A novel analog of olanzapine linked to sarcosinyl moiety (PGW5) demonstrates high efficacy and good safety profile in mouse models of schizophrenia

Gil-Ad, Irit; Portnoy, Moshe; Tarasenko, Igor; Bidder, Miri; Kramer, M. S.; Taler, Michal; Weizman, Abraham

doi:10.1016/j.euroneuro.2013.11.009

Cited by 8 publications

(5 citation statements)

References 45 publications

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“…It has been previously speculated that the metabolic side-effects may be inextricably linked to the therapeutic effect of APs 37 . To determine if co-treatment with minocycline impaired the therapeutic efficacy of olanzapine we used a standard test for antipsychotic efficacy in mice (amphetamine-induced hyperlocomotion) 38 – 40 . As expected, amphetamine treatment resulted in hyperactivity that was blunted by olanzapine treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

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A phenotypic Caenorhabditis elegans screen identifies a selective suppressor of antipsychotic-induced hyperphagia

et al. 2018

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Antipsychotic (AP) drugs are used to treat psychiatric disorders but are associated with significant weight gain and metabolic disease. Increased food intake (hyperphagia) appears to be a driving force by which APs induce weight gain but the mechanisms are poorly understood. Here we report that administration of APs to C. elegans induces hyperphagia by a mechanism that is genetically distinct from basal food intake. We exploit this finding to screen for adjuvant drugs that suppress AP-induced hyperphagia in C. elegans and mice. In mice AP-induced hyperphagia is associated with a unique hypothalamic gene expression signature that is abrogated by adjuvant drug treatment. Genetic analysis of this signature using C. elegans identifies two transcription factors, nhr-25/Nr5a2 and nfyb-1/NFYB to be required for AP-induced hyperphagia. Our study reveals that AP-induced hyperphagia can be selectively suppressed without affecting basal food intake allowing for novel drug discovery strategies to combat AP-induced metabolic side effects.

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Section: Resultsmentioning

confidence: 99%

“…Food intake and weight gain were measured daily throughout the two-week study. Amphetamine-induced hyper locomotion assay 38 . Twelve week old female C57BL/6 mice were divided into 4 groups (control, OLZ, MINO and MINO + OLZ, n = 12 per group).…”

Section: Methodsmentioning

confidence: 99%

A phenotypic Caenorhabditis elegans screen identifies a selective suppressor of antipsychotic-induced hyperphagia

et al. 2018

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“…BDNF is also a major regulator of inhibitory γ-aminobutyric acid (GABA)-ergic neurotransmission [ 3 ]. Elevating hippocampal BDNF levels attenuates chronic stress in a mouse model of depression [ 4 ], while chronic administration of antidepressant drugs increases BDNF expression within the hippocampus [ 5 , 6 ]. Interestingly, blood and hippocampal BDNF levels are reduced in patients with depression [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Salivary Gland Derived BDNF Overexpression in Mice Exerts an Anxiolytic Effect

Saruta

Sugimoto

et al. 2017

IJMS

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Brain-derived neurotrophic factor (BDNF) is abundant in the hippocampus and plays critical roles in memory and synapse formation, as well as exerting antidepressant-like effects in psychiatric disorders. We previously reported that BDNF is expressed in salivary glands and affects blood BDNF content. However, the function of salivary BDNF remains unclear. The aim of this study was to generate transgenic mice overexpressing BDNF in the salivary glands. Hence, we used the Lama construct (hemagglutinin (HA)-tagged mouse Bdnf cDNA) to specifically express BDNF in mouse salivary glands. Compared with control mice, Bdnf-HA transgenic mice showed increased blood BDNF and expressed salivary BDNF-HA. Molecular analysis revealed enhanced hippocampal BDNF levels and activation of the BDNF receptor, tyrosine kinase B (TrkB), in transgenic mice. In both the open field and elevated-plus maze tests, transgenic mice showed anxiolytic-like behavioral effects compared with control or sialoadenectomized mice. Among downstream components of the BDNF-TrkB signaling pathway, metabolic activation of the γ-aminobutyric acid (GABA) synthetic pathway was found, including higher levels of the GABA synthetic enzyme, glutamate decarboxylase 1 (GAD1). Thus, we have established a transgenic mouse expressing BDNF in the parotid gland that may be useful to examine the hippocampal effects of salivary BDNF.

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“…The observed increase in brain GAD65/67 levels are likely due to ethanol and/or caffeine-induced changes in neural circuits that serve to reduce excitotoxicity. For example, an ethanol-induced release of NMDA receptors from inhibition may increase GAD67 levels, so dopamine and glutamatergic AMPA receptors are inhibited, exerting a protective action against excitotoxicity [ 46 ]. An increase in GAD65/67 levels may consequently contribute to protection from symptoms of withdrawal from ethanol, which otherwise is capable of inducing excitotoxic neuronal damage.…”

Section: Discussionmentioning

confidence: 99%

Ethanol and caffeine age-dependently alter brain and retinal neurochemical levels without affecting morphology of juvenile and adult zebrafish (Danio rerio)

2023

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Adolescent alcohol exposure in humans is predictive of adult development of alcoholism. In rodents, caffeine pre-exposure enhances adult responsiveness to ethanol via a pathway targeted by both compounds. Embryonic exposure to either compound adversely affects development, and both compounds can alter zebrafish behaviors. Here, we evaluate whether co-exposure to caffeine and/or alcohol in adolescence exerts neurochemical changes in retina and brain. Zebrafish (Danio rerio) were given daily 20 min treatments to ethanol (1.5% v/v), caffeine (25–100 mg/L), or caffeine + ethanol for 1 week during mid-late adolescence (53–92 days post fertilization (dpf)) or early adulthood (93–142 dpf). Immediately after exposure, anatomical measurements were taken, including weight, heart rate, pigment density, length, girth, gill width, inner and outer eye distance. Brain and retinal tissue were subsequently collected either (1) immediately, (2) after a short interval (2-4d) following exposure, or (3) after a longer interval that included an acute 1.5% ethanol challenge. Chronic ethanol and/or caffeine exposure did not alter anatomical parameters. However, retinal and brain levels of tyrosine hydroxylase were elevated in fish sacrificed after the long interval following exposure. Protein levels of glutamic acid decarboxylase were also increased, with the highest levels observed in 70–79 dpf fish exposed to caffeine. The influence of ethanol and caffeine exposure on neurochemistry demonstrates specificity of their effects during postembryonic development. Using the zebrafish model to assess neurochemistry relevant to reward and anxiety may inform understanding of the mechanisms that reinforce co-addiction to alcohol and stimulants.

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A novel analog of olanzapine linked to sarcosinyl moiety (PGW5) demonstrates high efficacy and good safety profile in mouse models of schizophrenia

Cited by 8 publications

References 45 publications

A phenotypic Caenorhabditis elegans screen identifies a selective suppressor of antipsychotic-induced hyperphagia

A phenotypic Caenorhabditis elegans screen identifies a selective suppressor of antipsychotic-induced hyperphagia

Salivary Gland Derived BDNF Overexpression in Mice Exerts an Anxiolytic Effect

Ethanol and caffeine age-dependently alter brain and retinal neurochemical levels without affecting morphology of juvenile and adult zebrafish (Danio rerio)

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