Trends In Pharmacological Sciences Research Articles

Bridging the gap in neuropsychiatric translational research

Neuropsychiatric and mental health disorders, including schizophrenia, major depressive disorder, post-traumatic stress disorder, and substance use disorder, are highly debilitating conditions and are increasingly common. There is heightened interest in identifying novel therapies to cure these disorders. Jerry Madukwe, the Editor-in-Chief of Trends in Pharmacological Sciences (TIPS) asked expert clinicians and researchers, from academia and industry, passionate in understanding these disorders and finding new treatments, about the origins of their interest and to reflect on some of the global challenges and opportunities for novel therapy discovery.

Advancing cardiovascular translational research

The recent announcement of the first and only FDA-approved medication (mavacamten) for the treatment of the obstructive form of hypertrophic cardiomyopathy (HCM) is exciting and motivating. Mavacamten is an allosteric and reversible inhibitor selective for cardiac myosin, an important protein in HCM development. Jerry Madukwe, the Editor-in-Chief of Trends in Pharmacological Sciences asked experts in the cardiovascular field to reflect on some of the global challenges and opportunities in translating basic and preclinical research discoveries into new treatments.

The future of neuroimmunology research for CNS disease therapeutics

It is an exciting time to be in neuroimmunology research. Promising pharmacological targets and drug approaches for the treatment of diseases of the central nervous system (CNS) are emerging. Jerry Madukwe, the Editor-in-Chief of Trends in Pharmacological Sciences asked authors of the August 2022 special issue to reflect on the global challenges in the field and what they see as the future of neuroimmunology research for CNS disease therapy.

The Potential of Medicinal Plants and Bioactive Compounds in the Fight Against COVID-19

The Potential of Medicinal Plants and Bioactive Compounds in the Fight Against COVID-19

Screenning Bioactive Compounds from Allium sativum as HER2 Inhibitors Targeting Breast Cancer by Docking Methods

Screenning Bioactive Compounds from Allium sativum as HER2 Inhibitors Targeting Breast Cancer by Docking Methods

Comparing Acetylcholinesterase and Butyrylcholinesterase Inhibition Effect of Total Extract and Fractions with Alcaloid-Rich Extract of Huperzia Serrata (Thunb.) Trevis.

Herbal extract, rich with natural compounds, has been used for medicinal purpose such as treating neurological disorders such as cognitive defection for a long period of time, often without significant adverse effects. We compared AChE and BuChE – inhibition effect of total extracts and fractions of Huperzia serrata (Thunb.) Trevis. with alcaloid-rich extract. Our samples were subjected under supersonic extraction with ethanol 50o as solvent and fractionally extracted with n-hexane, EtOAc and n-butanol, respectively; alcaloid-rich extract was collected simutaneously. Ellman’s method was used to assay AChE and BuChE inhibition activity. Results: Alcaloid-rich extraction proved to be the superior AChE inhibiting agent, its activity nearly 6 fold of the most active Huperzia serrata extraction with IC50 value of 7.93 (5.43-10.98) µg/ml. While the fractions as well as the total extract did not provide any BuChE inhibition activity, alcaloid-rich extract showed weak ability (IC50 at 76.67 (64.78 – 91.84) µg/ml). Overall, the superior enzyme inhibition effect of alcaloid-rich extract might open a new approach in preventing and treating neurological disorders such as alzheimer’s.
 Keywords
 Huperzia serrata (Thunb.) Trevis, alcaloid, Acetylcholinesrerase inhibitors (AChE); butyrylcholinesterase (BuChE), Alzheimer.
 References
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Raju, Investigation of phytochemical and antimicrobial activity of Huperzia species, Pharmacologyonline 3 (2009) 688-692.[10] George.L.Ellman, K.Diane Courtney, et al., A new and rapid colorimetric determination of acetylcholinesterase activity, Biochemical Pharmacology 7(2) (1961) 88-95. https://doi.org/10.1016/0006-2952(61)90145-9.[11] Paul T Francis, et al., The cholinergic hypothesis of Alzheimer’s disease: a review of progress. Journal of Neurology, Neurosurgery & Psychiatry, 66(2) (1999) 137-147. http://dx.doi.org/10.1136/jnnp.66.2.137.[12] Prerna Upadhyaya, Vikas Seth, Mushtaq Ahmad, Therapy of Alzheimer’s disease: An update, African Journal of Pharmacy and Pharmacology 4(6) (2010) 408-421.[13] Hachiro Sugimoto, Hiroo Ogura, et al., Research and development of donepezil hydrochloride, a new type of acetylcholinesterase inhibitor, The Japanese journal of pharmacology 89(1) (2002) 7-20.[14] N.T.K. Thu, et al., Acetylcholinesterase and butyrylcholinesterase inhibition effect of fractions extract of Huperzia serrata (Thunb.) Trevis. The journal of Pharmeceutical 56(11) 49-53 (in Vietnamese).[15] Xiaoqiang Ma, Changheng Tan, et al, Is there a better source of huperzine A than Huperzia serrata? Huperzine A content of Huperziaceae species in China. J Agric Food Chem, 53(5) (2005)1393-8. https://doi.org/10.1021/jf048193n.[16] Ya-Bing Yang, Xue-Qiong Yang, et al., A New Flavone Glycoside from Huperzia serrata. Chinese Journal of Natural Medicines 6(6) (2008) 408-410.[17] G.T. Ha, R.K. Wong, Y. Zhang, Huperzine a as potential treatment of Alzheimer's disease: an assessment on chemistry, pharmacology, and clinical studies, Chemistry & biodiversity 8(7) (2011) 1189-1204. https://doi.org/10.1002/cbdv.201000269.[18] H.Y. Zhang, X.C. Tang, Neuroprotective effects of huperzine A: new therapeutic targets for neurodegenerative disease, Trends in pharmacological sciences 27(12) (2006) 619-625. https://doi.org/10.1016/j.tips.2006.10.004.[19] Y. Wang, X.C. Tang, H.Y. Zhang, Huperzine A alleviates synaptic deficits and modulates amyloidogenic and nonamyloidogenic pathways in APPswe/PS1dE9 transgenic mice, Journal of neuroscience research 90(2) (2012) 508-517. https://doi.org/10.1002/jnr.22775.[20] C.Y. Wang, et al., Huperzine A activates Wnt/β-catenin signaling and enhances the nonamyloidogenic pathway in an Alzheimer transgenic mouse model, Neuropsychopharmacology 36(5) (2011) 1073-1089. https://doi.org/10.1038/npp.2010.245.[21] R.K. Gordon, et al., The NMDA receptor ion channel: a site for binding of Huperzine A, Journal of applied toxicology 21(S1) (2001) S47-S51. https://doi.org/10.1002/jat.805.[22] M. Rafii, et al., A phase II trial of huperzine A in mild to moderate Alzheimer disease, Neurology 76(16) (2011) 1389-1394. https://doi.org/10.1212/WNL.0b013e318216eb7b.[23] N.H. Greig, et al., A new therapeutic target in Alzheimer's disease treatment: attention to butyrylcholinesterase, Current medical research and opinion 17(3) (2001)1 59-165.[24] A. Ferreira, et al., Huperzine A from Huperzia serrata: a review of its sources, chemistry, pharmacology and toxicology, Phytochemistry reviews 15(1) (2016) 51-85. https://doi.org/10.1007/s11101-014-9384-y.

Synthesis and Modeling of Transition Metal Complexes Using Histidine as the Ligand.

Synthesis and Modeling of Transition Metal Complexes Using Histidine as the Ligand.

Abstract 4203: Non-invasive imaging of tumor cell death induced by a TRAILR2 agonist

Abstract Imaging tumour cell death can give an early indication of treatment efficacy. Tumour necrosis factor (TNF)-related apoptosis-inducing ligand receptor2 (TRAILR2) is a member of the TNF receptor superfamily, which interacts with death receptors (DRs) and induces apoptosis in a broad range of cancer cells but not normal cells[1]. MEDI3039, a newly described agonist of TRAILR2, was used to induce tumour cell death. A NIRF fluorophore-labelled phosphatidylserine (PS)-binding protein (∼15kDa), the C2A domain of Synaptotagmin-I (C2Am-750), which binds to the PS exposed by apoptotic and necrotic cells, was used to image MEDI3039-induced cell death[2]. Non-specific binding was assessed using a site-directed mutant that is inactive in PS binding, which was conjugated to a different fluorophore (iC2Am-680). Binding of C2Am-750 to MEDI3039-treated human colon and breast adenocarcinoma cells in vitro (Colo205 and MDA-Dual respectively) was assessed by flow cytometry and confocal microscopy. Both methods showed that C2Am-750 labelled MEDI3039-treated Colo205 cells, while the inactive iC2Am-680 showed only low non-specific binding. C2Am-750 and iC2Am-680 were also used to monitor the effect of treatment in a Colo205 xenograft model. One cohort of mice (n = 5) received a single dose of MEDI3039 (0.4 mg/kg), while another untreated cohort (n = 5) served as a control group. All mice received a single i.v. injection of a 1:1 mixture of 0.1 μmole/kg C2Am-750 and iC2Am-680 at 16 h after drug treatment, followed by whole body fluorescence imaging (FLI) measurements using an IVIS200 camera at 0 and 3 h post probe injection. FLI measurements in MEDI3039-treated Colo205 tumours showed significant increases in the uptake of C2Am-750 relative to iC2Am-680, both in vivo (4-9 fold, P value <0.0001) and ex vivo (7-11 fold, P value <0.0001). Uptake of iC2Am-680 was low in both treated and untreated groups. Subsequent histological analyses showed that the C2Am-750 signal was strongly correlated with both cleaved caspase-3 and TUNEL staining of dead cells. NIRF fluorophore-labelled C2Am showed a favourable biodistribution profile, with good tumour penetration and quick clearance of unbound material in vivo. The probe can be used to investigate the efficacy of targeted therapy, or other anti-tumour therapies, at an early stage following treatment. 1. Prasad, S., Kim, J.H., Gupta, S.C. & Aggarwal, B.B. Targeting death receptors for TRAIL by agents designed by Mother Nature. Trends in pharmacological sciences 35, 520-536 (2014). 2. Alam, I.S., Neves, A.A., Witney, T.H., Boren, J. & Brindle, K.M. Comparison of the C2A domain of synaptotagmin-I and annexin-V as probes for detecting cell death. Bioconjugate chemistry 21, 884-891 (2010). Citation Format: Bangwen Xie, Andre Neves, Stefanie R. Mullins, David Tice, Danielle Carroll, Robert W. Wilkinson, Kevin M. Brindle. Non-invasive imaging of tumor cell death induced by a TRAILR2 agonist. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4203.

Could Direct Inhibition of Inflammation Be the “Next Big Thing” in Treating Atherosclerosis?

The treatment of atherosclerosis during the past 2 decades has been focused on reductions in atherogenic lipids, such as low-density lipoprotein cholesterol, and, more recently, has moved toward attempting to increase high-density lipoprotein cholesterol. However, another major component of atherosclerosis is inflammation. Although long recognized in the laboratory, clinical investigators1 have more recently measured high-sensitivity C-reactive protein (hsCRP) in large clinical trials and linked higher levels with increased risk of mortality and cardiovascular events. This has led to intense interest in inflammation as a target for treatment, with the possibility that it could be the “next big thing” in managing atherosclerosis. See accompanying article on page 2256 With this information as a backdrop, the model of vascular injury used by Sarov-Blat et al2 allows initial testing of the effects of a novel antiinflammatory agent in patients with atherosclerosis. The paradigm of coronary stenting, leading to vascular injury and resulting in an inflammatory response that signals neointimal proliferation, and subsequent in-stent restenosis share many similar features of the inflammatory cascade that propagates atherosclerosis.3,4 Such extracellular stimuli are relayed to coordinated cellular responses through intracellular phosphorylation cascades, such as the mitogen-activated protein kinase (MAPK) pathways.5 So far, 4 classes of mammalian MAPK have been identified: extracellular signal–regulated kinases, c-jun N-terminal kinase or stress-activated protein kinase, extracellular signal–regulated kinase/big MAP kinase 1, and the p38 MAPKs.6 In their study, Sarov-Blat et al turn their attention to the inhibition of p38 MAPK using a newly developed agent to attenuate the inflammatory stimulus generated …

Measuring Intra-Cellular and Intra-Mitochondrial Zinc Concentrations Following Hypoxia/Hypoglycemia with an Expressible Ratiometric Fluorescence Biosensor

Zinc is a “trace” metal necessary for proper cellular function. Studies have shown that the intra- and extra-cellular concentrations of labile zinc increase dramatically in models of cerebral ischemia (1) (2). Substantial evidence indicates that mitochondrial dysfunction plays a significant role in neuronal death following ischemia. Both mitochondrial dysfunction and increased intracellular zinc concentrations have been associated with increased reactive oxygen species (ROS) production and ultimately apoptosis (3, 4). We modified our fluorescent zinc biosensor (5) to be selectively expressed in the mitochondria of PC12 cells, enabling us to ratiometrically image the intra-mitochondrial concentration of labile zinc even at resting (picomolar) levels. We used this expressible biosensor and our previous sensor in cells which have undergone oxygen /glucose deprivation (OGD). Our initial results indicate that the concentration of labile, intra-mitochondrial zinc may not increase to the degree that we observed in the cytoplasm during hypoxic/hypoglycemic conditions, and may be lower than the concentrations observed in cells in more physiological conditions.1. Tonder, N., et al. (1990) Neuroscience Letters 109, 247-252.2. Frederickson, C.J., et al. (2006) Experimental Neurology 198, 285 - 293.3. Weiss, J. H., Sensi, S. L. & Koh, J.-y. (2000) Trends in Pharmacological Sciences 21, 395 - 401.4. Jiang, D., et al. (2001) Journal of Biological Chemistry 276, 47524 - 47529.5. Bozym, R. A., et al. (2006) ACS Chemical Biology 1, 103 - 111.

Impaired Fetal Growth, Cardiovascular Disease, and the Need to Move on

The final step in the acceptance of a new medical hypothesis is often the approval of significant funding to investigate it. In the case of developmental programming (ie, the notion that the in utero environment determines susceptibility to many diseases later in life), this has recently come in the form of support by the US Congress for the National Children’s Study, a $3 billion project to follow the impact of environmental factors before, during, and after pregnancy on disease manifestation in some 100 000 children up to the age of 25 years.1 This initiative will, no doubt, yield a wealth of correlative data and identify many new factors potentially affecting developmental programming. Article p 405 Much of the concept underlying the National Children’s Study stems from the pioneering work of Barker and colleagues,2 whose epidemiological observation of increased cardiovascular risk in children with low birth weight has spurred a large number of retrospective studies during the past 30 years. Despite some conflicting results, most of these studies support the notion that reduced birth weight is indeed associated with increased hypertension, diabetes mellitus, and cardiovascular disease. However, the strong correlation between birth weight and duration of gestation, plus the fact that a short gestation also may be associated with cardiovascular risk,3 poses the question to what extent low birth weight is truly responsible. In this issue of Circulation , an article by Kaijser and coworkers4 at the Karolinska Institute in Stockholm provides a convincing answer. By scanning 250 000 records of birth at 4 major delivery units in Sweden between 1925 and 1949, they identified a cohort of 6437 subjects, which included 2937 children born preterm (<37 weeks of gestation) and 2181 with a birth weight <2000 g for girls or <2100 g for boys. During the …

Prevalence of Cholesteryl Ester Storage Disease

Cholesteryl ester storage disease (CESD) is an autosomal recessive chronic liver disease caused by lysosomal acid lipase (LAL) deficiency. The gene is located on chromosome 10q23.2-q23.3, and the enzyme is essential for triglycerides and cholesteryl ester hydrolysis in lysosomes. CESD is characterized by hypercholesterolemia, hypertriglyceridemia, HDL deficiency, and abnormal lipid deposition in many organs. In the liver this results in hepatomegaly caused by hepatic steatosis and fibrosis that can lead to micronodular cirrhosis.1 Disease onset takes place during childhood or adolescence. Males and females are affected in about equal numbers. Patients rarely reach the age of 30. Biochemically, the disorder is recognized by largely reduced lysosomal acid lipase activity.2,3 Complete absence of LAL activity causes Wolman Disease, which is normally fatal within the first 6 months of life.1,4 Several groups have identified mutations in the LAL gene underlying CESD and Wolman disease.5–9 Mutations causing Wolman disease produce an enzyme with no residual activity or no enzyme at all, whereas CESD-causing mutations encode for LAL which retains some enzyme activity.4,10 A G-to-A transition at position −1 of the exon 8 splice donor (E8SJM, E xon 8 S plice J unction M utation) leads to an in-frame deletion of exon 8. The resulting protein is 24 amino acids shorter and has no residual LAL activity, however E8SJM does not cause Wolman Disease because 2% to 4% of normally spliced LAL is present in homozygote carriers.11,12 The vast majority of CESD …

Herbal Medicine in Stroke

See related article, pages 1973–1979. The lack of effective and widely applicable pharmacological treatments for ischemic stroke patients may explain a growing interest in traditional medicines, for which extensive observational and anecdotal experience has accumulated over the past thousand years. The World Health Organization (WHO) defines traditional medicine as “health practices, approaches, knowledge and beliefs incorporating plant, animal and mineral based medicines, spiritual therapies, manual techniques and exercises, applied singularly or in combination to treat, diagnose and prevent illnesses or maintain well-being”.1 Unlike Western medicine, which focuses on disease, traditional medicine takes the approach that the body provides external clues to an internal imbalance that can be addressed by interventions such as herbs and acupuncture (holistic treatment approach).2 According to a 2003 WHO report,1 traditional medicine is very popular in all developing countries, and its use is rapidly increasing in industrialized countries. For example, traditional herbal preparations account for 30% to 50% of the total medicinal consumption in China. In Europe, North America and other industrialized regions, over 50% of the population have used traditional medicine at least once. The global market for herbal medicines currently stands at over US $60 billion annually and is growing steadily.1 In recent years, several reviews have been published on the effect and potential benefits of traditional Eastern medicine in stroke.3–7 It has been suggested that some herbal medicines, or their products, may improve microcirculation in the brain,4,8 protect against ischemic reperfusion injury,8,9 possess neuroprotective properties3,4 and inhibit apoptosis,10 thus justifying their use in ischemic stroke patients. However, unlike industrially manufactured pharmacological drugs used in Western medicine, the active (potent) components of herbal medicines often have not been specified and measured precisely, although there have been recent attempts to regulate dosages and use of …

CD163-Mediated Hemoglobin-Heme Uptake Activates Macrophage HO-1, Providing an Antiinflammatory Function

See related article, pages 943–950 A study by Schaer et al,1 which appears in this issue of Circulation Research , provides evidence suggesting that CD163 acts as a hemoglobin (Hb) transporter and, via activation of macrophages, heme oxygenase-1 (HO-1) provides antiinflammatory activity, presumably by an increase in ferritin. Induction of HO-1 was observed to occur when the cultured macrophages, endothelial cells or tubular cells were exposed to heme or hemoglobin (for a review see Abraham and Kappas2). Heme and denatured hemoglobin toxicity play an important role in a broad spectrum of pathological circumstances such as myocardial ischemia, hypertension, cardiomyopathy, reperfusion, organ transplantation, pulmonary disorders, and inflammation among others.3 In the cell free system, hemoglobin is bound to haptoglobin before clearance by the macrophage hemoglobin scavenger receptor CD163. Schaer et al1 demonstrated that CD163-hemoglobin transport is regarded as a critical step in the hemoglobin clearance pathway in the macrophage, especially under conditions of extreme hemoglobin release resulting from hemolysis. Binding hemoglobin-haptoglobin to CD163 cells also elicits IL-10 secretion, which contributes to the induction of HO-1.4 Thus, CD163 has a functional role as an antioxidant by enhancing HO-1, the major cytoprotective response. This links heme transport directly to a known receptor with well characterized endocytic properties and signaling functions.5 Heme-hemopexin is also taken up by LRP/CD91 and, as such, may inhibit inflammatory functions in phagocytic and antiinflammatory macrophages; however, a link to functional HO-1 was not described. Schaer et al1 demonstrated that induction of HO-1 by Hb is functionally linked to CD163 and, using gene array analysis, were able to show that Hb elicits a noninflammatory transcriptional response in macrophages, presumably by the coordinated increase in ferritin synthesis following the activation of HO-1. This response was mediated by CD163 and did not involve the …

Pharmacological attenuation of blood pressure variability

Over the past few years, the research team of Professor Ding-feng SU has reported an impressive quantity of experimental data about the relationships between blood pressure variability (BPV) and end-organ damage, a topic of obvious clinical interest. This research work has been summarized in a paper that appeared in the August issue of the renowned journal Trends in Pharmacological Sciences [1]. The studies by Su et al provide convincing evidence that BPV is an independent cardiovascular risk factor that should be considered as such and, therefore, might become an important target for therapeutic interventions. Besides these exciting perspectives in the prevention and treatment of cardiovascular diseases, the work by Su et al raises a series of physiological questions.

MULTI-PRONGED INHIBITION OF AIRWAY HYPER-RESPONSIVENESS AND INFLAMMATION BY LIPOXIN A4

Levy BD, De Sanctis GT, Devchand PR, et al. Nature Med. 2002;8:1018–1023To investigate the potential counterregulatory role of lipoxin A4 (LXA4) and lipoxin A4 receptors (ALX) in allergic pulmonary inflammation and bronchial hyperresponsiveness (BHR) in asthma.In a murine model of allergic asthma, pulmonary inflammation and BHR with administration of a lipoxin A4 analog (LXa) was studied. Transgenic mice expressing human LXA4 receptors were also studied.LXa, administered intravenously after allergen sensitization and before airways allergen exposure, significantly reduced both BHR and allergic pulmonary inflammation, including eosinophils, lymphocytes, interleukin (IL)-5, IL-13, eotaxin, and cysteinyl leukotrienes. Similar findings were observed in transgenic mice that constitutively expressed human LXA4 receptors.Lipoxin A4 and its analog offer a novel therapeutic approach to the treatment of BHR and pulmonary inflammation in asthma.Lipoxins are endogenously produced eicosanoids with antiinflammatory actions. LXA4, the best-studied member of this family, has antiinflammatory activities in in vitro and in vivo model systems. Its antiinflammatory actions include downregulation of proinflammatory cytokines and chemokines involved in neutrophil and eosinophil trafficking, inhibition of cytokine-stimulated metalloproteinase activity and cell proliferation, and stimulation of macrophage clearance of apoptotic cells from an inflammatory focus. LAX4 has recently been shown to interfere with cysteinyl leukotriene (cysLT)-mediated inflammation by competitively binding the cysLT1 receptor. This and another recent study (Bonnas C, et al, Am J Respir Crit Care Med. 2002;165:1531–1535) reveal the therapeutic potential of LXA4 in asthma. Other potential applications of LAX4 are for topical use as an antiinflammatory agent for inflammatory skin conditions (Schottelius AJ, et al, J Immunol. 2002;169:7063–7070). Given the efficacy of the compound, LAX4 may be a compelling alternative to corticosteroids in certain clinical settings. A commentary on this study, titled “Good Lipids for Asthma” by Peters-Golden on pages 931–932 of the same issue, and an article titled “Lipoxins: Revelations on Resolution” by McMahon et al in Trends in Pharmacological Sciences (2001;22:391–395) are suggested for further review.

Online access to Trends in Pharmacological Sciences

Online access to Trends in Pharmacological Sciences

Trends in Endocrinology and Metabolism 1998

As Trends in Endocrinology and Metabolism enters its ninth year, the change in volume number also heralds some important changes in the production and distribution of TEM. From January 1998, beginning with this issue, TEM becomes part of the Elsevier Trends Journals imprint. The ETJ stable of journals comprises some of the most highly rated monthly review journals in clinical and biomedical science, including Trends in Neurosciences, Trends in Biochemical Sciences, Immunology Today and Trends in Pharmacological Sciences. Their high impact mix of news, reviews and debate has made these journals indispensible to researchers in academic, clinical and commercial environments, as well as to students and teachers.In line with this philosophy, TEM will expand its portfolio of editorial content styles and features. This will include more regular coverage of conferences and symposia, providing timely summaries of significant advances that have been discussed. Brief reviews and viewpoints will provide updates on recent progress in the field, where novel information has challenged existing paradigms and driven the development of new hypotheses. Where an area of research has thrown up (or has not resolved) recent controversy and conflicting ideas, TEM will debate the issues in pairs of balancing articles in which each protagonist may put forward their own opinions and interpretations, and briefly respond to the opposing viewpoint. Naturally, a core element of TEM will remain the more-balanced and grounded reviews of the `state of the field', providing detailed background and putting recent advances and consolidations in perspective.In line with these aims, next month TEM will produce a focused issue covering the Developmental Aspects of Androgen Excess Disorders. Furthermore, in common with many journals, TEM will be available online through ScienceDirect (http://www.sciencedirect.com)Fig. 1Fig. 1 a major new collection of electronic journals. These changes will allow TEM to better reflect the dynamic nature of the scientific and clinical disciplines of endocrinology and metabolism. Naturally, we welcome any and all comments on these changes and details of how to contact the editorial office are provided herein.Fig. 1View Large Image | Download PowerPoint SlideEditorial and subscription queries should be addressed to: Trends in Endocrinology and Metabolism 68 Hills Road Cambridge UK CB2 1LA Tel. +44 (0) 1223 315961 Fax. +44 (0) 1223 464430 e-mail TEM@elsevier.co.uk

Antisense to NPY-Y1 demonstrates that Y1 receptors in the hypothalamus underlie NPY hypothermia and feeding in rats.

Neuropeptide Y (NPY) is a highly potent endogenous peptide which when injected into the medial hypothalamus causes spontaneous eating behaviour and an intense fall in body temperature (Tb). This study used antisense oligodeoxynucleotides (ODNs) to determine whether the Y1 subtype of NPY receptor could underlie these remarkable physiological responses. In the unrestrained rat, the ventromedial hypothalamus (VMH) which is highly reactive to NPY was injected with antisense for NPY (aNPY), Y1 receptors (aNPY-Y1) and mismatched controls (mNPY; mNPY-Y1). After cannulae were implanted bilaterally in the brain of 19 rats, 0.4 or 0.8 microgram per 0.8 microliter of the phosphorothioate synthesised ODNs were delivered to the VMH of the rats at 12 h intervals over 2 d. Only the lower dose of aNPY-Y1, but not aNPY, evoked an intense phasic rise in the Tb following each micro-injection. Simultaneously, 0.4 microgram per 0.8 microliter of aNPY-Y1, but not aNPY, suppressed feeding behaviour after a sequence of micro-injections and on the following day. Body weights and locomotor activity of the rats likewise declined concomitantly with the hyperthermia and hypophagia caused by the Y1 receptor antisense. Neither of the control ODNs for NPY or Y1 receptors injected similarly in the VMH of the rats exerted any effects on these measures. These results clearly provide convincing evidence that in the VMH the Y1 subtype of NPY receptor mediates, in part, the neuronal mechanisms responsible for spontaneous feeding and hypothermia produced by native NPY when applied directly to this structure. The concurrent decline in body weight and activity caused by aNPY-Y1 could be caused by the episodes of hyperthermia.

Meeting Highlights: Central &amp; Peripheral Nervous Systems, Receptor classification: The integration of operational, transductional and structural information September 21–22, 1995, Verona, Italy

This meeting, organised by Drs D Trist, P Leff, GR Martin, J Shaw, NP Shankley, M Spedding and Professor P Humphrey, brought together several leading authorities in the field of receptor pharmacology, and attempted to arrive at a consensus regarding classification of neurohormonal receptors. The format of the meeting was such that each speaker had to address several criteria pertinent to receptor classification. Generally, this proved successful in that several aspects of this fascinating area were addressed. Moreover, a consensus emerged throughout the meeting regarding the importance of structural information in the classification of receptor subtypes. The proceedings of the meeting will be published in a volume of the Annals of the New York Academy of Sciences. A meeting report will also be published in Trends in Pharmacological Sciences.