China
Africa
Explore chapters and articles related to this topic
Monitoring and Maintenance of Brain Glucose Supply
Published in Ruth B.S. Harris, Appetite and Food Intake, 2017
The importance of A1/C1 neurons for stimulation of feeding has been confirmed using designer receptors exclusively activated by designer drug (DREADD) technology to selectively activate these neurons. hM3D(Gq), a “designer” receptor for the “designer drug” clozapine-N-oxide (CNO), was selectively expressed in A1/C1 CA neurons by injection of AAV-DIO-hM3D(Gq)-mCherry into the A1/C1 area of Th-Cre+ rats (Li et al. 2015b). Using this procedure, over 85% of mCherry-labeled neurons were double labeled for DBH, 92% of mCherry-labeled neurons were also TH-positive, and 90% of TH/mCherry cells expressed c-Fos after CNO treatment, which selectively activates only neurons transfected to express hM3D(Gq). Selective activation of A1/C1 neurons by a peripheral injection of CNO increased food intake. Rats consumed approximately 4 g of chow in the 4-hour test after CNO, compared to just 0.8 g after control injections. The magnitude of this response to CNO activation was equivalent to responses induced by systemic 2DG. These same rats, tested in the absence of food, did not exhibit increased blood glucose responses to CNO injections, supporting the hypothesis that the latter control is mediated by neurons distinct from those controlling food intake.
The Impact of Insulin on Brain Serotonergic System: Consequences on Diabetes-Associated Mood Disorders 1
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Hugo Martin, Sebastian Bullich, Bruno P. Guiard, Xavier Fioramonti
Optogenetics and pharmacogenetics approaches have been designed to remotely and selectively control spatiotemporally the activity of neurons to regulate the behavior and physiological functions (62). Optogenetics relies on the genetic modification of known microbial opsin genes encoding light-sensitive channels, which, once activated by light, either activate or inhibit targeted neurons. The pharmacogenetics approach, also called Designer Receptors Exclusively Activated by Designer Drugs (DREADD), consists of the use of receptor proteins that have been engineered to exclusively respond to inert agonist to activate or inhibit key downstream G protein-dependent signaling pathways (Gs-, Gq- or Gi-signaling pathways). The first DREADD has been designed from a modified human muscarinic acetylcholine receptor. Specific neurons can be targeted by injecting a viral vector (adeno-associated viral (AAV) most of the time) expressing the opsin or the DREADD in a cre-dependent manner in a transgenic mouse expressing the cre-recombinase in the selective neuronal population (TpH2-cre or Pet1-cre in the case of brain 5-HT neurons). The optogenetics approach requires that an optic fiber “lighting-up” the neurons addressing the opsin to be inserted by stereotaxy in the brain, in the area of interest. In opposition, the pharmacogenetics approach is less invasive as it only requires to administer the inert DREADD agonist intraperitoneally or in the drinking water for long term neuronal modulation (in some cases, injecting the inert agonist locally in the brain by stereotaxy could be necessary). Clozapine-N-oxide (CNO) is the first DREADD agonist developed and, so far, the most widely used. CNO selectively activates DREADDs but is not an active ligand for the endogenous muscarinic acetylcholine receptors. The cutting-edge optogenetics and pharmacogenetics are powerful tools in neuroscience that allow selective and bidirectional modulation of the activity of defined populations of neurons with unprecedented specificity. The applications of optogenetics and pharmacogenetics are limitless as these approaches allow the correlation between the activity of a specific neuronal network and a physiological function in a free moving animal. Almost all functions controlled by the brain can be studied inkling feeding behaviors, hormonal regulations, memory or mood. Figure 8.1 summarizes the application of optogenetics and pharmacogenetics in the study of 5-HT system-dependent emotional behaviors (Figure 8.1).
From leptin to lasers: the past and present of mouse models of obesity
Published in Expert Opinion on Drug Discovery, 2021
Joshua R. Barton, Adam E. Snook, Scott A. Waldman
Other methods of neuromodulation eliminate the need for light-producing hardware altogether. ‘Chemogenetics’ uses designer compounds to activate engineered G protein-coupled receptors (GPCRs) that modulate neuronal excitability and transmission [137]. These GPCRs, also known as designer receptors exclusively activated by designer drug (DREADDs), can be genetically encoded and expressed in particular tissues and cell types through viral or transgenic methods. Clozapine-N-oxide (CNO) is the designer drug used to activate DREADDs, as it is an inert, bioavailable compound that interacts solely with DREADDs [137]. Expression of an inhibitory DREADD (hM4D), in ARCAGRP+ neurons using the AGRP-Cre mouse, reduces feeding by 40% after injection of CNO [138]. These appetite-inducing ARCAGRP+ neurons were known to act on paraventricular hypothalamus SIM1+ neurons (PVHSIM1+), but the rest of the circuit was not known. Expression of the same inhibitory DREADD in PVHSIM1+ neurons revealed a new appetitive circuit from the PVH to the DRN in the brainstem. Injection of CNO into mice expressing hM4D in PVHSIM1+ neurons decreased synaptic transmission to the DRN and recapitulated the 40% feeding reduction produced by inhibiting ARCAGRP+ neurons [138].
Toxicoproteomics reveals an effect of clozapine on autophagy in human liver spheroids
Published in Toxicology Mechanisms and Methods, 2023
Catherine Nury, Celine Merg, Yvan Eb-Levadoux, David Bovard, Matthieu Porchet, Fabio Maranzano, Isidora Loncarevic, Shahrzad Tavalaei, Eleonore Lize, Ramona Liliana Demenescu, Hasmik Yepiskoposyan, Julia Hoeng, Nikolai V Ivanov, Kasper Renggli, Bjoern Titz
Clozapine is an atypical antipsychotic drug used to treat treatment-resistant schizophrenia (Haidary and Padhy 2020). As a drug developed in 1961, clozapine is still considered one of the most effective drugs against schizophrenia, which often induces remarkable symptom relief and improves quality of life (Orsolini et al. 2016; De Berardis et al. 2018). However, the side effects experienced by many patients preclude its common use as a first-line therapy for schizophrenia (Orsolini et al. 2016). Common side effects of clozapine include sedation, hypertension, weight gain, and seizures, and less common side effects include liver enzyme abnormalities and agranulocytosis or granulocytopenia (De Berardis et al. 2018). In addition, clozapine has a large inter-individual variability in plasma concentrations when the same dose is administered (Dailly et al. 2002; Lee et al. 2009). Combined with the narrow therapeutic window of the drug, therapeutic drug monitoring is advised (Thorn et al. 2018; Albitar et al. 2020; Jovanović et al. 2020). Clozapine is metabolized by the hepatic cytochrome P450 (CYP) microsomal system. The drug is converted to norclozapine by CYP3A4 and CYP1A2 and to clozapine N-oxide by CYP3A4 (Eiermann et al. 1997; Buur-Rasmussen and Brøsen 1999). Drug–drug interactions that affect P450 enzymes, such as oral contraceptives and antifungals, can lead to a significant change in clozapine metabolism. Miconazole and ketoconazole have been demonstrated to inhibit clozapine metabolism by more than 50% (Bun et al. 1999). This interaction leads to an increase in the plasma concentration of the parent compound, and a narrow therapeutic index leads to significant clozapine toxicity (Jovanović et al. 2020).
A comprehensive review of the clinical utility of and a combined analysis of the clozapine/norclozapine ratio in therapeutic drug monitoring for adult patients
Published in Expert Review of Clinical Pharmacology, 2019
Georgios Schoretsanitis, John M. Kane, Can-Jun Ruan, Edoardo Spina, Christoph Hiemke, Jose de Leon
There are three metabolic pathways for CLO. From least to most important they are 1) glucuronidation, 2) oxidation to clozapine-N-oxide and 3) demethylation to NCLO. The main metabolic pathway for demethylation is the cytochrome P450 1A2 (CYP1A2) which, according to a single-dose study, explains approximately 70% of the CLO metabolism [66]. An in vitro study suggests that other demethylation enzymes for CLO including cytochrome P450 2C19, 3A4, and 2D6 (CY2C19, CY3A4, and CYP2D6) may be minor pathways [67].