scholarly journals The Mammalian Target of Rapamycin (mTOR) Kinase Mediates Haloperidol-Induced Cataleptic Behavior

2020 ◽  
Author(s):  
Uri Nimrod Ramírez-Jarquín ◽  
Neelam Shahani ◽  
William Pryor ◽  
Alessandro Usiello ◽  
Srinivasa Subramaniam
Keyword(s):  
Side Effects ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Typical Antipsychotic ◽  
Dependent Manner ◽  
Serine Threonine Kinase ◽  
Therapeutic Benefits ◽  
Dopamine 2 Receptor ◽  
Pharmacological Method ◽  
Extrapyramidal Motor

ABSTRACTThe mammalian target of rapamycin (mTOR) is a ubiquitously expressed serine/threonine kinase protein complex (mTORC1 or mTORC2) that orchestrates diverse functions ranging from embryonic development to aging. However, its brain tissue-specific roles remain less explored. Here, we have identified that the depletion of the mTOR gene in the mice striatum completely prevented the extrapyramidal motor side-effects (catalepsy) induced by the dopamine 2 receptor (D2R) antagonist haloperidol, which is the most widely used typical antipsychotic drug. Conversely, a lack of striatal mTOR in mice did not affect catalepsy triggered by the dopamine 1 receptor (D1R) antagonist SCH23390. Along with the lack of cataleptic effects, the administration of haloperidol in mTOR mutants failed to increase striatal phosphorylation levels of ribosomal protein pS6 (S235/236) as seen in control animals. To confirm the observations of the genetic approach, we used a pharmacological method and determined that the mTORC1 inhibitor rapamycin has a profound influence upon post-synaptic D2R-dependent functions. We consistently found that pretreatment with rapamycin entirely prevented (in a time-dependent manner) the haloperidol-induced catalepsy in wild-type mice. Collectively, our data indicate that striatal mTORC1 blockade may offer therapeutic benefits with regard to the prevention of D2R-dependent extrapyramidal motor side-effects of haloperidol in psychiatric illness.

scholarly journals The mammalian target of rapamycin (mTOR) kinase mediates haloperidol-induced cataleptic behavior

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Uri Nimrod Ramírez-Jarquín ◽  
Neelam Shahani ◽  
William Pryor ◽  
Alessandro Usiello ◽  
Srinivasa Subramaniam
Keyword(s):  
Side Effects ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Typical Antipsychotic ◽  
Dependent Manner ◽  
Serine Threonine Kinase ◽  
Therapeutic Benefits ◽  
Dopamine 2 Receptor ◽  
Pharmacological Method ◽  
Extrapyramidal Motor

Abstract The mammalian target of rapamycin (mTOR) is a ubiquitously expressed serine/threonine kinase protein complex (mTORC1 or mTORC2) that orchestrates diverse functions ranging from embryonic development to aging. However, its brain tissue-specific roles remain less explored. Here, we have identified that the depletion of the mTOR gene in the mice striatum completely prevented the extrapyramidal motor side effects (catalepsy) induced by the dopamine 2 receptor (D2R) antagonist haloperidol, which is the most widely used typical antipsychotic drug. Conversely, a lack of striatal mTOR in mice did not affect catalepsy triggered by the dopamine 1 receptor (D1R) antagonist SCH23390. Along with the lack of cataleptic effects, the administration of haloperidol in mTOR mutants failed to increase striatal phosphorylation levels of ribosomal protein pS6 (S235/236) as seen in control animals. To confirm the observations of the genetic approach, we used a pharmacological method and determined that the mTORC1 inhibitor rapamycin has a profound influence upon post-synaptic D2R-dependent functions. We consistently found that pretreatment with rapamycin entirely prevented (in a time-dependent manner) the haloperidol-induced catalepsy, and pS6K (T389) and pS6 (S235/236) signaling upregulation, in wild-type mice. Collectively, our data indicate that striatal mTORC1 blockade may offer therapeutic benefits with regard to the prevention of D2R-dependent extrapyramidal motor side effects of haloperidol in psychiatric illness.

scholarly journals Mechanistic/mammalian target of rapamycin and side effects of antipsychotics: insights into mechanisms and implications for therapy

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Chuanjun Zhuo ◽  
Yong Xu ◽  
Weihong Hou ◽  
Jiayue Chen ◽  
Qianchen Li ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Weight Gain ◽  
Side Effects ◽  
Antipsychotic Drugs ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Target Of Rapamycin ◽  
Glucose And Lipid Metabolism ◽  
Pathway Activation ◽  
Extrapyramidal Motor

AbstractAntipsychotic pharmacotherapy has been widely recommended as the standard of care for the treatment of acute schizophrenia and psychotic symptoms of other psychiatric disorders. However, there are growing concerns regarding antipsychotic-induced side effects, including weight gain, metabolic syndrome (MetS), and extrapyramidal motor disorders, which not only decrease patient compliance, but also predispose to diabetes and cardiovascular diseases. To date, most studies and reviews on the mechanisms of antipsychotic-induced metabolic side effects have focused on central nervous system mediation of appetite and food intake. However, disturbance in glucose and lipid metabolism, and hepatic steatosis induced by antipsychotic drugs might precede weight gain and MetS. Recent studies have demonstrated that the mechanistic/mammalian target of rapamycin (mTOR) pathway plays a critical regulatory role in the pathophysiology of antipsychotic drug-induced disorders of hepatic glucose and lipid metabolism. Furthermore, antipsychotic drugs promote striatal mTOR pathway activation that contributes to extrapyramidal motor side effects. Although recent findings have advanced the understanding of the role of the mTOR pathway in antipsychotic-induced side effects, few reviews have been conducted on this emerging topic. In this review, we synthesize key findings by focusing on the roles of the hepatic and striatal mTOR pathways in the pathogenesis of metabolic and extrapyramidal side effects, respectively. We further discuss the potential therapeutic benefits of normalizing excessive mTOR pathway activation with mTOR specific inhibitors. A deeper understanding of pathogenesis may inform future intervention strategies using the pharmacological or genetic inhibitors of mTOR to prevent and manage antipsychotic-induced side effects.

scholarly journals Crosstalk of the Caspase Family and Mammalian Target of Rapamycin Signaling

2021 ◽  
Vol 22 (2) ◽  
pp. 817
Author(s):  
Junfang Yan ◽  
Yi Xie ◽  
Jing Si ◽  
Lu Gan ◽  
Hongyan Li ◽  
...  
Keyword(s):  
Cell Growth ◽  
Cell Survival ◽  
Cell Fate ◽  
Cellular Stress ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Target Of Rapamycin ◽  
Dependent Manner ◽  
Caspase Family ◽  
Mediate Cell

Cell can integrate the caspase family and mammalian target of rapamycin (mTOR) signaling in response to cellular stress triggered by environment. It is necessary here to elucidate the direct response and interaction mechanism between the two signaling pathways in regulating cell survival and determining cell fate under cellular stress. Members of the caspase family are crucial regulators of inflammation, endoplasmic reticulum stress response and apoptosis. mTOR signaling is known to mediate cell growth, nutrition and metabolism. For instance, over-nutrition can cause the hyperactivation of mTOR signaling, which is associated with diabetes. Nutrition deprivation can inhibit mTOR signaling via SH3 domain-binding protein 4. It is striking that Ras GTPase-activating protein 1 is found to mediate cell survival in a caspase-dependent manner against increasing cellular stress, which describes a new model of apoptosis. The components of mTOR signaling-raptor can be cleaved by caspases to control cell growth. In addition, mTOR is identified to coordinate the defense process of the immune system by suppressing the vitality of caspase-1 or regulating other interferon regulatory factors. The present review discusses the roles of the caspase family or mTOR pathway against cellular stress and generalizes their interplay mechanism in cell fate determination.

scholarly journals New Mammalian Target of Rapamycin (mTOR) Modulators Derived from Natural Product Databases and Marine Extracts by Using Molecular Docking Techniques

Marine Drugs ◽  
2018 ◽  
Vol 16 (10) ◽  
pp. 385 ◽  
Author(s):  
Verónica Ruiz-Torres ◽  
Maria Losada-Echeberría ◽  
Maria Herranz-López ◽  
Enrique Barrajón-Catalán ◽  
Vicente Galiano ◽  
...  
Keyword(s):  
Natural Products ◽  
Molecular Docking ◽  
Side Effects ◽  
Inhibitory Activity ◽  
Mammalian Target Of Rapamycin ◽  
Therapeutic Use ◽  
Cellular Growth ◽  
Target Of Rapamycin ◽  
Computational Techniques ◽  
Chemical Derivatives

Mammalian target of rapamycin (mTOR) is a PI3K-related serine/threonine protein kinase that functions as a master regulator of cellular growth and metabolism, in response to nutrient and hormonal stimuli. mTOR functions in two distinct complexes—mTORC1 is sensitive to rapamycin, while, mTORC2 is insensitive to this drug. Deregulation of mTOR’s enzymatic activity has roles in cancer, obesity, and aging. Rapamycin and its chemical derivatives are the only drugs that inhibit the hyperactivity of mTOR, but numerous side effects have been described due to its therapeutic use. The purpose of this study was to identify new compounds of natural origin that can lead to drugs with fewer side effects. We have used computational techniques (molecular docking and calculated ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) parameters) that have enabled the selection of candidate compounds, derived from marine natural products, SuperNatural II, and ZINC natural products, for inhibitors targeting, both, the ATP and the rapamycin binding sites of mTOR. We have shown experimental evidence of the inhibitory activity of eleven selected compounds against mTOR. We have also discovered the inhibitory activity of a new marine extract against this enzyme. The results have been discussed concerning the necessity to identify new molecules for therapeutic use, especially against aging, and with fewer side effects.

scholarly journals T-2 Toxin Exposure Induces Apoptosis in TM3 Cells by Inhibiting Mammalian Target of Rapamycin/Serine/Threonine Protein Kinase(mTORC2/AKT) to Promote Ca2+Production

2018 ◽  
Vol 19 (11) ◽  
pp. 3360 ◽  
Author(s):  
Ji Wang ◽  
Chenglin Yang ◽  
Zhihang Yuan ◽  
Jine Yi ◽  
Jing Wu
Keyword(s):  
Cell Injury ◽  
Mammalian Target Of Rapamycin ◽  
Annexin V ◽  
Target Of Rapamycin ◽  
Dependent Manner ◽  
Toxin Exposure ◽  
Concentration Changes ◽  
Vitro Model ◽  
Induced Apoptosis

Although mTOR (the mammalian target of rapamycin) can regulate intracellular free Ca2+concentration in normal cultured podocytes, it remains elusive as to how mTORC2/AKT-mediated Ca2+participates in the process of T-2 toxin-induced apoptosis. The potential signaling responsible for intracellular Ca2+ concentration changes was investigated using immunoblot assays in an in vitro model of TM3 cell injury induced by T-2 toxin. Changes in Ca2+ were assessed using the Ca2+-sensitive fluorescent indictor dye Fura 2-AM. The cytotoxicity of TM3 cells was assessed with an MTT bioassay, and apoptosis was measured using Annexin V-FITC staining. Following T-2 toxin treatment, the growth of cells, phospho-mTORSer2481, phospho-mTORSer2448, and phospho-AktSer473 were significantly decreased in a time-dependent manner, whereas Ca2+ and apoptosis were increased. T-2 toxin-induced apoptosis was prevented by BAPTA-AM (a Ca2+chelator) and MHY1485 (an mTOR activator), and the application of mTOR activator MHY1485 also prevented the increase of intracellular free Ca2+concentration in TM3 cells. Our results strongly suggest that T-2 toxin exposure induces apoptosis in TM3 cells by inhibiting mTORC2/AKT to promote Ca2+ production.

scholarly journals Mammalian Target of Rapamycin Complex 2 Controls CD8 T Cell Memory Differentiation in a Foxo1-Dependent Manner

Cell Reports ◽  
2016 ◽  
Vol 14 (5) ◽  
pp. 1206-1217 ◽  
Author(s):  
Lianjun Zhang ◽  
Benjamin O. Tschumi ◽  
Isabel C. Lopez-Mejia ◽  
Susanne G. Oberle ◽  
Marten Meyer ◽  
...  
Keyword(s):  
T Cell ◽  
Mammalian Target Of Rapamycin ◽  
Cd8 T Cell ◽  
Target Of Rapamycin ◽  
T Cell Memory ◽  
Dependent Manner ◽  
Cell Memory ◽  
Memory Differentiation ◽  
Cd8 T Cell Memory

scholarly journals Interferon α Induces Nucleus-independent Apoptosis by Activating Extracellular Signal-regulated Kinase 1/2 and c-Jun NH2-Terminal Kinase Downstream of Phosphatidylinositol 3-Kinase and Mammalian Target of Rapamycin

2008 ◽  
Vol 19 (1) ◽  
pp. 41-50 ◽  
Author(s):  
Theocharis Panaretakis ◽  
Linn Hjortsberg ◽  
Katja Pokrovskaja Tamm ◽  
Ann-Charlotte Björklund ◽  
Bertrand Joseph ◽  
...  
Keyword(s):  
Apoptotic Cell ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Interferon Α ◽  
Dependent Manner ◽  
Phosphatidylinositol 3 Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Induced Apoptosis ◽  
Phosphatidylinositol 3

Interferon (IFN)α induces apoptosis via Bak and Bax and the mitochondrial pathway. Here, we investigated the role of known IFNα-induced signaling cascades upstream of Bak activation. By pharmacological and genetic inhibition of the kinases protein kinase C (PKC)δ, extracellular signal-regulated kinase (ERK), and c-Jun NH2-terminal kinase (JNK) in U266-1984 and RHEK-1 cells, we could demonstrate that all three enzymes are critical for the apoptosis-associated mitochondrial events and apoptotic cell death induced by IFNα, at a step downstream of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR). Furthermore, the activation of JNK was found to occur in a PKCδ/ERK-dependent manner. Inhibition of these kinases did not affect the canonical IFNα-stimulated Janus tyrosine kinase-signal transducer and activator of transcription signaling or expression of IFN-responsive genes. Therefore, enucleated cells (cytoplasts) were examined for IFNα-induced apoptosis, to test directly whether this process depends on gene transcription. Cytoplasts were found to undergo apoptosis after IFNα treatment, as analyzed by several apoptosis markers by using flow cytometry, live cell imaging, and biochemical analysis of flow-sorted cytoplasts. Furthermore, inhibition of mTOR, ERK, and JNK blocked IFNα-induced apoptosis in cytoplasts. In conclusion, IFNα-induced apoptosis requires activation of ERK1/2, PKCδ, and JNK downstream of PI3K and mTOR, and it can occur in a nucleus-independent manner, thus demonstrating for the first time that IFNα induces apoptosis in the absence of de novo transcription.

scholarly journals (R,S)-Ketamine Metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine Increase the Mammalian Target of Rapamycin Function

2014 ◽  
Vol 121 (1) ◽  
pp. 149-159 ◽  
Author(s):  
Rajib K. Paul ◽  
Nagendra S. Singh ◽  
Mohammed Khadeer ◽  
Ruin Moaddel ◽  
Mitesh Sanghvi ◽  
...  
Keyword(s):  
Parent Compound ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Target Of Rapamycin ◽  
Dependent Manner ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Concentration Dependent Manner ◽  
Pheochromocytoma Cells ◽  
The Impact

Abstract Background: Subanesthetic doses of (R,S)-ketamine are used in the treatment of neuropathic pain and depression. In the rat, the antidepressant effects of (R,S)-ketamine are associated with increased activity and function of mammalian target of rapamycin (mTOR); however, (R,S)-ketamine is extensively metabolized and the contribution of its metabolites to increased mTOR signaling is unknown. Methods: Rats (n = 3 per time point) were given (R,S)-ketamine, (R,S)-norketamine, and (2S,6S)-hydroxynorketamine and their effect on the mTOR pathway determined after 20, 30, and 60 min. PC-12 pheochromocytoma cells (n = 3 per experiment) were treated with escalating concentrations of each compound and the impact on the mTOR pathway was determined. Results: The phosphorylation of mTOR and its downstream targets was significantly increased in rat prefrontal cortex tissue by more than ~2.5-, ~25-, and ~2-fold, respectively, in response to a 60-min postadministration of (R,S)-ketamine, (R,S)-norketamine, and (2S,6S)-hydroxynorketamine (P < 0.05, ANOVA analysis). In PC-12 pheochromocytoma cells, the test compounds activated the mTOR pathway in a concentration-dependent manner, which resulted in a significantly higher expression of serine racemase with ~2-fold increases at 0.05 nM (2S,6S)-hydroxynorketamine, 10 nM (R,S)-norketamine, and 1,000 nM (R,S)-ketamine. The potency of the effect reflected antagonistic activity of the test compounds at the α7-nicotinic acetylcholine receptor. Conclusions: The data demonstrate that (R,S)-norketamine and (2S,6S)-hydroxynorketamine have potent pharmacological activity both in vitro and in vivo and contribute to the molecular effects produced by subanesthetic doses of (R,S)-ketamine. The results suggest that the determination of the mechanisms underlying the antidepressant and analgesic effects of (R,S)-ketamine requires a full study of the parent compound and its metabolites.

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