TY - JOUR AB - Background: Pharmacotherapies targeting motivational aspects of feeding and palatable food reward, while sparing mood and cognitive function, represent an alluring approach to reverse obesity and maintain weight loss in an obesogenic environment. A novel glucagon-like peptide-1/dexamethasone (GLP-1/Dexa) conjugate, developed to selectively activate glucocorticoid receptors in GLP-1 receptor-expressing cells was shown to decrease food intake and lower body weight in obese mice. Here, we investigate if this novel drug candidate modulates the rewarding properties of food and if it affects behavioral indices of mood and memory. Methods: C57Bl6 mice treated with the GLP-1/Dexa conjugate, GLP-1 or vehicle lever-pressed for high-fat, high sugar (HFHS) food rewards in an operant task. Alterations in food-motivated behavior were also assessed following a HFHS diet withdrawal manipulation (switch to chow). The effects of repeated GLP-1/Dexa conjugate, GLP-1 or vehicle on free-feeding intake, body weight, anxiodepressive behaviors (elevated-plus maze, open field test & forced swim test), memory (novel object recognition) and mRNA expression of reward-relevant markers in the nucleus accumbens were also evaluated in mice fed a HFHS diet for 12 weeks. Results: Mice treated with a GLP-1 analogue displayed a transient (4 h) reduction in their motivation to lever press for HFHS reward, whereas treatment with equimolar doses of GLP-1/Dexa delivered a superior and sustained (20 h) suppression of food-motivated behavior. GLP-1/Dexa also inhibited food reward following withdrawal from the HFHS diet. These benefits coincided with related transcriptional changes of dopaminergic markers in the nucleus accumbens. Importantly, repeated GLP-1/Dexa treatment during a HFHS diet caused weight loss without affecting anxiodepressive behavior and memory. Conclusion: Via its actions to blunt the rewarding effects of palatable food without affecting mood and recognition memory, GLP-1-directed targeting of dexamethasone may serve as a promising and safe anti-obesity strategy. AU - Décarie-Spain, L.* AU - Fisette, A. AU - Zhu, Z.* AU - Yang, B.* AU - DiMarchi, R.D.* AU - Tschöp, M.H. AU - Finan, B.* AU - Fulton, S.* AU - Clemmensen, C.* C1 - 55813 C2 - 46579 SP - 55-63 TI - GLP-1/dexamethasone inhibits food reward without inducing mood and memory deficits in mice. JO - Neuropharmacol. VL - 151 PY - 2019 SN - 0028-3908 ER - TY - JOUR AB - Pathological aggregates of alpha-synuclein are the common hallmarks of synucleinopathies, including Parkinson's disease. There is currently no disease-modifying therapy approved for neurodegenerative synucleinopathies. The induction of macroautophagy by small compounds may be a strategy to reduce the cellular alpha-synuclein burden and to confer neuroprotection. Therefore, in the present study, we investigated a broad spectrum of druggable molecular signaling pathways reported to induce macroautophagy in human cells and compared their protective efficacy against alpha-synuclein-induced toxicity in cultured human postmitotic dopaminergic neurons. Several compounds affecting different pathways were able to activate macroautophagy. All compounds that activated autophagy also protected against alpha-synuclein-induced toxicity. The compounds with the lowest effective concentrations were PI-103, L-690,330, and NF 449, making them particularly interesting for further investigations, including in vivo models. Our findings demonstrate that activation of macroautophagy, as a neuroprotective approach in synucleinopathies, is accessible to pharmacotherapy. Moreover, pharmacological activation of macroautophagy via diverse signaling pathways is effective to protect human dopaminergic neurons against alpha-synuclein-induced toxicity. AU - Höllerhage, M.* AU - Fussi, N.* AU - Rösler, T.W.* AU - Wurst, W. AU - Behrends, C.* AU - Höglinger, G.U.* C1 - 55443 C2 - 46251 CY - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, England SP - 13-26 TI - Multiple molecular pathways stimulating macroautophagy protect from alpha-synuclein-induced toxicity in human neurons. JO - Neuropharmacol. VL - 149 PB - Pergamon-elsevier Science Ltd PY - 2019 SN - 0028-3908 ER - TY - JOUR AB - The obesity epidemic continues unabated and currently available pharmacological treatments are not sufficiently effective. Combining gut/brain peptide, GLP-1, with estrogen into a conjugate may represent a novel, safe and potent, strategy to treat diabesity. Here we demonstrate that the central administration of GLP-1-estrogen conjugate reduced food reward, food intake, and body weight in rats. In order to determine the brain location of the interaction of GLP-1 with estrogen, we avail of single-photon emission computed tomography imaging of regional cerebral blood flow and pinpoint a brain site unexplored for its role in feeding and reward, the supramammillary nucleus (SUM) as a potential target of the conjugated GLP-1-estrogen. We confirm that conjugated GLP-1 and estrogen directly target the SUM with site-specific microinjections. Additional microinjections of GLP-1-estrogen into classic energy balance controlling nuclei, the lateral hypothalamus (LH) and the nucleus of the solitary tract (NTS) revealed that the metabolic benefits resulting from GLP-1-estrogen injections are mediated through the LH and to some extent by the NTS. In contrast, no additional benefit of the conjugate was noted on food reward when the compound was microinjected into the LH or the NTS, identifying the SUM as the only neural substrate identified here to underlie the reward reducing benefits of GLP-1 and estrogen conjugate. Collectively we discover a surprising neural substrate underlying food intake and reward effects of GLP-1 and estrogen and uncover a new brain area capable of regulating energy balance and reward. AU - Vogel, H.* AU - Wolf, S.* AU - Rabasa, C.* AU - Rodriguez-Pacheco, F.* AU - Babaei, C.S.* AU - Stöber, F.* AU - Goldschmidt, J.* AU - DiMarchi, R.D.* AU - Finan, B. AU - Tschöp, M.H. AU - Dickson, S.L.* AU - Schürmann, A.* AU - Skibicka, K.P.* C1 - 49240 C2 - 33659 CY - Oxford SP - 396-406 TI - GLP-1 and estrogen conjugate acts in the supramammillary nucleus to reduce food-reward and body weight. JO - Neuropharmacol. VL - 110 PB - Pergamon-elsevier Science Ltd PY - 2016 SN - 0028-3908 ER - TY - JOUR AB - Quetiapine is an atypical antipsychotic which has been suggested to possess also antidepressant efficacy in the treatment of bipolar and unipolar depression. Recently, a link between the activation of the ERK/MAPK signalling pathway and the release of GDNF has been proposed as a specific feature of antidepressants. To obtain a first insight into the putative molecular mechanism of action of quetiapine, we examined its impact and that of its major metabolite norquetiapine on the activation of the ERK/MAPK signalling pathway in C6 glioma cells. Additionally, we investigated the induction of GDNF release as a possible physiological consequence of this activation. We found that norquetiapine, similarly to the antidepressant reboxetine, activated both ERK1 and ERK2 (pERK) with consequent enhanced release of GDNF; this release was dependent on pERK, as demonstrated by its reversibility after pre-treatment with a pharmacological pERK inhibitor. In contrast, quetiapine induced activation of ERK2 only. It also caused release of GDNF, but this release was independent of ERK activation. To test whether the simultaneous activation of ERK1 with ERK2 was critical for the observed pERK-dependent GDNF release, we specifically inactivated ERK1 mRNA via RNA interference. Our data show that indeed ERK1 plays an essential role, as GDNF release was hampered after Erk1 downregulation comparably to a pharmacological pERK inhibitor. Thus, activation of only ERK2 appears not to be sufficient for promoting GDNF release. Our results reveal the release of GDNF as a consequence of ERK/MAPK signalling activation by norquetiapine, which may contribute to the putative antidepressant properties of quetiapine. This article is part of a Special Issue entitled 'Anxiety and Depression'. AU - di Benedetto, B.* AU - Kühn, R. AU - Nothdurfter, C.* AU - Rein, T.* AU - Wurst, W. AU - Rupprecht, R.* C1 - 6479 C2 - 28777 SP - 209-216 TI - N-desalkylquetiapine activates ERK1/2 to induce GDNF release in C6 glioma cells: A putative cellular mechanism for quetiapine as antidepressant. JO - Neuropharmacol. VL - 62 IS - 1 PB - Elsevier PY - 2012 SN - 0028-3908 ER - TY - JOUR AB - The fact that cells with glial characteristics such as forebrain radial glia during development and astroglial stem cells in the adult neurogenic zones serve as neuronal precursors provokes the question why glia in most other areas of the adult central nervous system are apparently incapable of generating new neurons. Besides being of pivotal biological interest answers to this question may also open new avenues for cell-based therapies of neurodegenerative diseases that involve a permanent loss of neurons which are not replaced naturally. For if one could indeed instruct glia to generate neurons, such a strategy would carry the enormous advantage of making use of a large pool of endogenous, and hence autologous cells, thereby circumventing many of the problems associated with therapeutic strategies based on transplantation. Accordingly, the recent years have seen increasing effort in assessing the plasticity of astroglia and other types of resident non-neuronal cells as a potential source for new neurons in the injured brain or eye. For instance, following injury astroglia in the cerebral cortex and Muller glia in the retina can de-differentiate and acquire stem or precursor cell like properties. Moreover, it has been shown that astroglia can be reprogrammed in vitro by forced expression of neurogenic transcription factors to transgress their lineage restriction and stably acquire a neuronal identity. In this review I will discuss the status quo of these early attempts, the limitations currently encountered and the future challenges before the full potential of this approach can be weighed. AU - Berninger, B. C1 - 5018 C2 - 28238 SP - 894-202 TI - Making neurons from mature glia: A far-fetched dream? JO - Neuropharmacol. VL - 58 IS - 6 PB - Pergamon-Elsevier Science Ltd. PY - 2010 SN - 0028-3908 ER -