Histone deacetylases: Focus on the nervous system

Neurodegenerative disease strikes millions worldwide and there is mounting evidence suggesting that underlying the onset and progression of these debilitating diseases is inappropriate neuronal apoptosis. Recent reports have implicated a family of proteins known as histone deacetylases (HDACs) in various neuronal processes including the neuronal death program. Initial headway in this field has been made largely through the use of broad-spectrum HDAC inhibitors. In fact, pharmacological inhibition of HDAC activity has been shown to protect neurons in several models of neurodegeneration. The observation that HDAC inhibitors can have opposing effects in different paradigms of neurodegeneration suggests that individual members of the HDAC protein family may play distinct roles that could depend on the specific cell type under study. The purpose of this review is to detail work involving the use of HDAC inhibitors within the context of neurodegeneration and examine the roles of individual HDAC members in the nervous system with specific focus on neuronal cell death. Received 25 January 2007; received after revision 3 April 2007; accepted 26 April 2007     

Glycine receptors and glycine transporters: targets for novel analgesics?

Glycinergic neurotransmission has long been known for its role in spinal motor control. During the last two decades, additional functions have become increasingly recognized—among them is a critical contribution to spinal pain processing. Studies in rodent pain models provide proof-of-concept evidence that enhancing inhibitory glycinergic neurotransmission reduces chronic pain symptoms. Apparent strategies for pharmacological intervention include positive allosteric modulators of glycine receptors and modulators or inhibitors of the glial and neuronal glycine transporters GlyT1 and GlyT2. These prospects have led to drug discovery efforts in academia and in industry aiming at compounds that target glycinergic neurotransmission with high specificity. Available data show promising analgesic efficacy. Less is currently known about potential unwanted effects but the presence of glycinergic innervation in CNS areas outside the nociceptive system prompts for a careful evaluation not only of motor function, but also of potential respiratory impairment and addictive properties.     

Opioids and behavior: genetic aspects

Three animal models, based on genetic differences in endogenous opioid peptides and opioid receptors, are described. Obese mice and rats, whose pituitary opioid content is elevated, may be used to investigate eating disorders. Recombinant inbred strains of mice, which differ in brain opioid receptors and analgesic responsiveness, can be used for study of opioid- and nonopioid-mediated mechanisms of pain inhibition. Individual reactivity to opioids can be examined in C57BL/6 and DBA/2 inbred strains of mice. A model that combines a variety of opioid effects is offered and suggests the existence of a genetically determined dissociation of opioid effects on locomotor activity and pain inhibition. In addition, stimulatory locomotor responses in the C57BL/6 reaction type are linked to a high risk of drug addiction and facilitatory effects on adaptive processes, while high analgesic potency in the DBA/2 reaction type is accompanied by a low proneness to drug abuse and amnesic properties of opioids.     

Opioids and behavior: genetic aspects

Summary Three animal models, based on genetic differences in endogenous opioid peptides and opioid receptors, are described. Obese mice and rats, whose pituitary opioid content is elevated, may be used to investigate eating disorders. Recombinant inbred strains of mice, which differ in brain opioid receptors and analgesic responsiveness, can be used for study of opioid-and nonopioid-mediated mechanisms of pain inhibition. Individual reactivity to opioids can be examined in C57BL/6 and DBA/2 inbred strains of mice. A model that combines a variety of opioid effects is offered and suggests the existence of a genetically determined dissociation of opioid effects on locomotor activity and pain inhibition. In addition, stimulatory locomotor responses in the C57BL/6 reaction type are linked to a high risk of drug addiction and facilitatory effects on adaptive processes, while high analgesic potency in the DBA/2 reaction type is accompanied by a low proneness to drug abuse and amnesic properties of opioids.     

Galanin – 25 years with a multitalented neuropeptide

There has been increasing interest in the ability of neuropeptides involved in feeding to modulate circuits important for responses to drugs of abuse. A number of peptides with effects on hypothalamic function also modulate the mesolimbic dopamine system (ventral tegmental area and nucleus accumbens). Similarly, common stress-related pathways can modulate food intake, drug reward and symptoms of drug withdrawal. Galanin promotes food intake and the analgesic properties of opiates; thus it initially seemed possible that galanin might potentiate opiate reinforcement. Instead, galanin agonists decrease opiate reward, measured by conditioned place preference, and opiate withdrawal signs, whereas opiate reward and withdrawal are increased in knock-out mice lacking galanin. This is consistent with studies showing that galanin decreases activity-evoked dopamine release in striatal slices and decreases the firing rate of noradrenergic neurons in locus coeruleus, areas involved in drug reward and withdrawal, respectively. These data suggest that polymorphisms in genes encoding galanin or galanin receptors might be associated with susceptibility to opiate abuse. Further, galanin receptors might be potential targets for development of novel treatments for addiction.     

LIM domain only 4 protein promotes granulocyte colony-stimulating factor-induced signaling in neurons

Granulocyte colony-stimulating factor (GCSF) is currently in clinical trials to treat neurodegenerative diseases and stroke. Here, we tested whether LIM domain only 4 protein (LMO4), a hypoxia-inducible gene that protects neurons from ischemic injury, could modulate the neuroprotective effect of GCSF. We showed that GCSF treatment acetylates and phosphorylates Stat3, activates expression of a Stat3-dependent anti-apoptotic gene, p27, and increases neuron survival from ischemic injury. LMO4 participates in Stat3 signaling in hepatocytes and associates with histone deacetylase 2 (HDAC2) in cancer cells. In the absence of LMO4, GCSF fails to rescue neurons from ischemic insults. In wild-type neurons, inhibition of HDAC promoted Stat3 acetylation and the antiapoptotic effect of GCSF. In LMO4 null cortical neurons, expression of wild-type but not HDAC-interaction-deficient LMO4 restored GCSF-induced Stat3 acetylation and p27 expression. Thus, our results indicate that LMO4 enhances GCSF-induced Stat3 signaling in neurons, in part by sequestering HDAC.     

Intensification of amphetamine-induced excitation by methysergide,a serotonergic receptor blocker

Summary Methysergide, a serotonergic receptor blocker, was studied to determine its effects against d-amphetamine-induced excitation as measured by convulsions elicited by handling in mice. Significant intensification (p<0.01) of the action of d-amphetamine was observed in mice. These results indicate that reduction in serotonergic activity in the central nervous system enhances excitation induced by d-amphetamine.This work was supported by the Pharmaceutical Manufacturer Association Starter Grant, No. 5 S01 RR 05654-06 and the Air Force Office of Scientific Research Grant. The authors are grateful to Ben Wiggins, Michael Wallace, Maria Salazar, and Sanford Futterman for their technical assistance. The authors are also grateful to Dr Boris Tabakoff for supplying the formula of the CSF used in this experiment and we are indebted to San Antonio College for the use of their computer facilities. Dr Blum is a Career Teacher in drug addiction sponsored by NIDA, grant No. 1-T01-DA00290-01.     

The enhancement of antiproliferative and proapoptotic activity of HDAC inhibitors by curcumin is mediated by Hsp90 inhibition

Curcumin, a natural polyphenol, has been described to exhibit effects on signaling pathways, leading to induction of apoptosis. In this study, we observed that curcumin inhibited Hsp90 activity causing depletion of client proteins implicated in survival pathways. Based on this observation, this study was designed to investigate the cellular effects of curcumin combination with the pan-HDAC inhibitors, vorinostat and panobinostat, which induce hyperacetylation of Hsp90, resulting in inhibition of its chaperone function. The results showed that, at subtoxic concentrations, curcumin markedly sensitized tumor cells to vorinostat- and panobinostat-induced growth inhibition and apoptosis. The sensitization was associated with persistent depletion of Hsp90 client proteins (EGFR, Raf-1, Akt, and survivin). In conclusion, our findings document a novel mechanism of action of curcumin and support the therapeutic potential of curcumin/HDAC inhibitors combination, because the synergistic interaction was observed at pharmacologically achievable concentrations, which were ineffective when each drug was used alone.     

Effects of lesions of the anterior raphe nuclei on the self-administration of d-amphetamine in the rat : considerable increase of desire for the poison

The acquisition of the intravenous self-administration of d-amphetamine was studied after separate lesions of anterior raphe nuclei (dorsal or median). Every lever-press delivered 2.5 microliter of a d-amphetamine solution dosed at 7.5 microgram/kg. Lesion of anterior raphe nuclei produced an hyper-sensitivity to d-amphetamine as indicated by a dramatic increase in self-administration by experimental Rats compared to the controls. Moreover this enhanced self-administration behavior is observed with a low blood concentration of d-amphetamine. The greater increase was obtained for median raphe lesioned Rats. These effects are interpreted in terms of 5HT-DA balance and could provide an experimental model for neurobiological bases of drug addiction studies.     

Mylip makes an Idol turn into regulation of LDL receptor

High blood low-density-lipoprotein (LDL) cholesterol is a serious health problem among an increased number of patients in the Western world. Statins and other cholesterol lowering drugs have proven to be beneficial as therapy but are not optimal and show adverse effects in some patients. The LDL receptor is a crucial determinant of cholesterol metabolism in the body and amenable for drug interventions. Novel insights into the physiology of this receptor come from studies on the ubiquitination and degradation of LDL receptor by the ubiquitin ligase Mylip/Idol that is induced in cells by the nuclear receptor, LXR. This may open up new possibilities in the future to influence LDL receptor levels and cholesterol metabolism pharmacologically in various diseases.     

Eugenics and politics in Britain in the 1930s

This paper discusses the surprising resurgence in the fortunes of the British eugenics movement in the 1930s. It is argued that although mass unemployment may in the long run have discredited that version of eugenics in which social dependence and destitution were attributed to genetic defect, in the short run the Depression was often perceived as a vindication of the eugenical creed. In particular, the attempt to reduce the fertility of the unemployed by popularising birth control techniques, and the voluntary sterilization campaign aimed at preventing the propagation of defectives from the so-called Social Problem Group, satisfied the urge felt by many conservative members from the professional classes to respond creatively to the country's crisis, without endangering existing social and economic institutions. It is also shown that not until 1938 did events in Germany cause substantial damage to the cause of eugenics in Britain. In fact, the ‘German experiment’ was actually greeted with approval by certain British eugenists of an authoritarian cast of mind. However, the Society as a whole never identified with these right-wing extremists, thanks in part to the moderating influence exercised by its General Secretary, Dr. C. P. Blacker, whose prime concern was with psycho-medical problems likely to concern people of all party persuasions.     

The roles of cannabinoid and dopamine receptor systems in neural emotional learning circuits: implications for schizophrenia and addiction

Cannabinoids represent one of the most widely used hallucinogenic drugs and induce profound alterations in sensory perception and emotional processing. Similarly, the dopamine (DA) neurotransmitter system is critical for the central processing of emotion and motivation. Functional disturbances in either of these neurotransmitter systems are well-established correlates of the psychopathological symptoms and behavioral manifestations observed in addiction and schizophrenia. Increasing evidence from the anatomical, pharmacological and behavioral neuroscience fields points to complex functional interactions between these receptor systems at the anatomical, pharmacological and neural systems levels. An important question relates to whether these systems act in an orchestrated manner to produce the emotional processing and sensory perception deficits underlying addiction and schizophrenia. This review describes evidence for functional neural interactions between cannabinoid and DA receptor systems and how disturbances in this neural circuitry may underlie the aberrant emotional learning and processing observed in disorders such as addiction and schizophrenia. Received 20 January 2006; received after revision 14 March 2006; accepted 29 March 2006     

HDAC2 and TXNL1 distinguish aneuploid from diploid colorectal cancers

DNA aneuploidy has been identified as a prognostic factor for epithelial malignancies. Further understanding of the translation of DNA aneuploidy into protein expression will help to define novel biomarkers to improve therapies and prognosis. DNA ploidy was assessed by image cytometry. Comparison of gel-electrophoresis-based protein expression patterns of three diploid and four aneuploid colorectal cancer cell lines detected 64 ploidy-associated proteins. Proteins were identified by mass spectrometry and subjected to Ingenuity Pathway Analysis resulting in two overlapping high-ranked networks maintaining Cellular Assembly and Organization, Cell Cycle, and Cellular Growth and Proliferation. CAPZA1, TXNL1, and HDAC2 were significantly validated by Western blotting in cell lines and the latter two showed expression differences also in clinical samples using a tissue microarray of normal mucosa (n?=?19), diploid (n?=?31), and aneuploid (n?=?47) carcinomas. The results suggest that distinct protein expression patterns, affecting TXNL1 and HDAC2, distinguish aneuploid with poor prognosis from diploid colorectal cancers.     

The imperative for inclusion: A gender analysis of genetics

It has now been more than thirty years since Joan Wallach Scott (1986) argued that gender is a legitimate and necessary category of historical analysis that applies to all fields, including genetics. In the intervening years, a substantial body of work has appeared that adds women to the historiography of genetics. While this is a necessary component for including gender as a category of analysis in genetics, it is not sufficient. Gender analysis involves the broader goal of integrating gender into the interrogation of how social factors within research practices and institutional organization influence scientific work and knowledge production in genetics. This article argues for the imperative for inclusion—including both women and gender analysis—which, taken together, not only provide a more equitable and informative picture of the discipline's development, but also yield a historiography that more faithfully reflects the activity of doing science.