Neuropeptides and Neuropeptide Receptors: Drug Targets, and Peptide and Non-Peptide Ligands: A Tribute to Prof. Dieter Seebach.

Neuropeptides and neuropeptide receptors: drug targets, and Peptide and non-Peptide ligands: a tribute to prof. Dieter seebach.

Filed under: Depression Treatment

Chem Biodivers. 2012 Nov; 9(11): 2367-87
Hoyer D, Bartfai T

The number of neuropeptides and their corresponding receptors has increased steadily over the last fourty years: initially, peptides were isolated from gut or brain (e.g., Substance P, somatostatin), then by targeted mining in specific regions (e.g., cortistatin, orexin in the brain), or by deorphanization of G-protein-coupled receptors (GPCRs; orexin, ghrelin receptors) and through the completion the Human Genome Project. Neuropeptides (and their receptors) have regionally restricted distributions in the central and peripheral nervous system. The neuropeptide signaling is somewhat more distinct spatially than signaling with classical, low-molecular-weight neurotransmitters that are more widely expressed, and, therefore, one assumes that drugs acting at neuropeptide receptors may have more selective pharmacological actions with possibly fewer side effects than drugs acting on glutamatergic, GABAergic, monoaminergic, or cholinergic systems. Neuropeptide receptors, which may have a few or multiple subtypes and splice variants, belong almost exclusively to the GPCR family also known as seven-transmembrane receptors (7TM), a favorite class of drug targets in the pharmaceutical industry. Most neuropeptides are co-stored and co-released with classic neurotransmitters, albeit often only at higher frequencies of stimulation or at bursting activity, thus restricting the neuropeptide signaling to specific circumstances, another reason to assume that neuropeptide drug mimics may have less side effects. Neuropeptides possess a wide spectrum of functions from neurohormone, neurotransmitter to growth factor, but also as key inflammatory mediators. Neuropeptides become ‘active’ when the nervous system is challenged, e.g., by stress, injury, drug abuse, or neuropsychiatric disorders with genetic, epigenetic, and/or environmental components. The unsuspected number of true neuropeptides and their cognate receptors provides opportunities to identify novel targets for the treatment of both central and peripheral nervous system disorders. Both, receptor subtype-selective antagonists and agonists are being developed, as illustrated by the success of somatostatin agonists, angiotensin, and endothelin antagonists, and the expected clinical applications of NK-1/2/3 (substance P) receptor antagonists, CRF, vasopressin, NPY, neurotensin, orexin antagonists, or neuropeptide receptor modulators; such ligands have efficacy in preclinical or clinical models of pain and neuropsychiatric diseases, such as migraine, chronic/neuropathic pain, anxiety, sleep disorders, depression, and schizophrenia. In addition, both positive and negative allosteric modulators have been described with interesting in vivo activities (e.g., at galanin receptors). The field has become more complex now that an increasing number of heteromeric neuropeptide receptors are described, e.g., ghrelin receptors with 5-HT(2C) or dopamine D(1) , D(2) receptors. At long last, structure-based drug discovery can now be envisaged with confidence, since crystal or solution structure of GPCRs and GPCR?ligand complexes, including peptide receptors, are published almost on a monthly basis. Finally, although most compounds acting at peptide receptors are still peptidomimetics, the last decade has seen the emergence of low-molecular-weight nonpeptide ligands (e.g., for orexin, ghrelin, or neurokinin receptors), and surprising progress has been made with ?- and ?-peptides as very stable and potent mimetics of, e.g., somatostatin (SRIF), where the native SRIF has a half-life limited to 2-3?min. This last point will be illustrated more specifically, as we have had a long-standing collaboration with Prof. D. Seebach to whom this review is dedicated at the occasion of his 75th birthday.
HubMed – depression

Protein and peptide profiling as a tool for biomarker discovery in depression.

Filed under: Depression Treatment

Electrophoresis. 2012 Oct 15;
Alawam DK, Dudley DE, Donev DR, Thome PJ

This study sought to determine whether protein and/or peptide profiles from serum were able to distinguish patients suffering from depression from healthy control subjects and thereby act as biomarker candiadtes with potential diagnostic value. Serum samples were collected from patients (n = 39) and controls (n = 30). A C8 magnetic bead protocol was used to prepare serum proteins, whilst a micro-extraction C18 packed tip was used to isolate serum peptides. Both protein and peptide profiles were recorded by MALDI-MS and the data exported for further analysis. No protein signals differentiated patients from controls and principle component analysis of the entire peptide profile did not allow for distinct clustering of the two groups. Further analysis of individual peptides however identified three peptide signals whose intensities were significantly different between patients and control subjects. The efficacy of these potential biomarker candidates to identify patients was therefore studied using a receiver operating characteristic (ROC) curve and the combined use of all three candiadtes together offered the most specific and sensitive identification of true positive cases of depression.
HubMed – depression

Neurobehavioral, cellular, and molecular consequences of single and multiple mild blast exposure.

Filed under: Depression Treatment

Electrophoresis. 2012 Oct 15;
Kamnaksh A, Kwon SK, Kovesdi E, Ahmed F, Barry ES, Grunberg NE, Long J, Agoston D

Mild traumatic brain injury, caused by the exposure to single or repeated blast overpressure (BOP), is a principal concern due to its pathological complexity and neurobehavioral similarities with post-traumatic stress disorder. In this study, we exposed rats to a single or multiple (5 total; administered on consecutive days) mild blasts and assessed their behavior at an early and a late time point (1 and 16 days post-injury, respectively) followed by histological and protein analyses of brains and plasma. One day post-injury, Multiple-Injured (MI) rats showed the least general locomotion and the most depression- and anxiety-related behaviors among the experimental groups; there were no such differences at 16 days. However, at the later time point both injured groups displayed elevated levels of select protein biomarkers. Histology showed significantly increased numbers of TUNEL+ (terminal-deoxy-transferase-mediated dUTP nick-end labeling)-positive cells in the dorsal and the ventral hippocampus (DHC and VHC) of both injured groups as early as 2 hours after injury. At 22 days, the increase was limited to the VHC of MI animals. Our findings suggest that the exposure to mild BOP triggers early hippocampal cell death as well as neuronal, glial, and vascular damage that likely contribute to significant, albeit transient increases in depression- and anxiety-related behaviors. However, the severity of the observed pathological changes in MI rats failed to support the hypothesized cumulative effect of repeated injury. We infer that at this blast frequency, a potential conditioning phenomenon counteracts with and reduces the extent of subsequent damage in MI rats.
HubMed – depression

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