Krisztina Németh, Brachyahu M. Kestecher, Sayam Ghosal, Bernadett R. Bodnár, Ágnes Kittel, Szabolcs Hambalkó, Csenger Kovácsházi, Zoltán Giricz, Péter Ferdinandy, Xabier Osteikoetxea, Ralph Burkhardt, Edit I. Buzas, Evelyn Orsó
In recent years, various approaches have been undertaken to eliminate lipoproteins co-isolated with extracellular vesicles, as they were initially regarded as contaminating entities. However, novel discoveries are reshaping our perspective. In body fluids, these distinct particles not only co-exist, but also interactions between them are likely to occur. Extracellular vesicles and lipoproteins can associate with each other, share cargo, influence each other's functions, and jointly have a role in the pathomechanisms of diseases. Additionally, their association carries important implications for therapeutic and pharmacological aspects of lipid-lowering strategies. Extracellular vesicles and lipoprotein particles may have roles in the elimination of each other from the circulation. The objective of this minireview is to delve into these aspects. Here, we show that under certain physiological and pathological conditions, extracellular vesicles and lipoproteins are ‘partners’ rather than ‘strangers’ or ‘rivals’.
{"title":"Therapeutic and pharmacological applications of extracellular vesicles and lipoproteins","authors":"Krisztina Németh, Brachyahu M. Kestecher, Sayam Ghosal, Bernadett R. Bodnár, Ágnes Kittel, Szabolcs Hambalkó, Csenger Kovácsházi, Zoltán Giricz, Péter Ferdinandy, Xabier Osteikoetxea, Ralph Burkhardt, Edit I. Buzas, Evelyn Orsó","doi":"10.1111/bph.17336","DOIUrl":"10.1111/bph.17336","url":null,"abstract":"<p>In recent years, various approaches have been undertaken to eliminate lipoproteins co-isolated with extracellular vesicles, as they were initially regarded as contaminating entities. However, novel discoveries are reshaping our perspective. In body fluids, these distinct particles not only co-exist, but also interactions between them are likely to occur. Extracellular vesicles and lipoproteins can associate with each other, share cargo, influence each other's functions, and jointly have a role in the pathomechanisms of diseases. Additionally, their association carries important implications for therapeutic and pharmacological aspects of lipid-lowering strategies. Extracellular vesicles and lipoprotein particles may have roles in the elimination of each other from the circulation. The objective of this minireview is to delve into these aspects. Here, we show that under certain physiological and pathological conditions, extracellular vesicles and lipoproteins are ‘partners’ rather than ‘strangers’ or ‘rivals’.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 23","pages":"4733-4749"},"PeriodicalIF":6.8,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17336","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pál Tod, Anita Varga, Viktor Román, Balázs Lendvai, Roland Pálkovács, Beáta Sperlágh, E. Sylvester Vizi
Background and Purpose
Tetrabenazine (TBZ), used for treating hyperkinetic disorders, inhibits vesicular monoamine transporter-2 (VMAT-2), which sequesters monoamines into vesicles for exocytosis. However, our knowledge of the effect of TBZ on monoaminergic transmission is limited. Herein, we provide neurochemical evidence regarding the effect of VMAT-2 inhibition on vesicular neurotransmitter release from the prefrontal cortex (PFC) and striatum (STR) (brain regions involved in characteristic TBZ treatment side effects). The interaction between TBZ and MDMA was also assessed regarding motor behaviour in mice.
Experimental Approach
Vesicular storage capacity and release of [3H]-noradrenaline ([3H]-NA), [3H]-dopamine ([3H]-DA), [3H]-serotonin ([3H]-5-HT), and [3H]-acetylcholine ([3H]-ACh) was studied in mouse PFC and STR ex vivo slice preparations using electrical field stimulation. Additionally, locomotor activity was assessed in vehicle-treated mice and compared with that of MDMA, TBZ, and co-administered animals (n = 6) using the LABORAS system.
Key Results
TBZ lowered the storage capacity and inhibited the vesicular release of [3H]-NA and [3H]-DA from the PFC, and [3H]-DA and [3H]-5-HT from the STR in a concentration-dependent manner. Unlike vesamicol (vesicular ACh uptake inhibitor), TBZ failed to inhibit the vesicular release of [3H]-ACh from the PFC. When the vesicular storage of the investigated monoamines was inhibited by TBZ in the PFC and STR, MDMA induced the release of transmitters through transporter reversal; MDMA dose dependently increased locomotor activity in vivo.
Conclusion and Implications
Our observations provide neurochemical evidence explaining the mechanism of VMAT-2 inhibitors in the brain and support the involvement of dopaminergic and noradrenergic transmission in hyperkinetic movement disorders.
{"title":"Tetrabenazine, a vesicular monoamine transporter 2 inhibitor, inhibits vesicular storage capacity and release of monoamine transmitters in mouse brain tissue","authors":"Pál Tod, Anita Varga, Viktor Román, Balázs Lendvai, Roland Pálkovács, Beáta Sperlágh, E. Sylvester Vizi","doi":"10.1111/bph.17348","DOIUrl":"10.1111/bph.17348","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Tetrabenazine (TBZ), used for treating hyperkinetic disorders, inhibits vesicular monoamine transporter-2 (VMAT-2), which sequesters monoamines into vesicles for exocytosis. However, our knowledge of the effect of TBZ on monoaminergic transmission is limited. Herein, we provide neurochemical evidence regarding the effect of VMAT-2 inhibition on vesicular neurotransmitter release from the prefrontal cortex (PFC) and striatum (STR) (brain regions involved in characteristic TBZ treatment side effects). The interaction between TBZ and MDMA was also assessed regarding motor behaviour in mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Vesicular storage capacity and release of [<sup>3</sup>H]-noradrenaline ([<sup>3</sup>H]-NA), [<sup>3</sup>H]-dopamine ([<sup>3</sup>H]-DA), [<sup>3</sup>H]-serotonin ([<sup>3</sup>H]-5-HT), and [<sup>3</sup>H]-acetylcholine ([<sup>3</sup>H]-ACh) was studied in mouse PFC and STR ex vivo slice preparations using electrical field stimulation. Additionally, locomotor activity was assessed in vehicle-treated mice and compared with that of MDMA, TBZ, and co-administered animals (n = 6) using the LABORAS system.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>TBZ lowered the storage capacity and inhibited the vesicular release of [<sup>3</sup>H]-NA and [<sup>3</sup>H]-DA from the PFC, and [<sup>3</sup>H]-DA and [<sup>3</sup>H]-5-HT from the STR in a concentration-dependent manner. Unlike vesamicol (vesicular ACh uptake inhibitor), TBZ failed to inhibit the vesicular release of [<sup>3</sup>H]-ACh from the PFC. When the vesicular storage of the investigated monoamines was inhibited by TBZ in the PFC and STR, MDMA induced the release of transmitters through transporter reversal; MDMA dose dependently increased locomotor activity in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Our observations provide neurochemical evidence explaining the mechanism of VMAT-2 inhibitors in the brain and support the involvement of dopaminergic and noradrenergic transmission in hyperkinetic movement disorders.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 24","pages":"5094-5109"},"PeriodicalIF":6.8,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17348","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Flavia T. T. Antunes, Maria A. Gandini, Vinicius M. Gadotti, Nara Lins Meira Quintão, José Roberto Santin, Ivana A. Souza, Laurence S. David, Terrance P. Snutch, Michael Hildebrand, Gerald W. Zamponi
The chemotherapy agent oxaliplatin can give rise to oxaliplatin-induced peripheral neuropathy (OIPN). Here, we investigated whether T-type calcium channels (Cav3) contribute to OIPN.
化疗药物奥沙利铂可引起奥沙利铂诱导的周围神经病变（OIPN）。在此，我们研究了 T 型钙通道（Cav3）是否对 OIPN 起作用。
{"title":"Contribution of T-type calcium channel isoforms to cold and mechanical sensitivity in naïve and oxaliplatin-treated mice of both sexes","authors":"Flavia T. T. Antunes, Maria A. Gandini, Vinicius M. Gadotti, Nara Lins Meira Quintão, José Roberto Santin, Ivana A. Souza, Laurence S. David, Terrance P. Snutch, Michael Hildebrand, Gerald W. Zamponi","doi":"10.1111/bph.17337","DOIUrl":"https://doi.org/10.1111/bph.17337","url":null,"abstract":"The chemotherapy agent oxaliplatin can give rise to oxaliplatin-induced peripheral neuropathy (OIPN). Here, we investigated whether T-type calcium channels (Ca<sub>v</sub>3) contribute to OIPN.","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"25 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maja Tomić, Katarina Nastić, Miroslav Dinić, Emilija Brdarić, Jelena Kotur-Stevuljević, Uroš Pecikoza, David Pavićević, Ana Micov, Danijela Milenković, Aleksandar Jovanović, Radica Stepanović-Petrović
Vortioxetine, a multimodal-acting antidepressant, has recently shown analgesic properties. We aimed to investigate its prophylactic effect in the osteoarthritis (OA) model and gain insights into the underlying molecular mechanisms. Duloxetine was studied as a reference.
{"title":"Vortioxetine reduces the development of pain-related behaviour in a knee osteoarthritis model in rats: Involvement of nerve growth factor (NGF) down-regulation","authors":"Maja Tomić, Katarina Nastić, Miroslav Dinić, Emilija Brdarić, Jelena Kotur-Stevuljević, Uroš Pecikoza, David Pavićević, Ana Micov, Danijela Milenković, Aleksandar Jovanović, Radica Stepanović-Petrović","doi":"10.1111/bph.17342","DOIUrl":"https://doi.org/10.1111/bph.17342","url":null,"abstract":"Vortioxetine, a multimodal-acting antidepressant, has recently shown analgesic properties. We aimed to investigate its prophylactic effect in the osteoarthritis (OA) model and gain insights into the underlying molecular mechanisms. Duloxetine was studied as a reference.","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"24 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anwesha Ghosh, Leonor Ribeiro-Rodrigues, Gabriele Ruffolo, Veronica Alfano, Cátia Domingos, Nádia Rei, Dilip K. Tosh, Diogo M. Rombo, Tatiana P. Morais, Cláudia A. Valente, Sara Xapelli, Beatriz Bordadágua, Alexandre Rainha-Campos, Carla Bentes, Eleonora Aronica, Maria José Diógenes, Sandra H. Vaz, Joaquim A. Ribeiro, Eleonora Palma, Kenneth A. Jacobson, Ana M. Sebastião
Background and Purpose
Adenosine, through the A1 receptor (A1R), is an endogenous anticonvulsant. The development of adenosine receptor agonists as antiseizure medications has been hampered by their cardiac side effects. A moderately A1R-selective agonist, MRS5474, has been reported to suppress seizures without considerable cardiac action. Hypothesizing that this drug could act through other than A1R and/or through a disease-specific mechanism, we assessed the effect of MRS5474 on the hippocampus.
Experimental Approach
Excitatory synaptic currents, field potentials, spontaneous activity, [3H]GABA uptake and GABAergic currents were recorded from rodent or human hippocampal tissue. Alterations in adenosine A3 receptor (A3R) density in human tissue were assessed by Western blot.
Key Results
MRS5474 (50–500 nM) was devoid of effect upon rodent excitatory synaptic signals in hippocampal slices, except when hyperexcitability was previously induced in vivo or ex vivo. MRS5474 inhibited GABA transporter type 1 (GAT-1)-mediated γ-aminobutyric acid (GABA) uptake, an action not blocked by an A1R antagonist but blocked by an A3R antagonist and mimicked by an A3R agonist. A3R was overexpressed in human hippocampal tissue samples from patients with epilepsy that had focal resection from surgery. MRS5474 induced a concentration-dependent potentiation of GABA-evoked currents in oocytes micro-transplanted with human hippocampal membranes prepared from epileptic hippocampal tissue but not from non-epileptic tissue, an action blocked by an A3R antagonist.
Conclusion and Implications
We identified a drug that activates A3R and has selective actions on epileptic hippocampal tissue. This underscores A3R as a promising target for the development of antiseizure medications.
{"title":"Selective modulation of epileptic tissue by an adenosine A3 receptor-activating drug","authors":"Anwesha Ghosh, Leonor Ribeiro-Rodrigues, Gabriele Ruffolo, Veronica Alfano, Cátia Domingos, Nádia Rei, Dilip K. Tosh, Diogo M. Rombo, Tatiana P. Morais, Cláudia A. Valente, Sara Xapelli, Beatriz Bordadágua, Alexandre Rainha-Campos, Carla Bentes, Eleonora Aronica, Maria José Diógenes, Sandra H. Vaz, Joaquim A. Ribeiro, Eleonora Palma, Kenneth A. Jacobson, Ana M. Sebastião","doi":"10.1111/bph.17319","DOIUrl":"10.1111/bph.17319","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Adenosine, through the A<sub>1</sub> receptor (A<sub>1</sub>R), is an endogenous anticonvulsant. The development of adenosine receptor agonists as antiseizure medications has been hampered by their cardiac side effects. A moderately A<sub>1</sub>R-selective agonist, MRS5474, has been reported to suppress seizures without considerable cardiac action. Hypothesizing that this drug could act through other than A<sub>1</sub>R and/or through a disease-specific mechanism, we assessed the effect of MRS5474 on the hippocampus.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Excitatory synaptic currents, field potentials, spontaneous activity, [<sup>3</sup>H]GABA uptake and GABAergic currents were recorded from rodent or human hippocampal tissue. Alterations in adenosine A<sub>3</sub> receptor (A<sub>3</sub>R) density in human tissue were assessed by Western blot.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>MRS5474 (50–500 nM) was devoid of effect upon rodent excitatory synaptic signals in hippocampal slices, except when hyperexcitability was previously induced in vivo or ex vivo. MRS5474 inhibited GABA transporter type 1 (GAT-1)-mediated γ-aminobutyric acid (GABA) uptake, an action not blocked by an A<sub>1</sub>R antagonist but blocked by an A<sub>3</sub>R antagonist and mimicked by an A<sub>3</sub>R agonist. A<sub>3</sub>R was overexpressed in human hippocampal tissue samples from patients with epilepsy that had focal resection from surgery. MRS5474 induced a concentration-dependent potentiation of GABA-evoked currents in oocytes micro-transplanted with human hippocampal membranes prepared from epileptic hippocampal tissue but not from non-epileptic tissue, an action blocked by an A<sub>3</sub>R antagonist.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>We identified a drug that activates A<sub>3</sub>R and has selective actions on epileptic hippocampal tissue. This underscores A<sub>3</sub>R as a promising target for the development of antiseizure medications.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 24","pages":"5041-5061"},"PeriodicalIF":6.8,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17319","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yue Wu, Bernd Meibohm, Taichang Zhang, Xinfeng Hou, Haitao Wang, Xiaona Sun, Ming Jiang, Bo Zhang, Wenjing Zhang, Ye Liu, Wei Jin, Fan Wang
Background and PurposeBifunctional small molecule degraders, which link the target protein with E3 ubiquitin ligase, could lead to the efficient degradation of the target protein. BGB‐16673 is a Bruton's tyrosine kinase (BTK) degrader. A translational PK/PD modelling approach was used to predict the human BTK degradation of BGB‐16673 from preclinical in vitro and in vivo data.Experimental ApproachA simplified mechanistic PK/PD model was used to establish the correlation between the in vitro and in vivo BTK degradation by BGB‐16673 in a mouse model. Human and mouse species differences were compared using the parameters generated from in vitro human or mouse blood, and human or mouse serum spiked TMD‐8 cells. Human PD was then predicted using the simplified mechanistic PK/PD model.Key ResultsBGB‐16673 showed potent BTK degradation in mouse whole blood, human whole blood, and TMD‐8 tumour cells in vitro. Furthermore, BGB‐16673 showed BTK degradation in a murine TMD‐8 xenograft model in vivo. The PK/PD model predicted human PD and the observed BTK degradation in clinical studies both showed robust BTK degradation in blood and tumour at clinical dose range.Conclusion and ImplicationsThe presented simplified mechanistic model with reduced number of model parameters is practically easier to be applied to research projects compared with the full mechanistic model. It can be used as a tool to better understand the PK/PD behaviour for targeted protein degraders and increase the confidence when moving to the clinical stage.
{"title":"Translational modelling to predict human pharmacokinetics and pharmacodynamics of a Bruton's tyrosine kinase‐targeted protein degrader BGB‐16673","authors":"Yue Wu, Bernd Meibohm, Taichang Zhang, Xinfeng Hou, Haitao Wang, Xiaona Sun, Ming Jiang, Bo Zhang, Wenjing Zhang, Ye Liu, Wei Jin, Fan Wang","doi":"10.1111/bph.17332","DOIUrl":"https://doi.org/10.1111/bph.17332","url":null,"abstract":"Background and PurposeBifunctional small molecule degraders, which link the target protein with E3 ubiquitin ligase, could lead to the efficient degradation of the target protein. BGB‐16673 is a Bruton's tyrosine kinase (BTK) degrader. A translational PK/PD modelling approach was used to predict the human BTK degradation of BGB‐16673 from preclinical in vitro and in vivo data.Experimental ApproachA simplified mechanistic PK/PD model was used to establish the correlation between the in vitro and in vivo BTK degradation by BGB‐16673 in a mouse model. Human and mouse species differences were compared using the parameters generated from in vitro human or mouse blood, and human or mouse serum spiked TMD‐8 cells. Human PD was then predicted using the simplified mechanistic PK/PD model.Key ResultsBGB‐16673 showed potent BTK degradation in mouse whole blood, human whole blood, and TMD‐8 tumour cells in vitro. Furthermore, BGB‐16673 showed BTK degradation in a murine TMD‐8 xenograft model in vivo. The PK/PD model predicted human PD and the observed BTK degradation in clinical studies both showed robust BTK degradation in blood and tumour at clinical dose range.Conclusion and ImplicationsThe presented simplified mechanistic model with reduced number of model parameters is practically easier to be applied to research projects compared with the full mechanistic model. It can be used as a tool to better understand the PK/PD behaviour for targeted protein degraders and increase the confidence when moving to the clinical stage.","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"189 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aimi Yamagishi, Naomi Yonemochi, Ai Kimura, Fumiko Takenoya, Seiji Shioda, John L. Waddington, Hiroko Ikeda
Background and Purpose
Diabetic patients have an increased risk of psychiatric disorders. Because hyperglycaemia increases L-lactate in the brain and L-lactate inhibits AMP-activated protein kinase (AMPK), this study investigated the role of L-lactate and AMPK in strengthened fear memory, a model for human psychiatric disorders, in diabetic mice.
Experimental Approach
The diabetic model was mice injected with streptozotocin. Fear memory was measured using the conditioned fear test with low (0.45 mA) or high (0.50 mA) foot shock to cause low and high freezing, respectively. Protein levels of AMPK and phosphorylated AMPK (pAMPK) were measured by western blotting and immunohistochemistry.
Key Results
At 0.45 mA, the AMPK inhibitor dorsomorphin increased freezing, which was inhibited by the AMPK activator acadesine. In contrast, at 0.50 mA, acadesine decreased freezing, which was inhibited by dorsomorphin. In diabetic mice, pAMPK was decreased in the amygdala and hippocampus. Diabetic mice showed increased freezing at 0.45 mA, which was inhibited by acadesine. In the amygdala and hippocampus, L-lactate was increased in diabetic mice and injection of L-lactate into non-diabetic mice increased freezing at 0.45 mA. In addition, L-lactate decreased pAMPK in the hippocampus, but not the amygdala, and increase in freezing induced by L-lactate was inhibited by acadesine. Dorsomorphin-induced increase in freezing was inhibited by the AMPA receptor antagonist NBQX.
Conclusions and Interpretation
In diabetic mice, L-lactate is increased in the amygdala and hippocampus, possibly through hyperglycaemia, which strengthens fear memory through inhibition of AMPK and activation of glutamatergic function.
{"title":"AMP-activated protein kinase in the amygdala and hippocampus contributes to enhanced fear memory in diabetic mice","authors":"Aimi Yamagishi, Naomi Yonemochi, Ai Kimura, Fumiko Takenoya, Seiji Shioda, John L. Waddington, Hiroko Ikeda","doi":"10.1111/bph.17338","DOIUrl":"10.1111/bph.17338","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Diabetic patients have an increased risk of psychiatric disorders. Because hyperglycaemia increases L-lactate in the brain and L-lactate inhibits AMP-activated protein kinase (AMPK), this study investigated the role of L-lactate and AMPK in strengthened fear memory, a model for human psychiatric disorders, in diabetic mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>The diabetic model was mice injected with streptozotocin. Fear memory was measured using the conditioned fear test with low (0.45 mA) or high (0.50 mA) foot shock to cause low and high freezing, respectively. Protein levels of AMPK and phosphorylated AMPK (pAMPK) were measured by western blotting and immunohistochemistry.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>At 0.45 mA, the AMPK inhibitor dorsomorphin increased freezing, which was inhibited by the AMPK activator acadesine. In contrast, at 0.50 mA, acadesine decreased freezing, which was inhibited by dorsomorphin. In diabetic mice, pAMPK was decreased in the amygdala and hippocampus. Diabetic mice showed increased freezing at 0.45 mA, which was inhibited by acadesine. In the amygdala and hippocampus, L-lactate was increased in diabetic mice and injection of L-lactate into non-diabetic mice increased freezing at 0.45 mA. In addition, L-lactate decreased pAMPK in the hippocampus, but not the amygdala, and increase in freezing induced by L-lactate was inhibited by acadesine. Dorsomorphin-induced increase in freezing was inhibited by the AMPA receptor antagonist NBQX.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Interpretation</h3>\u0000 \u0000 <p>In diabetic mice, L-lactate is increased in the amygdala and hippocampus, possibly through hyperglycaemia, which strengthens fear memory through inhibition of AMPK and activation of glutamatergic function.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"181 24","pages":"5028-5040"},"PeriodicalIF":6.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Qin Zhang, Hang Ruan, Xiaochuan Wang, Ailin Luo, Xiao Ran
Ulinastatin has beneficial effects in patients undergoing coronary artery bypass grafting (CABG) surgery due to its anti-inflammatory properties, but the underlying mechanism remains unclear.
{"title":"Ulinastatin attenuated cardiac ischaemia/reperfusion injury by suppressing activation of the tissue kallikrein-kinin system","authors":"Qin Zhang, Hang Ruan, Xiaochuan Wang, Ailin Luo, Xiao Ran","doi":"10.1111/bph.16477","DOIUrl":"https://doi.org/10.1111/bph.16477","url":null,"abstract":"Ulinastatin has beneficial effects in patients undergoing coronary artery bypass grafting (CABG) surgery due to its anti-inflammatory properties, but the underlying mechanism remains unclear.","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"33 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zoltán Bereczki, Bettina Benczik, Olivér M. Balogh, Szandra Marton, Eszter Puhl, Mátyás Pétervári, Máté Váczy-Földi, Zsolt Tamás Papp, András Makkos, Kimberly Glass, Fabian Locquet, Gerhild Euler, Rainer Schulz, Péter Ferdinandy, Bence Ágg
Three types of highly promising small RNA therapeutics, namely, small interfering RNAs (siRNAs), microRNAs (miRNAs) and the RNA subtype of antisense oligonucleotides (ASOs), offer advantages over small-molecule drugs. These small RNAs can target any gene product, opening up new avenues of effective and safe therapeutic approaches for a wide range of diseases. In preclinical research, synthetic small RNAs play an essential role in the investigation of physiological and pathological pathways as silencers of specific genes, facilitating discovery and validation of drug targets in different conditions. Off-target effects of small RNAs, however, could make it difficult to interpret experimental results in the preclinical phase and may contribute to adverse events of small RNA therapeutics. Out of the two major types of off-target effects we focused on the hybridization-dependent, especially on the miRNA-like off-target effects. Our main aim was to discuss several approaches, including sequence design, chemical modifications and target prediction, to reduce hybridization-dependent off-target effects that should be considered even at the early development phase of small RNA therapy. Because there is no standard way of predicting hybridization-dependent off-target effects, this review provides an overview of all major state-of-the-art computational methods and proposes new approaches, such as the possible inclusion of network theory and artificial intelligence (AI) in the prediction workflows. Case studies and a concise survey of experimental methods for validating in silico predictions are also presented. These methods could contribute to interpret experimental results, to minimize off-target effects and hopefully to avoid off-target-related adverse events of small RNA therapeutics.
{"title":"Mitigating off-target effects of small RNAs: conventional approaches, network theory and artificial intelligence","authors":"Zoltán Bereczki, Bettina Benczik, Olivér M. Balogh, Szandra Marton, Eszter Puhl, Mátyás Pétervári, Máté Váczy-Földi, Zsolt Tamás Papp, András Makkos, Kimberly Glass, Fabian Locquet, Gerhild Euler, Rainer Schulz, Péter Ferdinandy, Bence Ágg","doi":"10.1111/bph.17302","DOIUrl":"https://doi.org/10.1111/bph.17302","url":null,"abstract":"Three types of highly promising small RNA therapeutics, namely, small interfering RNAs (siRNAs), microRNAs (miRNAs) and the RNA subtype of antisense oligonucleotides (ASOs), offer advantages over small-molecule drugs. These small RNAs can target any gene product, opening up new avenues of effective and safe therapeutic approaches for a wide range of diseases. In preclinical research, synthetic small RNAs play an essential role in the investigation of physiological and pathological pathways as silencers of specific genes, facilitating discovery and validation of drug targets in different conditions. Off-target effects of small RNAs, however, could make it difficult to interpret experimental results in the preclinical phase and may contribute to adverse events of small RNA therapeutics. Out of the two major types of off-target effects we focused on the hybridization-dependent, especially on the miRNA-like off-target effects. Our main aim was to discuss several approaches, including sequence design, chemical modifications and target prediction, to reduce hybridization-dependent off-target effects that should be considered even at the early development phase of small RNA therapy. Because there is no standard way of predicting hybridization-dependent off-target effects, this review provides an overview of all major state-of-the-art computational methods and proposes new approaches, such as the possible inclusion of network theory and artificial intelligence (AI) in the prediction workflows. Case studies and a concise survey of experimental methods for validating <i>in silico</i> predictions are also presented. These methods could contribute to interpret experimental results, to minimize off-target effects and hopefully to avoid off-target-related adverse events of small RNA therapeutics.","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"32 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Denise Pajonczyk, Merle F. Sternschulte, Oliver Soehnlein, Marcel Bermudez, Carsten A. Raabe, Ursula Rescher
The pattern recognition receptors, formyl peptide receptors, FPR1 and FPR2, are G protein-coupled receptors that recognize many different pathogen- and host-derived ligands. While FPR1 conveys pro-inflammatory signals, FPR2 is linked with pro-resolving outcomes. To analyse how the two very similar FPRs exert opposite effects in modulating inflammatory responses despite their high homology, a shared expression profile on immune cells and an overlapping ligand repertoire, we questioned whether the signalling profile differs between these two receptors.
{"title":"Comparative analysis of formyl peptide receptor 1 and formyl peptide receptor 2 reveals shared and preserved signalling profiles","authors":"Denise Pajonczyk, Merle F. Sternschulte, Oliver Soehnlein, Marcel Bermudez, Carsten A. Raabe, Ursula Rescher","doi":"10.1111/bph.17334","DOIUrl":"https://doi.org/10.1111/bph.17334","url":null,"abstract":"The pattern recognition receptors, formyl peptide receptors, FPR1 and FPR2, are G protein-coupled receptors that recognize many different pathogen- and host-derived ligands. While FPR1 conveys pro-inflammatory signals, FPR2 is linked with pro-resolving outcomes. To analyse how the two very similar FPRs exert opposite effects in modulating inflammatory responses despite their high homology, a shared expression profile on immune cells and an overlapping ligand repertoire, we questioned whether the signalling profile differs between these two receptors.","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"101 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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