan-inhibitors of hypoxia-inducible factor prolyl hydroxylase 1-3 (HIF PHD1-3) for the treatment of anemia

The discovery of 1,3,8-triazaspiro[4.5]decane-2,4-diones (spirohydantoins) as a structural class of pan-inhibitors of the prolyl hydroxylase (PHD) family of enzymes for the treatment of anemia is described. The initial hit class, spirooxindoles, was identified through affinity selection mass spectrometry (AS-MS) and optimized for PHD2 inhibition and optimal PK/PD profile (short-acting PHDi inhibitors). 1,3,8-Triazaspiro[4.5]decane-2,4-diones (spirohydantoins) were optimized as an advanced lead class derived from the original spiroindole hit. A new set of general conditions for C-N coupling, developed using a high-throughput experimentation (HTE) technique, enabled a full SAR analysis of the spirohydantoins. This rapid and directed SAR exploration has resulted in the first reported examples of hydantoin derivatives with good PK in preclinical species. Potassium channel off-target activity (hERG) was successfully eliminated through the systematic introduction of acidic functionality to the molecular structure. Undesired upregulation of alanine aminotransferese (ALT) liver enzymes was mitigated and a robust on-/off-target margin was achieved. Spirohydantoins represent a class of highly efficacious, short-acting PHD1-3 inhibitors causing a robust erythropoietin (EPO) upregulation in vivo in multiple preclinical species. This profile deems spirohydantoins as attractive short-acting PHDi inhibitors with the potential for treatment of anemia.     

Current perspectives of the roles of the central norepinephrine system in anxiety and depression

Norepinephrine (NE) is a major monoamine neurotransmitter that has widespread effects across multiple brain areas to regulate arousal and stress responses. The underlying function of the NE cortical system is to balance vigilance/scanning behavior with focused attention on novel environmental stimuli and the state of arousal. The central NE system is involved intrinsically with the stress response system, and dysregulation within the NE system has been implicated in the pathogenesis of anxiety and depressive disorders. Central NE activity paradoxically has either anxiogenic or anxiolytic effects, depending on whether the time course of the stress is acute or chronic, whether the stress is predictable or unpredictable, and which underlying brain regions are affected. Under conditions of chronic stress, NE system activity dysregulation of the hypothalamic‐pituitary‐adrenal system may turn a homeostatic stress response into a pathological stress response. Data suggest that the NE interplay with the serotonin system may exert neurobiological normalization of the pathophysiological state of anxious depression. Accordingly, pharmacological interventions targeting the NE system can result in anxiolytic, rather than anxiogenic, outcomes when used to treat patients with anxiety and depression. Depression and Anxiety, 2010. © 2009 Wiley‐Liss, Inc.     

What is the purpose of launching the World Journal of Psychiatry?

The first issue of World Journal of Psychiatry (WJP), whose preparatory work was initiated on May 18, 2011, will be published on December 31, 2011. The WJP Editorial Board has now been established and consists of 103 distinguished experts from 32 countries. Our purpose of launching WJP is to publish peer-reviewed, high-quality articles via an open-access online publishing model, thereby acting as a platform for communication between peers and the wider public, and maximizing the benefits to editorial board members, authors and readers.     

Exposure to high- and low-light conditions in an open-field test of anxiety increases c-Fos expression in specific subdivisions of the rat basolateral amygdaloid complex

Anxiety states and anxiety-related behaviors appear to be regulated by a distributed and highly interconnected system of forebrain structures including the basolateral amygdaloid complex (basolateral amygdala). Despite a wealth of research examining the role of the basolateral amygdala in anxiety-related behaviors and anxiety states, the specific subdivisions of the basolateral amygdala that are involved in responses to anxiogenic stimuli have not been examined. In this study, we investigated the effects of exposure to a novel open-field environment, with either low- or high-levels of illumination, on expression of the protein product of the immediate-early gene c-Fos in subdivisions of the rat basolateral amygdala. The subdivisions studied included the lateral, ventrolateral and ventromedial parts of the lateral amygdaloid nucleus, the anterior, posterior and ventral parts of the basolateral amygdaloid nucleus and the anterior and posterior part of the basomedial amygdaloid nucleus. Small increases in the number of c-Fos-immunoreactive cells were observed in several, but not all, of the subdivisions of the basolateral amygdala studied following exposure of rats to either the high- or low-light conditions, compared to home cage or handled control groups. Open-field exposure in both the high- and low-light conditions resulted in a marked increase in c-Fos expression in the anterior part of the basolateral amygdaloid nucleus compared to either home cage or handled control groups. These findings point toward anatomical and functional heterogeneity within the basolateral amygdaloid complex and an important role of the anterior part of the basolateral amygdaloid nucleus in the neural mechanisms underlying physiological or behavioral responses to this anxiety-related stimulus.     

Quantitative trait locus for body weight identified on rat chromosome 4 in inbred alcohol-preferring and -nonpreferring rats: Potential implications for neuropeptide Y and corticotrophin releasing hormone 2

The alcohol-preferring (P) and -nonpreferring (NP) rat lines were developed using bidirectional selective breeding for alcohol consumption (g/kg/day) and alcohol preference (water:ethanol ratio). During a preliminary study, we detected a difference in body weight between inbred P (iP) and inbred NP (iNP) rats that appeared to be associated with the transfer of the Chromosome 4 quantitative trait locus (QTL) seen in the P.NP and NP.P congenic strains. After the initial confirmation that iP rats displayed lower body weight when compared to iNP rats (data not shown), body weight and growth rates of each chromosome 4 reciprocal congenic rat strain (P.NP and NP.P) were measured, and their body weight was consistent with their respective donor strain phenotype, confirming that a quantitative trait locus for body weight mapped to the chromosome 4 interval. Utilizing the newly developed interval-specific congenic strains (ISCS-A and ISCS-B), the QTL interval was further narrowed identifying the following candidate genes of interest: neuropeptide Y (Npy), juxtaposed with another zinc finger gene 1 (Jazf1), corticotrophin releasing factor receptor 2 (Crfr2) and LanC lantibiotic synthetase component C-like 2 (Lancl2). These findings indicate that a biologically active variant(s) regulates body weight on rat chromosome 4 in iP and iNP rats. This QTL for body weight was successfully captured in the P.NP and NP.P congenic strains, and interval-specific congenic strains (ISCSs) were subsequently employed to fine-map the QTL interval identifying the following candidate genes of interest: Npy, Jazf1, Crfr2 and Lancl2. Both Npy and Crfr2 have been previously identified as candidate genes of interest underlying the chromosome 4 QTL for alcohol consumption in iP and iNP rats.     

Gross total excision of pediatric giant cystic craniopharyngioma with huge retroclival extension to the level of foramen magnum by anterior trans petrous approach: report of two cases and review of literature

Purpose Craniopharyngiomas with a large posterior fossa extension beyond the level of the foramen magnum are very rare and usually removed in two stages. The objective of this paper is to report that such rare cases of giant cystic predominantly retrochiasmatic retroclival craniopharyngiomas can be completely excised by an anterior transpetrous approach in a single stage. Materials and methods The first case was a 6-year-old boy who presented with a 1-year history of recurrent episodes of seizures, headache, and vomiting. The second case was a 10-year-old girl who presented with history of headache, visual deterioration, and left-side hemiparesis for one and half years. Preoperative computed tomography (CT) and magnetic resonance imaging (MRI) in both these patients revealed a giant sellar suprasellar cystic lesion with areas of calcification and the lesion was predominantly retrochiasmatic with a huge retroclival posterior fossa extension down to the level of the C1 vertebra and laterally to the cerebellopontine angle. Gross total excision of both suprasellar and posterior fossa extensions could be done in both the patients through an anterior transpetrous transtentorial approach (Kawase’s approach). Results Postoperative imaging (MRI/CT) revealed no obvious evidence of residual tumor. The first patient had right hemiparesis from which he recovered completely. The second patient died suddenly on postoperative day 4 after initial uneventful postoperative period, and the exact cause of death is not known. Conclusion Giant cystic craniopharyngiomas, which are predominatly retrochiasmatic and associated with huge retroclival posterior fossa extensions, can be removed in single stage by Kawase’s approach.     

Eyeblink conditioning anomalies in bipolar disorder suggest cerebellar dysfunction

Objectives:  Accumulating research implicates the cerebellum in non-motor psychological processes and psychiatric diseases, including bipolar disorder (BD). Despite recent evidence that cerebellar lesions have been documented to trigger bipolar-like symptoms, few studies have directly examined the functional integrity of the cerebellum in those afflicted with BD.
Methods:  Using a single-cue delay eyeblink conditioning procedure, the functional integrity of the cerebellum was examined in 28 individuals with BD (9 manic, 8 mixed, and 11 euthymic) and 28 age-matched healthy controls.
Results:  Analysis of the bipolar group as a whole indicated a conditioned response acquisition and timing deficit compared to controls. However, when the bipolar group was categorized according to mood state (mixed, manic, euthymic), individuals tested during mixed episodes were strikingly impaired, performing significantly worse than all other groups on both the acquisition and timing of conditioned responses.
Conclusions:  These findings extend prior research implicating cerebellar functional abnormalities in BD and suggest that cerebellar dysfunction may be associated with mood state and course of illness.