Mosapride increases levels of this peptide, im sure there are other meds that activate it or increase circulating levels, so it can do whatever this peptide can do, interesting innit?
Most drugs change levels or activate side receptors/peptide's wich have relevance for a lot of things, the point is to find them and combine them to get a strong synergetic effect, kinda like the cilltep stack.
EDIT:
Curr Alzheimer Res. 2005 Jul;2(3):377-85.
Enhancing central nervous system endogenous GLP-1 receptor pathways for intervention in Alzheimer's disease.
Perry T, Greig NH.
Source
Drug Design & Development Section, Laboratory of Neurosciences, Gerontology Research Center, Intramural Research Program National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. tracyann.perry@amylin.com
Abstract
Glucagon-like peptide-1 (7-36)--amide (GLP-1) is an endogenous insulinotropic peptide that is secreted from the gastrointestinal tract in response to food. It enhances pancreatic islet beta-cell proliferation, glucose-dependent insulin secretion, and lowers blood glucose and food intake in patients with type 2 diabetes mellitus. GLP-1 receptors, are coupled to the cyclic AMP second messenger pathway, and are expressed throughout the brain of rodents and humans. We previously reported that GLP-1 and exendin-4, a naturally occurring, long-acting analogue of GLP-1 that binds the GLP-1 receptor (GLP-1R), possess neurotrophic properties. GLP-1R agonists protect neurons against amyloid-beta peptide (Abeta) and glutamate-induced apoptosis in cell culture studies and attenuate cholinergic neuron atrophy in the basal forebrain of the rat following an excitotoxic lesion. The biochemical cascades activated by neural GLP-1R stimulation are discussed in comparison to those activated by pancreatic receptors, and, additionally, are compared to signaling pathways associated with the classical neurotrophins. GLP-1R stimulation promotes pathways that favour cell survival over apoptosis. GLP-1 readily enters brain, and its diverse physiological actions, which include insulinotropic, cardiovascular as well as neurotrophic ones, may prove beneficial in a variety of diseases prevalent in aging, including Alzheimer's disease (AD). Its ability to lower brain levels of Abeta in mice would appear to be particularly pertinent in this regard. Furthermore, the ready availability of clinical material and the clinical history of its long term use in subjects with type 2 diabetes would support testing the value of GLP-1R agonists in AD trials.
Br J Pharmacol. 2012 Jul;166(5):1586-99. doi: 10.1111/j.1476-5381.2012.01971.x.
Neuroprotective and neurotrophic actions of glucagon-like peptide-1: an emerging opportunity to treat neurodegenerative and cerebrovascular disorders.
Salcedo I, Tweedie D, Li Y, Greig NH.
Source
Drug Design & Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Abstract
Like type-2 diabetes mellitus (T2DM), neurodegenerative disorders and stroke are an ever increasing, health, social and economic burden for developed Westernized countries. Age is an important risk factor in all of these; due to the rapidly increasing rise in the elderly population T2DM and neurodegenerative disorders, both represent a looming threat to healthcare systems. Whereas several efficacious drugs are currently available to ameliorate T2DM, effective treatments to counteract pathogenic processes of neurodegenerative disorders are lacking and represent a major scientific and pharmaceutical challenge. Epidemiological data indicate an association between T2DM and most major neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Likewise, there is an association between T2DM and stroke incidence. Studies have revealed that common pathophysiological features, including oxidative stress, insulin resistance, abnormal protein processing and cognitive decline, occur across these. Based on the presence of shared mechanisms and signalling pathways in these seemingly distinct diseases, one could hypothesize that an effective treatment for one disorder could prove beneficial in the others. Glucagon-like peptide-1 (GLP-1)-based anti-diabetic drugs have drawn particular attention as an effective new strategy to not only regulate blood glucose but also to reduce apoptotic cell death of pancreatic beta cells in T2DM. Evidence supports a neurotrophic and neuroprotective role of GLP-1 receptor ® stimulation in an increasing array of cellular and animal neurodegeneration models as well as in neurogenesis. Herein, we review the physiological role of GLP-1 in the nervous system, focused towards the potential benefit of GLP-1R stimulation as an immediately translatable treatment strategy for acute and chronic neurological disorders.
Biochim Biophys Acta. 2013 Jan 11. pii: S0925-4439(13)00012-4. doi: 10.1016/j.bbadis.2013.01.008. [Epub ahead of print]
Crosstalk between diabetes and brain: Glucagon-like peptide-1 mimetics as a promising therapy against neurodegeneration.
Duarte AI, Candeias E, Correia SC, Santos RX, Carvalho C, Cardoso S, Plácido A, Santos MS, Oliveira CR, Moreira PI.
Source
Center for Neuroscience and Cell Biology, Life Sciences Department, University of Coimbra, Largo Marquês de Pombal, 3004-517 Coimbra, Portugal. Electronic address: anaimduarte@gmail.com.
Abstract
According to World Health Organization estimates, type 2 diabetes (T2D) is an epidemic (particularly in under development countries) and a socio-economic challenge. This is even more relevant since increasing evidence points T2D as a risk factor for Alzheimer's disease (AD), supporting the hypothesis that AD is a "type 3 diabetes" or "brain insulin resistant state". Despite the limited knowledge on the molecular mechanisms and the etiological complexity of both pathologies, evidence suggests that neurodegeneration/death underlying cognitive dysfunction (and ultimately dementia) upon long-term T2D may arise from a complex interplay between T2D and brain aging. Additionally, decreased brain insulin levels/signaling and glucose metabolism in both pathologies further suggests that an effective treatment strategy for one disorder may be also beneficial in the other. In this regard, one such promising strategy is a novel successful anti-T2D class of drugs, the glucagon-like peptide-1 (GLP-1) mimetics (e.g. exendin-4 or liraglutide), whose potential neuroprotective effects have been increasingly shown in the last years. In fact, several studies showed that, besides improving peripheral (and probably brain) insulin signaling, GLP-1 analogs minimize cell loss and possibly rescue cognitive decline in models of AD, Parkinson's (PD) or Huntington's disease. Interestingly, exendin-4 is undergoing clinical trials to test its potential as an anti-PD therapy. Herewith, we aim to integrate the available data on the metabolic and neuroprotective effects of GLP-1 mimetics in the central nervous system (CNS) with the complex crosstalk between T2D-AD, as well as their potential therapeutic value against T2D-associated cognitive dysfunction.
J Neurosci Res. 2013 Jan 18. doi: 10.1002/jnr.23181. [Epub ahead of print]
Val(8) -GLP-1 remodels synaptic activity and intracellular calcium homeostasis impaired by amyloid β peptide in rats.
Wang XH, Yang W, Hölscher C, Wang ZJ, Cai HY, Li QS, Qi JS.
Source
Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, China; Department of Pathology, Shanxi Medical University, Taiyuan, China.
Abstract
Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer's disease (AD) in the elderly. Glucagon-like peptide-1 (GLP-1), a modulator in T2DM therapy, has been shown to have neuroprotective properties. However, the native GLP-1 can be rapidly degraded by the enzyme dipeptidyl peptidase IV (DPP IV); the neuroprotective mechanism of GLP-1 in the central nervous system is still an open question, and whether GLP-1 can prevent amyloid β (Aβ)-induced synaptic dysfunction and calcium disorder is still unclear. The present study, by using patch clamp and calcium imaging techniques, investigated the effects of Val(8) -GLP-1(7-36), a GLP-1 analogue with profound resistance to DPP IV, on the excitatory and inhibitory synaptic transmission and intracellular calcium concentration ([Ca(2+) ](i) ) in the absence or presence of Aβ1-40. The results showed that 1) Aβ1-40 significantly reduced the frequency of miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) in CA1 pyramidal neurons of rat brain slices; 2) Val(8) -GLP-1(7-36) did not affect the activity of miniature postsynaptic currents but effectively protected against the Aβ1-40-induced decrease in mEPSC and mIPSC frequency; 3) Aβ1-40 significantly increased [Ca(2+) ](i) in primary neuronal cultures; and 4) Val(8) -GLP-1(7-36) alone did not change the intracellular calcium level but prevented Aβ1-40-induced persistent elevation of [Ca(2+) ](i) . These findings demonstrate for the first time that central application of Val(8) -GLP-1(7-36) could protect against Aβ-induced synaptic dysfunction and intracellular calcium overloading, suggesting that the neuroprotection of GLP-1 may be involved in the remodeling of synaptic activity and intracellular calcium homeostasis in the brain. © 2013 Wiley Periodicals, Inc.
Therapeutic Potential of N-Acetyl-Glucagon-Like Peptide-1 in Primary Motor Neuron Cultures Derived From Non-Transgenic and SOD1-G93A ALS Mice.
Sun H, Knippenberg S, Thau N, Ragancokova D, Körner S, Huang D, Dengler R, Döhler K, Petri S.
Source
Department of Neurology, Hannover Medical School, OE 7210, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurons (MN) in the motor cortex, brainstem, and spinal cord. In the present study, we established an ALS in vitro model of purified embryonic MNs, derived from non-transgenic and mutant SOD1-G93A transgenic mice, the most commonly used ALS animal model. MNs were cultured together with either non-transgenic or mutant SOD1-G93A astrocyte feeder layers. Cell viability following exposure to kainate as excitotoxic stimulus was assessed by immunocytochemistry and calcium imaging. We then examined the neuroprotective effects of N-acetyl-GLP-1(7-34) amide (N-ac-GLP-1), a long-acting, N-terminally acetylated, C-terminally truncated analog of glucagon-like peptide-1 (GLP-1). GLP-1 has initially been studied as a treatment for type II diabetes based on its function as insulin secretagogue. We detected neuroprotective effects of N-ac-GLP-1 in our in vitro system, which could be attributed to an attenuation of intracellular calcium transients, not only due to these antiexcitotoxic capacities but also with respect to the increasing knowledge about metabolic deficits in ALS which could be positively influenced by N-ac-GLP-1, this compound represents an interesting novel candidate for further in vivo evaluation in ALS.
J Comp Neurol. 2012 Dec 14. doi: 10.1002/cne.23282. [Epub ahead of print]
Glucagon-like peptide-1 in the rat brain- distribution of expression and functional implication.
Gu G, Roland B, Tomaselli K, Dolman CS, Lowe C, Heilig JS.
Source
Amylin Pharmaceuticals, LLC, San Diego, CA 92121, USA. gug726@yahoo.com.
Abstract
Glucagon-like-peptide 1 (GLP-1) is expressed not only in gut endocrine cells, but also in cells in the caudal brainstem and taste buds. To better understand functions of the central GLP-1, GLP-1 expression was immunohistochemically profiled in normal rat brain and its distribution correlated with FOS induction following systemic administration of a GLP-1 receptor agonist, exendin-4. In the present study, only a small number of GLP-1-immunoreactive cell bodies were observed in the nucleus of the solitary tract (NTS). However, these neurons send abundant projections to other regions of the brain, in particular the forebrain, including the paraventricular and dorsomedial nuclei of the hypothalamus, the central nucleus of the amygdala, the oval nucleus of the bed nuclei of the stria terminalis, and the paraventricular nucleus of the thalamus. Intraperitoneal administration of exendin-4 resulted in extensive FOS expression in areas of the forebrain and the hindbrain. In the forebrain, FOS expression was largely confined to regions where high density of GLP-1-immunoreactive terminals was also localized. The majority of GLP-1-immunoreactive cells in the NTS were not FOS-positive. FOS-positive cells appeared to represent a different population from those expressing GLP-1. Thus, GLP-1-containing neurons in the brainstem may not be involved in receiving and relaying to other regions of the brain the physiological signals of prandial GLP-1 secreted by intestinal L-cells. Projections of GLP-1-containing neurons to the distinctive structures in the forebrain imply that central GLP-1 may play an important role in the behavioral and metabolic integration of autonomic control and arousal in the rat. J. Comp. Neurol., 2012. © 2012 Wiley Periodicals, Inc.
The glucagon-like peptide 1 analogue Exendin-4 attenuates alcohol mediated behaviors in rodents.
Egecioglu E, Steensland P, Fredriksson I, Feltmann K, Engel JA, Jerlhag E.
Source
Institute of Neuroscience and Physiology, Department of Pharmacology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
Abstract
Development of alcohol use disorders largely depends on the effects of alcohol on the brain reward systems. Emerging evidence indicate that common mechanisms regulate food and alcohol intake and raise the possibility that endocrine signals from the gut may play an important role for alcohol consumption, alcohol-induced reward and the motivation to consume alcohol. Glucagon-like peptide 1 (GLP-1), a gastrointestinal peptide regulating food intake and glucose homeostasis, has recently been shown to target central brain areas involved in reward and motivation, including the ventral tegmental area and nucleus accumbens. Herein we investigated the effects of the GLP-1 receptor agonist, Exendin-4 (Ex4), on various measures of alcohol-induced reward as well as on alcohol intake and alcohol seeking behavior in rodents. Treatment with Ex4, at a dose with no effect per se, attenuated alcohol-induced locomotor stimulation and accumbal dopamine release in mice. Furthermore, conditioned place preference for alcohol was abolished by both acute and chronic treatment with Ex4 in mice. Finally we found that Ex4 treatment decreased alcohol intake, using the intermittent access 20% alcohol two-bottle-choice model, as well as alcohol seeking behavior, using the progressive ratio test in the operant self-administration model, in rats. These novel findings indicate that GLP-1 signaling attenuates the reinforcing properties of alcohol implying that the physiological role of GLP-1 extends beyond glucose homeostasis and food intake regulation. Collectively these findings implicate that the GLP-1 receptor may be a potential target for the development of novel treatment strategies for alcohol use disorders.
Glucagon-like peptide-1 cleavage product GLP-1(9-36) amide rescues synaptic plasticity and memory deficits in Alzheimer's disease model mice.
Ma T, Du X, Pick JE, Sui G, Brownlee M, Klann E.
Source
Center for Neural Science, New York University, New York, New York 10003, USA.
Abstract
Glucagon-like peptide-1 (GLP-1) is an endogenous intestinal peptide that enhances glucose-stimulated insulin secretion. Its natural cleavage product GLP-1(9-36)(amide) possesses distinct properties and does not affect insulin secretion. Here we report that pretreatment of hippocampal slices with GLP-1(9-36)(amide) prevented impaired long-term potentiation (LTP) and enhanced long-term depression induced by exogenous amyloid β peptide Aβ((1-42)). Similarly, hippocampal LTP impairments in amyloid precursor protein/presenilin 1 (APP/PS1) mutant mice that model Alzheimer's disease (AD) were prevented by GLP-1(9-36)(amide). In addition, treatment of APP/PS1 mice with GLP-1(9-36)(amide) at an age at which they display impaired spatial and contextual fear memory resulted in a reversal of their memory defects. At the molecular level, GLP-1(9-36)(amide) reduced elevated levels of mitochondrial-derived reactive oxygen species and restored dysregulated Akt-glycogen synthase kinase-3β signaling in the hippocampus of APP/PS1 mice. Our findings suggest that GLP-1(9-36)(amide) treatment may have therapeutic potential for AD and other diseases associated with cognitive dysfunction.
The peptide-hormone glucagon-like peptide-1 activates cAMP and inhibits growth of breast cancer cells.
Ligumsky H, Wolf I, Israeli S, Haimsohn M, Ferber S, Karasik A, Kaufman B, Rubinek T.
Source
Institute of Oncology, Chaim Sheba Medical Center, 52621 Ramat-Gan, Israel.
Abstract
The incretin hormone glucagon-like peptide (GLP)-1 is secreted from intestinal L cells in response to food intake, and promotes insulin secretion and pancreatic β-cell proliferation. Reduced GLP-1 levels are observed in obesity and type 2 diabetes mellitus (T2DM) and are associated with reduced insulin secretion and increased insulin resistance. GLP-1 mediates its activities through activation of a G-protein coupled receptor, which is expressed in the pancreas, as well as other tissues. Long-acting GLP-1 receptor (GLP-1R) agonists, such as exendin-4, are currently approved for the treatment of T2DM. As obesity and T2DM are associated with increased risk of breast cancer, we aimed to explore the effects of GLP-1 and exendin-4, on breast cancer cells. Treatment with GLP-1 or exendin-4 reduced viability and enhanced apoptosis of breast cancer cells but did not affect viability of nontumorigenic cells. Moreover, exendin-4 attenuated tumor formation by breast cancer cells in athymic mice. Treatment with either GLP-1 or exendin-4 elevated cAMP levels, activated the down-stream target CREB, and enhanced CRE promoter transcription, in breast cancer cells. Moreover, inhibition of exendin-4-induced adenylate cyclase activation restored cell viability, thus suggesting cAMP as a principle mediator of exendin-4 anti-tumorigenic activity. While the pancreatic form of the GLP-1R could not be detected in breast cancer cells, several lines of evidence indicated the existence of an alternative GLP-1R in mammary cells. Thus, internalization of GLP-1 into MCF-7 cells was evidenced, infection of MCF-7 cells with the pancreatic receptor enhanced proliferation, and treatment with exendin-(9-39), a GLP-1R antagonist, further increased cAMP levels. Our studies indicate the incretin hormone GLP-1 as a potent inducer of cAMP and an inhibitor of breast cancer cell proliferation. Reduced GLP-1 levels may, therefore, serve as a novel link between obesity, diabetes mellitus, and breast cancer.
Edited by medievil, 08 February 2013 - 10:46 PM.
