Abstract:
:Over the past decade, hypothalamic circuits have been described that impact energy homeostasis in rodents and humans. Our drug development efforts for the treatment of obesity and the metabolic syndrome have largely focused on selected genetic and/or pharmacologically validated pathways. The translation of these pathways into therapeutics for the treatment of obesity will find its first clinical successes over the coming decade. Initial efforts have focused on gaining a better understanding of the relevance of rodent pharmacological and genetic observations for the development of therapeutics for the treatment of human obesity. We pursue pathways defined by the expression of the ghrelin receptor, melanin-concentrating hormone receptors, melanocortin receptors, cannabinoid receptors and neuropeptide Y1 and Y5 receptors. In this review, we will discuss drug development efforts for the treatment of obesity, focused on selective melanocortin 4 receptor agonists and neuropeptide Y1 and Y5 receptor antagonists. These drug development efforts required an in-depth understanding of cell-based observations which drive the development of compound structure-activity relationships. These include understanding of receptor function in selected cell-based backgrounds and early evaluation and validation of ex vivo observations in appropriate in vivo models. In order to develop selective and safe anti-obesity drugs, diverse approaches are needed to increase the likelihood of clinical success, including: (i) developing a detailed understanding of the predictive value of rodent pathways for treatment of human disease; (ii) knowledge of the exact location of targeted receptor subtypes for the clinical indication under study in order to derive a suitable compound profile; (iii) predictive measures of in vivo and/or ex vivo receptor occupancy required to bring about a desired physiological effect; (iv) predictive parameters that outline that the drug-derived effects are safe and mechanism-based; and (v) the refinement of selected compound classes, aimed at their clinical use.
journal_name
Prog Brain Resjournal_title
Progress in brain researchauthors
Van der Ploeg LH,Kanatani A,MacNeil D,Ming Fong T,Strack A,Nargund R,Guan XMdoi
10.1016/S0079-6123(06)53005-5subject
Has Abstractpub_date
2006-01-01 00:00:00pages
107-18eissn
0079-6123issn
1875-7855pii
S0079-6123(06)53005-5journal_volume
153pub_type
杂志文章,评审abstract::Miniature eye movements occur involuntarily during visual fixation. The most prominent contribution to these fixational eye movements is generated by microsaccades, which are rapid small-amplitude saccades with a rate of about one per second. Recent work demonstrates that microsaccades are optimized to counteract perc...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/S0079-6123(06)54009-9
更新日期:2006-01-01 00:00:00
abstract::Otoacoustic emissions can be used to study cochlear function in an objective, non-invasive and rapid manner. These and other desirable features of emissions have inspired a significant amount of investigation into the practicalities of utilizing evoked emissions as clinical tests of hearing. Variables which affect the...
journal_title:Progress in brain research
pub_type: 杂志文章
doi:10.1016/s0079-6123(08)62265-7
更新日期:1993-01-01 00:00:00
abstract::Downbeat nystagmus (DBN) is the most frequent form of acquired persisting fixation nystagmus. It is hypothesized to occur when physiological inhibitory cerebellar input, namely of the flocculus, to the vestibular nuclei is inhibited. The second most frequent form of acquired nystagmus is upbeat nystagmus (UBN). UBN is...
journal_title:Progress in brain research
pub_type: 杂志文章
doi:10.1016/S0079-6123(08)00676-6
更新日期:2008-01-01 00:00:00
abstract::Until recently, the constraints imposed on decision makers by the human physical condition - situated both as a physical agent and within physical space - have played only an incidental, if not entirely inconsequential, role in conceptualizations of human decision making. The act of deciding has been positioned as the...
journal_title:Progress in brain research
pub_type: 杂志文章
doi:10.1016/S0079-6123(09)01316-8
更新日期:2009-01-01 00:00:00
abstract::One of the more interesting and complex phenomena involving neurohypophysial hormones is the milk ejection reflex and the events surrounding it. Accordingly, many investigations over the years have taken up the challenge of elucidating its myriad aspects. Much has been learned from in vivo preparations about the seque...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/S0079-6123(08)00414-7
更新日期:2008-01-01 00:00:00
abstract::Alzheimer's disease (AD), the most common type of adult-onset dementia, is characterized by a variety of brain abnormalities, including degeneration of certain populations of nerve cells, alterations in the neuronal cytoskeleton, and the abnormal deposition of amyloid within brain parenchyma. Pathogenetic processes th...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/s0079-6123(08)63186-6
更新日期:1990-01-01 00:00:00
abstract::Metabolic status varies predictably on a daily and seasonal basis in order to adapt to the cyclical environment. The hypothalamic circadian pacemaker of the suprachiasmatic nuclei (SCN) co-ordinates these metabolic cycles. Circadian timing is based upon a transcriptional/post-translational negative feedback loop invol...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/S0079-6123(06)53015-8
更新日期:2006-01-01 00:00:00
abstract::Antidepressants are commonly prescribed for tinnitus. Research thus far provides some support for that treatment, but the literature also raises concerns because tinnitus is a side effect of antidepressant medication. In this chapter, four published double blind placebo-controlled trials of antidepressants for tinnitu...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/S0079-6123(07)66024-5
更新日期:2007-01-01 00:00:00
abstract::Orexin, also known as hypocretin, is a hypothalamic neuropeptide important for mediation of arousal and sleep as well as feeding and energy homeostasis. Recent studies have indicated that orexin also plays a key role regulating motivation and reward associated with food intake and with drugs of abuse. Based on those f...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/B978-0-444-59489-1.00006-9
更新日期:2012-01-01 00:00:00
abstract::Postural instability and falls are common causes of morbidity and mortality in the second most prevalent neurodegenerative condition, Parkinson's disease (PD). Poor understanding of balance dysfunction in PD has hampered the development of novel therapeutic measures for postural instability and balance dysfunction. We...
journal_title:Progress in brain research
pub_type: 杂志文章
doi:10.1016/bs.pbr.2019.03.034
更新日期:2019-01-01 00:00:00
abstract::Three rhythmic movements, breathing, walking, and chewing, are considered from the perspective of the emerging factors that control their coordination. This takes us beyond the concept of a core excitatory kernel and into the common principles that govern the interaction between components of the neural networks that ...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/B978-0-444-53825-3.00017-6
更新日期:2011-01-01 00:00:00
abstract::A persistent nineteenth-century urban legend was the notion that photograph-like images of the last-seen object or person would be preserved in the eyes of the dead. This popular notion followed technological developments (the daguerreotype and ophthalmoscope) that antedated by decades a basic understanding of retinal...
journal_title:Progress in brain research
pub_type: 历史文章,杂志文章
doi:10.1016/B978-0-444-63273-9.00004-6
更新日期:2013-01-01 00:00:00
abstract::Intron-specific probes measure heteronuclear RNA (hnRNA) levels and thus approximate the transcription rates of genes, in part because of the rapid turnover of this intermediate form of RNA in the cell nucleus. Previously, we used oxytocin (Oxt)- and vasopressin (Avp)- intron-specific riboprobes to measure changes in ...
journal_title:Progress in brain research
pub_type: 杂志文章
doi:10.1016/S0079-6123(08)00404-4
更新日期:2008-01-01 00:00:00
abstract::Studies on the visual thalamic relays, the lateral geniculate nucleus and pulvinar, provide three key properties that have dramatically changed the view that the thalamus serves as a simple relay to get information from subcortical sites to cortex. First, the retinal input, although a small minority (7%) in terms of n...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/S0079-6123(05)49009-3
更新日期:2005-01-01 00:00:00
abstract::Nitric oxide (NO) is widespread in the nervous system and is thought to play a role in a variety of different neuronal functions, including learning and memory (see other chapters, this volume). A number of behavioral studies have indicated that NO is involved in several types of learning such as motor learning (Yanag...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/s0079-6123(08)63206-9
更新日期:1998-01-01 00:00:00
abstract::The serotonin (5-HT) neurotransmitter system provides fundamental modulatory regulation of the limbic-corticostriatal circuitry known to be vital in the development of addiction as well as the aspects of addiction that hinder recovery and contribute to relapse. Thus, components of the 5-HT system may provide novel tar...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/S0079-6123(08)00916-3
更新日期:2008-01-01 00:00:00
abstract::Throughout life, thalamocortical (TC) network alternates between activated states (wake or rapid eye movement sleep) and slow oscillatory state dominating slow-wave sleep. The patterns of neuronal firing are different during these distinct states. I propose that due to relatively regular firing, the activated states p...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/B978-0-444-53839-0.00009-0
更新日期:2011-01-01 00:00:00
abstract::A problem for studies of all cortex, including prefrontal cortex, is how to relate results to proposed subdivisions of the brain and how to compare results across species. Investigators have been highly dependent on traditional architectonic maps of neocortex. However, over the last 20 years, other methods, especially...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/s0079-6123(08)62673-4
更新日期:1990-01-01 00:00:00
abstract::The main topic of this overview is an analysis of the concepts of phase and synchrony, as used in neurophysiology, in their various meanings. A number of notions related to the concepts of phase and synchrony, which are incorporated in contemporary neurophysiology, particularly in the domain of neuro-cognitive physiol...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/S0079-6123(06)59001-6
更新日期:2006-01-01 00:00:00
abstract::Humans can communicate their emotional state via facial expression and affective prosody. This chapter reviews behavioural, neuroanatomical, electrophysiological and neuroimaging studies pertaining to audiovisual integration of emotional communicative signals. Particular emphasis will be given to neuroimaging studies ...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/S0079-6123(06)56019-4
更新日期:2006-01-01 00:00:00
abstract::Immunoreactive oxytocin (OXT) detected in extracts of human coeliac ganglia and nn. vagi was characterized by high-performance liquid chromatography (HPLC). HPLC/RIA examinations demonstrated that a major part of the immunoreactive material in both investigated areas co-eluted with a reference synthetic OXT, but in th...
journal_title:Progress in brain research
pub_type: 杂志文章
doi:10.1016/s0079-6123(08)62321-3
更新日期:1992-01-01 00:00:00
abstract::There is increasing evidence that human cognitive functions can be addressed from a robust neuroscience perspective. In particular, the distributed coherent electrical properties of central neuronal ensembles are considered to be a promising avenue of inquiry concerning global brain functions. The intrinsic oscillator...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/S0079-6123(05)50010-4
更新日期:2005-01-01 00:00:00
abstract::The aim of this chapter is to review recent literature describing how developments in cognition may contribute to age-related changes in emotional processes, specifically emotion regulation and emotion perception. In general, older adults are more likely than young adults to report feeling positive. Prominent conceptu...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/bs.pbr.2019.02.007
更新日期:2019-01-01 00:00:00
abstract::Human and nonhuman primates predictively use smooth pursuit and saccades to track visual targets that move in a fronto-parallel plane. This behaviour is believed to be facilitated by short-term memory of the target motion and/or an efference copy of the subject's motor effort. Subjects in our experiments tracked dicho...
journal_title:Progress in brain research
pub_type: 杂志文章
doi:10.1016/S0079-6123(08)00666-3
更新日期:2008-01-01 00:00:00
abstract::Individual differences in cognitive functioning during extended work hours and shift work are of considerable magnitude, and observed both in the laboratory and in the workplace. These individual differences have a biological basis in trait-like, differential vulnerability to fatigue from sleep loss and circadian misa...
journal_title:Progress in brain research
pub_type: 杂志文章
doi:10.1016/B978-0-444-53817-8.00009-8
更新日期:2011-01-01 00:00:00
abstract::Although the perception of our world is experienced as effortless, the processes that underlie object recognition in the brain are often difficult to determine. In this chapter, we review the effects of familiarity on the recognition of moving or static objects. In particular, we concentrate on exemplar-level stimuli ...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/S0079-6123(06)54017-8
更新日期:2006-01-01 00:00:00
abstract::Molecular biology techniques have begun to shed light on the genetic basis of autosomal dominant central DI, but several very basic questions remain to be answered. The disorder was initially presumed to have a developmental, degenerative, or autoimmune basis based on the autopsy findings in the hypothalamus of a limi...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/s0079-6123(08)64580-x
更新日期:1992-01-01 00:00:00
abstract::We tend to regard consciousness as a fundamentally subjective phenomenon, yet we can only study it scientifically if it has objective, publicly visible, manifestations. This creates a central, recurring, tension in consciousness science which remains unresolved. On one 'objectivist' view, consciousness is not merely r...
journal_title:Progress in brain research
pub_type: 杂志文章
doi:10.1016/S0079-6123(09)17701-4
更新日期:2009-01-01 00:00:00
abstract::Mechanism is at the heart of understanding, and this chapter addresses underlying brain mechanisms and pathways of cognition and the impact of sleep on these processes, especially those serving learning and memory. This chapter reviews the current understanding of the relationship between sleep/waking states and cogni...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/B978-0-444-53702-7.00001-4
更新日期:2010-01-01 00:00:00
abstract::Local recurrent connections endow the cerebellar cortex with an intrinsic dynamics. We performed computer simulations to predict the frequency bands of the oscillations that will most likely emerge. Feedback inhibition from the Golgi to the granule cells induced 10-50 Hz oscillations, the period at resonance being app...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/S0079-6123(04)48015-7
更新日期:2005-01-01 00:00:00