Pub Date : 2024-08-21Epub Date: 2024-07-31DOI: 10.1021/acschemneuro.4c00301
Kasun Gamage, Binyou Wang, Eldon R Hard, Thong Van, Ana Galesic, George R Phillips, Matthew Pratt, Lisa J Lapidus
The intrinsically disordered protein α-Synuclein is identified as a major toxic aggregate in Parkinson's as well as several other neurodegenerative diseases. Recent work on this protein has focused on the effects of posttranslational modifications on aggregation kinetics. Among them, O-GlcNAcylation of α-Synuclein has been observed to inhibit the aggregation propensity of the protein. Here, we investigate the monomer dynamics of two O-GlcNAcylated α-Synucleins, α-Syn(gT72), and α-Syn(gS87) and correlate them with the aggregation kinetics. We find that, compared to the unmodified protein, glycosylation at T72 makes the protein less compact and more diffusive, while glycosylation at S87 makes the protein more compact and less diffusive. Based on a model of the earliest steps in aggregation, we predict that T72 should aggregate slower than unmodified protein, which is confirmed by ThT fluorescence measurements. In contrast, S87 should aggregate faster, which is not mirrored in ThT kinetics of later fibril formation but does not rule out a higher rate of formation of small oligomers. Together, these results show that posttranslational modifications do not uniformly affect aggregation propensity.
{"title":"O-GlcNAc Modification of α-Synuclein Can Alter Monomer Dynamics to Control Aggregation Kinetics.","authors":"Kasun Gamage, Binyou Wang, Eldon R Hard, Thong Van, Ana Galesic, George R Phillips, Matthew Pratt, Lisa J Lapidus","doi":"10.1021/acschemneuro.4c00301","DOIUrl":"10.1021/acschemneuro.4c00301","url":null,"abstract":"<p><p>The intrinsically disordered protein α-Synuclein is identified as a major toxic aggregate in Parkinson's as well as several other neurodegenerative diseases. Recent work on this protein has focused on the effects of posttranslational modifications on aggregation kinetics. Among them, O-GlcNAcylation of α-Synuclein has been observed to inhibit the aggregation propensity of the protein. Here, we investigate the monomer dynamics of two O-GlcNAcylated α-Synucleins, α-Syn(gT72), and α-Syn(gS87) and correlate them with the aggregation kinetics. We find that, compared to the unmodified protein, glycosylation at T72 makes the protein less compact and more diffusive, while glycosylation at S87 makes the protein more compact and less diffusive. Based on a model of the earliest steps in aggregation, we predict that T72 should aggregate slower than unmodified protein, which is confirmed by ThT fluorescence measurements. In contrast, S87 should aggregate faster, which is not mirrored in ThT kinetics of later fibril formation but does not rule out a higher rate of formation of small oligomers. Together, these results show that posttranslational modifications do not uniformly affect aggregation propensity.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11342298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141854059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-21DOI: 10.1021/acschemneuro.4c0043810.1021/acschemneuro.4c00438
Marcin Jakubiec, Michał Abram, Mirosław Zagaja, Katarzyna Socała, Vanja Panic, Gniewomir Latacz, Szczepan Mogilski, Małgorzata Szafarz, Joanna Szala-Rycaj, Jerry Saunders, Peter J. West, Dorota Nieoczym, Katarzyna Przejczowska-Pomierny, Bartłomiej Szulczyk, Anna Krupa, Elżbieta Wyska, Piotr Wlaź, Cameron S. Metcalf, Karen Wilcox, Marta Andres-Mach, Rafał M. Kamiński and Krzysztof Kamiński*,
We developed a focused series of original phenyl-glycinamide derivatives which showed potent activity across in vivo mouse seizure models, namely, maximal electroshock (MES) and 6 Hz (using both 32 and 44 mA current intensities) seizure models. Following intraperitoneal (i.p.) administration, compound (R)-32, which was identified as a lead molecule, demonstrated potent protection against all seizure models with ED50 values of 73.9 mg/kg (MES test), 18.8 mg/kg (6 Hz, 32 mA test), and 26.5 mg/kg (6 Hz, 44 mA test). Furthermore, (R)-32 demonstrated efficacy in both the PTZ-induced kindling paradigm and the ivPTZ seizure threshold test. The expression of neurotrophic factors, such as mature brain-derived neurotrophic factor (mBDNF) and nerve growth factor (NGF), in the hippocampus and/or cortex of mice, and the levels of glutamate and GABA were normalized after PTZ-induced kindling by (R)-32. Importantly, besides antiseizure activity, (R)-32 demonstrated potent antinociceptive efficacy in formalin-induced pain, capsaicin-induced pain, as well as oxaliplatin- and streptozotocin-induced peripheral neuropathy in mice (i.p.). No influence on muscular strength and body temperature in mice was observed. Pharmacokinetic studies and in vitro ADME-Tox data (i.e., high metabolic stability in human liver microsomes, a weak influence on CYPs, no hepatotoxicity, satisfactory passive transport, etc.) proved favorable drug-like properties of (R)-32. Thermal stability of (R)-32 shown in thermogravimetry and differential scanning calorimetry gives the opportunity to develop innovative oral solid dosage forms loaded with this compound. The in vitro binding and functional assays indicated its multimodal mechanism of action. (R)-32, beyond TRPV1 antagonism, inhibited calcium and sodium currents at a concentration of 10 μM. Therefore, the data obtained in the current studies justify a more detailed preclinical development of (R)-32 for epilepsy and pain indications.
{"title":"Discovery and Profiling of New Multimodal Phenylglycinamide Derivatives as Potent Antiseizure and Antinociceptive Drug Candidates","authors":"Marcin Jakubiec, Michał Abram, Mirosław Zagaja, Katarzyna Socała, Vanja Panic, Gniewomir Latacz, Szczepan Mogilski, Małgorzata Szafarz, Joanna Szala-Rycaj, Jerry Saunders, Peter J. West, Dorota Nieoczym, Katarzyna Przejczowska-Pomierny, Bartłomiej Szulczyk, Anna Krupa, Elżbieta Wyska, Piotr Wlaź, Cameron S. Metcalf, Karen Wilcox, Marta Andres-Mach, Rafał M. Kamiński and Krzysztof Kamiński*, ","doi":"10.1021/acschemneuro.4c0043810.1021/acschemneuro.4c00438","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00438https://doi.org/10.1021/acschemneuro.4c00438","url":null,"abstract":"<p >We developed a focused series of original phenyl-glycinamide derivatives which showed potent activity across <i>in vivo</i> mouse seizure models, namely, maximal electroshock (MES) and 6 Hz (using both 32 and 44 mA current intensities) seizure models. Following intraperitoneal (<i>i.p</i>.) administration, compound <b>(</b><b><i>R</i></b><b>)-32</b>, which was identified as a lead molecule, demonstrated potent protection against all seizure models with ED<sub>50</sub> values of 73.9 mg/kg (MES test), 18.8 mg/kg (6 Hz, 32 mA test), and 26.5 mg/kg (6 Hz, 44 mA test). Furthermore, <b>(</b><b><i>R</i></b><b>)-32</b> demonstrated efficacy in both the PTZ-induced kindling paradigm and the <i>iv</i>PTZ seizure threshold test. The expression of neurotrophic factors, such as mature brain-derived neurotrophic factor (mBDNF) and nerve growth factor (NGF), in the hippocampus and/or cortex of mice, and the levels of glutamate and GABA were normalized after PTZ-induced kindling by <b>(<i>R</i>)-32</b>. Importantly, besides antiseizure activity, (<b><i>R</i></b>)<b>-32</b> demonstrated potent antinociceptive efficacy in formalin-induced pain, capsaicin-induced pain, as well as oxaliplatin- and streptozotocin-induced peripheral neuropathy in mice (<i>i.p</i>.). No influence on muscular strength and body temperature in mice was observed. Pharmacokinetic studies and <i>in vitro</i> ADME-Tox data (<i>i.e.</i>, high metabolic stability in human liver microsomes, a weak influence on CYPs, no hepatotoxicity, satisfactory passive transport, <i>etc.</i>) proved favorable drug-like properties of (<b><i>R</i></b>)<b>-32</b>. Thermal stability of (<b><i>R</i></b>)-<b>32</b> shown in thermogravimetry and differential scanning calorimetry gives the opportunity to develop innovative oral solid dosage forms loaded with this compound. The <i>in vitro</i> binding and functional assays indicated its multimodal mechanism of action. (<b><i>R</i></b>)<b>-32</b>, beyond TRPV1 antagonism, inhibited calcium and sodium currents at a concentration of 10 μM. Therefore, the data obtained in the current studies justify a more detailed preclinical development of (<b><i>R</i></b>)<b>-32</b> for epilepsy and pain indications.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.4c00438","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142135323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-21Epub Date: 2024-07-31DOI: 10.1021/acschemneuro.4c00349
Mahan Farzan, Behnaz Abedi, Iman Bhia, Atossa Madanipour, Mahour Farzan, Mohammad Bhia, Ava Aghaei, Iman Kheirollahi, Mahzad Motallebi, Hossein Amini-Khoei, Yavuz Nuri Ertas
Sinapic acid (SA) is a phenylpropanoid derivative found in various natural sources that exhibits remarkable versatile properties, including antioxidant, anti-inflammatory, and metal-chelating capabilities, establishing itself as a promising candidate for the prevention and treatment of conditions affecting the central nervous system, such as Alzheimer's disease (AD), Parkinson's disease (PD), ischemic stroke, and other neurological disorders. These effects also include neuroprotection in epilepsy models, as evidenced by a reduction in seizure-like behavior, cell death in specific hippocampal regions, and lowered neuroinflammatory markers. In AD, SA treatment enhances memory, reverses cognitive deficits, and attenuates astrocyte activation. SA also has positive effects on cognition by improving memory and lowering oxidative stress. This is shown by lower levels of oxidative stress markers, higher levels of antioxidant enzyme activity, and better memory retention. Additionally, in ischemic stroke and PD models, SA provides microglial protection and exerts anti-inflammatory effects. This review emphasizes SA's multifaceted neuroprotective properties and its potential role in the prevention and treatment of various brain disorders. Despite the need for further research to fully understand its mechanisms of action and clinical applicability, SA stands out as a valuable bioactive compound in the ongoing quest to combat neurodegenerative diseases and enhance the quality of life for affected individuals.
西那平酸(SA)是一种存在于各种天然资源中的苯丙类衍生物,具有显著的多功能特性,包括抗氧化、抗炎和金属螯合能力,是预防和治疗影响中枢神经系统疾病(如阿尔茨海默病(AD)、帕金森病(PD)、缺血性中风和其他神经系统疾病)的理想候选物质。这些作用还包括在癫痫模型中的神经保护作用,具体表现为减少癫痫发作样行为、特定海马区的细胞死亡以及降低神经炎症标志物。在注意力缺失症中,SA 治疗可增强记忆、逆转认知障碍并减轻星形胶质细胞的激活。通过改善记忆和降低氧化应激,SA 还能对认知产生积极影响。具体表现为氧化应激标志物水平降低、抗氧化酶活性提高以及记忆保持能力增强。此外,在缺血性中风和帕金森病模型中,SA 还能提供微神经胶质细胞保护并发挥抗炎作用。本综述强调了 SA 的多方面神经保护特性及其在预防和治疗各种脑部疾病中的潜在作用。尽管还需要进一步的研究来充分了解其作用机制和临床适用性,但在对抗神经退行性疾病和提高患者生活质量的不断探索中,SA 已成为一种有价值的生物活性化合物。
{"title":"Pharmacological Activities and Molecular Mechanisms of Sinapic Acid in Neurological Disorders.","authors":"Mahan Farzan, Behnaz Abedi, Iman Bhia, Atossa Madanipour, Mahour Farzan, Mohammad Bhia, Ava Aghaei, Iman Kheirollahi, Mahzad Motallebi, Hossein Amini-Khoei, Yavuz Nuri Ertas","doi":"10.1021/acschemneuro.4c00349","DOIUrl":"10.1021/acschemneuro.4c00349","url":null,"abstract":"<p><p>Sinapic acid (SA) is a phenylpropanoid derivative found in various natural sources that exhibits remarkable versatile properties, including antioxidant, anti-inflammatory, and metal-chelating capabilities, establishing itself as a promising candidate for the prevention and treatment of conditions affecting the central nervous system, such as Alzheimer's disease (AD), Parkinson's disease (PD), ischemic stroke, and other neurological disorders. These effects also include neuroprotection in epilepsy models, as evidenced by a reduction in seizure-like behavior, cell death in specific hippocampal regions, and lowered neuroinflammatory markers. In AD, SA treatment enhances memory, reverses cognitive deficits, and attenuates astrocyte activation. SA also has positive effects on cognition by improving memory and lowering oxidative stress. This is shown by lower levels of oxidative stress markers, higher levels of antioxidant enzyme activity, and better memory retention. Additionally, in ischemic stroke and PD models, SA provides microglial protection and exerts anti-inflammatory effects. This review emphasizes SA's multifaceted neuroprotective properties and its potential role in the prevention and treatment of various brain disorders. Despite the need for further research to fully understand its mechanisms of action and clinical applicability, SA stands out as a valuable bioactive compound in the ongoing quest to combat neurodegenerative diseases and enhance the quality of life for affected individuals.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141854060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Exosomes have shown good potential for alleviating neurological deficits and delaying memory deterioration, but the neuroprotective effects of exosomes remain unknown. Methylmalonic acidemia is a metabolic disorder characterized by the accumulation of methylmalonic acid (MMA) in various tissues that inhibits neuronal survival and function, leading to accelerated neurological deterioration. Effective therapies to mitigate these symptoms are lacking. The purpose of this study was to explore the neuroprotective effects of plasma exosomes on cells and a mouse model of MMA-induced injury. We evaluated the ability of plasma exosomes to reduce the neuronal apoptosis, cross the blood-brain barrier, and affect various parameters related to neuronal function. MMA promoted cell apoptosis, disrupted the metabolic balance, and altered the expression of B-cell lymphoma-2 (Bcl-2), Bcl2-associated X (Bax), and synaptophysin-1 (Syp-1), and these changes may be involved in MMA-induced neuronal apoptosis. Additionally, plasma exosomes normalized learning and memory and protected against MMA-induced neuronal apoptosis. Our findings indicate that neurological deficits are linked to the pathogenesis of methylmalonic acidemia, and healthy plasma exosomes may exert neuroprotective and therapeutic effects by altering the expression of exosomal microRNAs, facilitating neuronal functional recovery in the context of this inherited metabolic disease. Intravenous plasma-derived exosome treatment may be a novel clinical therapeutic strategy for methylmalonic acidemia.
{"title":"Healthy Plasma Exosomes Exert Potential Neuroprotective Effects against Methylmalonic Acid-Induced Hippocampal Neuron Injury.","authors":"Wei Zhou, Huizhong Li, Jinxiu Song, Feng Suo, Maosheng Gu, Suhua Qi","doi":"10.1021/acschemneuro.4c00224","DOIUrl":"10.1021/acschemneuro.4c00224","url":null,"abstract":"<p><p>Exosomes have shown good potential for alleviating neurological deficits and delaying memory deterioration, but the neuroprotective effects of exosomes remain unknown. Methylmalonic acidemia is a metabolic disorder characterized by the accumulation of methylmalonic acid (MMA) in various tissues that inhibits neuronal survival and function, leading to accelerated neurological deterioration. Effective therapies to mitigate these symptoms are lacking. The purpose of this study was to explore the neuroprotective effects of plasma exosomes on cells and a mouse model of MMA-induced injury. We evaluated the ability of plasma exosomes to reduce the neuronal apoptosis, cross the blood-brain barrier, and affect various parameters related to neuronal function. MMA promoted cell apoptosis, disrupted the metabolic balance, and altered the expression of B-cell lymphoma-2 (Bcl-2), Bcl2-associated X (Bax), and synaptophysin-1 (Syp-1), and these changes may be involved in MMA-induced neuronal apoptosis. Additionally, plasma exosomes normalized learning and memory and protected against MMA-induced neuronal apoptosis. Our findings indicate that neurological deficits are linked to the pathogenesis of methylmalonic acidemia, and healthy plasma exosomes may exert neuroprotective and therapeutic effects by altering the expression of exosomal microRNAs, facilitating neuronal functional recovery in the context of this inherited metabolic disease. Intravenous plasma-derived exosome treatment may be a novel clinical therapeutic strategy for methylmalonic acidemia.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141722649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-21Epub Date: 2024-07-15DOI: 10.1021/acschemneuro.4c00113
Camila A E F Cardinali, Yandara A Martins, Ruan C M Moraes, Andressa P Costa, Mayke B Alencar, Ariel M Silber, Andrea S Torrão
Alzheimer's disease (AD) is a complex neurodegenerative process, also considered a metabolic condition due to alterations in glucose metabolism and insulin signaling pathways in the brain, which share similarities with diabetes. This study aimed to investigate the therapeutic effects of benfotiamine (BFT), a vitamin B1 analog, in the early stages of the neurodegenerative process in a sporadic model of Alzheimer's-like disease induced by intracerebroventricular injection of streptozotocin (STZ). Supplementation with 150 mg/kg of BFT for 7 days reversed the cognitive impairment in short- and long-term memories caused by STZ in rodents. We attribute these effects to BFT's ability to modulate glucose transporters type 1 and 3 (GLUT1 and GLUT3) in the hippocampus, inhibit GSK3 activity in the hippocampus, and modulate the insulin signaling in the hippocampus and entorhinal cortex, as well as reduce the activation of apoptotic pathways (BAX) in the hippocampus. Therefore, BFT emerges as a promising and accessible intervention in the initial treatment of conditions similar to AD.
{"title":"Exploring the Therapeutic Potential of Benfotiamine in a Sporadic Alzheimer's-Like Disease Rat Model: Insights into Insulin Signaling and Cognitive function.","authors":"Camila A E F Cardinali, Yandara A Martins, Ruan C M Moraes, Andressa P Costa, Mayke B Alencar, Ariel M Silber, Andrea S Torrão","doi":"10.1021/acschemneuro.4c00113","DOIUrl":"10.1021/acschemneuro.4c00113","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a complex neurodegenerative process, also considered a metabolic condition due to alterations in glucose metabolism and insulin signaling pathways in the brain, which share similarities with diabetes. This study aimed to investigate the therapeutic effects of benfotiamine (BFT), a vitamin B1 analog, in the early stages of the neurodegenerative process in a sporadic model of Alzheimer's-like disease induced by intracerebroventricular injection of streptozotocin (STZ). Supplementation with 150 mg/kg of BFT for 7 days reversed the cognitive impairment in short- and long-term memories caused by STZ in rodents. We attribute these effects to BFT's ability to modulate glucose transporters type 1 and 3 (GLUT1 and GLUT3) in the hippocampus, inhibit GSK3 activity in the hippocampus, and modulate the insulin signaling in the hippocampus and entorhinal cortex, as well as reduce the activation of apoptotic pathways (BAX) in the hippocampus. Therefore, BFT emerges as a promising and accessible intervention in the initial treatment of conditions similar to AD.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11342302/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141615219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-21Epub Date: 2024-08-01DOI: 10.1021/acschemneuro.4c00279
Samuel C Woodburn, Caleb M Levitt, Allison M Koester, Alex C Kwan
A variety of classic psychedelics and MDMA have been shown to enhance fear extinction in rodent models. This has translational significance because a standard treatment for post-traumatic stress disorder (PTSD) is prolonged exposure therapy. However, few studies have investigated psilocybin's potential effect on fear learning paradigms. More specifically, the extents to which dose, timing of administration, and serotonin receptors may influence psilocybin's effect on fear extinction are not understood. In this study, we used a delay fear conditioning paradigm to determine the effects of psilocybin on fear extinction, extinction retention, and fear renewal in male and female mice. Psilocybin robustly enhances fear extinction when given acutely prior to testing for all doses tested. Psilocybin also exerts long-term effects to elevate extinction retention and suppress fear renewal in a novel context, although these changes were sensitive to dose. Analysis of sex differences showed that females may respond to a narrower range of doses than males. Administration of psilocybin prior to fear learning or immediately after extinction yielded no change in behavior, indicating that concurrent extinction experience is necessary for the drug's effects. Cotreatment with a 5-HT2A receptor antagonist blocked psilocybin's effects for extinction, extinction retention, and fear renewal, whereas 5-HT1A receptor antagonism attenuated only the effect on fear renewal. Collectively, these results highlight dose, context, and serotonin receptors as crucial factors in psilocybin's ability to facilitate fear extinction. The study provides preclinical evidence to support investigating psilocybin as a pharmacological adjunct for extinction-based therapy for PTSD.
{"title":"Psilocybin Facilitates Fear Extinction: Importance of Dose, Context, and Serotonin Receptors.","authors":"Samuel C Woodburn, Caleb M Levitt, Allison M Koester, Alex C Kwan","doi":"10.1021/acschemneuro.4c00279","DOIUrl":"10.1021/acschemneuro.4c00279","url":null,"abstract":"<p><p>A variety of classic psychedelics and MDMA have been shown to enhance fear extinction in rodent models. This has translational significance because a standard treatment for post-traumatic stress disorder (PTSD) is prolonged exposure therapy. However, few studies have investigated psilocybin's potential effect on fear learning paradigms. More specifically, the extents to which dose, timing of administration, and serotonin receptors may influence psilocybin's effect on fear extinction are not understood. In this study, we used a delay fear conditioning paradigm to determine the effects of psilocybin on fear extinction, extinction retention, and fear renewal in male and female mice. Psilocybin robustly enhances fear extinction when given acutely prior to testing for all doses tested. Psilocybin also exerts long-term effects to elevate extinction retention and suppress fear renewal in a novel context, although these changes were sensitive to dose. Analysis of sex differences showed that females may respond to a narrower range of doses than males. Administration of psilocybin prior to fear learning or immediately after extinction yielded no change in behavior, indicating that concurrent extinction experience is necessary for the drug's effects. Cotreatment with a 5-HT<sub>2A</sub> receptor antagonist blocked psilocybin's effects for extinction, extinction retention, and fear renewal, whereas 5-HT<sub>1A</sub> receptor antagonism attenuated only the effect on fear renewal. Collectively, these results highlight dose, context, and serotonin receptors as crucial factors in psilocybin's ability to facilitate fear extinction. The study provides preclinical evidence to support investigating psilocybin as a pharmacological adjunct for extinction-based therapy for PTSD.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-21Epub Date: 2024-08-05DOI: 10.1021/acschemneuro.4c00307
Ashwarya S Devason, Christoph A Thaiss, Cesar de la Fuente-Nunez
The past decade has seen an explosion in our knowledge about the interactions between gut microbiota, the central nervous system, and the immune system. The gut-brain axis has recently gained much attention due to its role in regulating host physiology. This review explores recent findings concerning potential pathways linking the gut-brain axis to the initiation, pathophysiology, and development of neurological disorders. Our objective of this work is to uncover causative factors and pinpoint particular pathways and therapeutic targets that may facilitate the translation of experimental animal research into practical applications for human patients. We highlight three distinct yet interrelated mechanisms: (1) disruptions of both the intestinal and blood-brain barriers, (2) persistent neuroinflammation, and (3) the role of the vagus nerve.
{"title":"Neuromicrobiology Comes of Age: The Multifaceted Interactions between the Microbiome and the Nervous System.","authors":"Ashwarya S Devason, Christoph A Thaiss, Cesar de la Fuente-Nunez","doi":"10.1021/acschemneuro.4c00307","DOIUrl":"10.1021/acschemneuro.4c00307","url":null,"abstract":"<p><p>The past decade has seen an explosion in our knowledge about the interactions between gut microbiota, the central nervous system, and the immune system. The gut-brain axis has recently gained much attention due to its role in regulating host physiology. This review explores recent findings concerning potential pathways linking the gut-brain axis to the initiation, pathophysiology, and development of neurological disorders. Our objective of this work is to uncover causative factors and pinpoint particular pathways and therapeutic targets that may facilitate the translation of experimental animal research into practical applications for human patients. We highlight three distinct yet interrelated mechanisms: (1) disruptions of both the intestinal and blood-brain barriers, (2) persistent neuroinflammation, and (3) the role of the vagus nerve.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-20DOI: 10.1021/acschemneuro.4c0031010.1021/acschemneuro.4c00310
Fan Qi*, Hao He and Yujie Zhu*,
Dendritic spines function as postsynaptic sites, receiving excitatory signals from presynaptic axons. The synaptic plasticity of spines underlies the refinement of neuronal circuits. Neural cognitive disorders are commonly associated with the impairment and elimination of dendritic spines. In this study, we report an all-optical method to activate dendritic spine growth and regeneration by a single short flash of femtosecond laser stimulation. The inhibited development and loss of spines can be rescued by a transient illumination of the laser inside a micrometer region of the soma by activating the extracellular signal-regulated kinase (ERK) signaling pathway. The rescued neurons exhibit function. Hence we provide a potential noninvasive method for the regeneration of dendritic spines.
{"title":"Neural Development and Repair Induced by Femtosecond Laser Stimulation","authors":"Fan Qi*, Hao He and Yujie Zhu*, ","doi":"10.1021/acschemneuro.4c0031010.1021/acschemneuro.4c00310","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00310https://doi.org/10.1021/acschemneuro.4c00310","url":null,"abstract":"<p >Dendritic spines function as postsynaptic sites, receiving excitatory signals from presynaptic axons. The synaptic plasticity of spines underlies the refinement of neuronal circuits. Neural cognitive disorders are commonly associated with the impairment and elimination of dendritic spines. In this study, we report an all-optical method to activate dendritic spine growth and regeneration by a single short flash of femtosecond laser stimulation. The inhibited development and loss of spines can be rescued by a transient illumination of the laser inside a micrometer region of the soma by activating the extracellular signal-regulated kinase (ERK) signaling pathway. The rescued neurons exhibit function. Hence we provide a potential noninvasive method for the regeneration of dendritic spines.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142135533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-19DOI: 10.1021/acschemneuro.4c0036510.1021/acschemneuro.4c00365
Izabella Góral, Tomasz Wichur, Emilia Sługocka, Przemysław Grygier, Monika Głuch-Lutwin, Barbara Mordyl, Ewelina Honkisz-Orzechowska, Natalia Szałaj, Justyna Godyń, Dawid Panek, Paula Zaręba, Anna Sarka, Paweł Żmudzki, Gniewomir Latacz, Katarzyna Pustelny, Adam Bucki, Anna Czarna, Filipe Menezes* and Anna Więckowska*,
In the pathogenesis of Alzheimer’s disease, the overexpression of glycogen synthase kinase-3β (GSK-3β) stands out due to its multifaced nature, as it contributes to the promotion of amyloid β and tau protein accumulation, as well as neuroinflammatory processes. Therefore, in the present study, we have designed, synthesized, and evaluated a new series of GSK-3β inhibitors based on the N-(pyridin-2-yl)cyclopropanecarboxamide scaffold. We identified compound 36, demonstrating an IC50 of 70 nM against GSK-3β. Subsequently, through crystallography studies and quantum mechanical analysis, we elucidated its binding mode and identified the structural features crucial for interactions with the active site of GSK-3β, thereby understanding its inhibitory potency. Compound 36 was effective in the cellular model of hyperphosphorylated tau-induced neurodegeneration, where it restored cell viability after okadaic acid treatment and showed anti-inflammatory activity in the LPS model, significantly reducing NO, IL-6, and TNF-α release. In ADME-tox in vitro studies, we confirmed the beneficial profile of 36, including high permeability in PAMPA (Pe equals 9.4) and high metabolic stability in HLMs as well as lack of significant interactions with isoforms of the CYP enzymes and lack of considerable cytotoxicity on selected cell lines (IC50 > 100 μM on HT-22 cells and 89.3 μM on BV-2 cells). Based on promising pharmacological activities and favorable ADME-tox properties, compound 36 may be considered a promising candidate for in vivo research as well as constitute a reliable starting point for further studies.
{"title":"Exploring Novel GSK-3β Inhibitors for Anti-Neuroinflammatory and Neuroprotective Effects: Synthesis, Crystallography, Computational Analysis, and Biological Evaluation","authors":"Izabella Góral, Tomasz Wichur, Emilia Sługocka, Przemysław Grygier, Monika Głuch-Lutwin, Barbara Mordyl, Ewelina Honkisz-Orzechowska, Natalia Szałaj, Justyna Godyń, Dawid Panek, Paula Zaręba, Anna Sarka, Paweł Żmudzki, Gniewomir Latacz, Katarzyna Pustelny, Adam Bucki, Anna Czarna, Filipe Menezes* and Anna Więckowska*, ","doi":"10.1021/acschemneuro.4c0036510.1021/acschemneuro.4c00365","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00365https://doi.org/10.1021/acschemneuro.4c00365","url":null,"abstract":"<p >In the pathogenesis of Alzheimer’s disease, the overexpression of glycogen synthase kinase-3β (GSK-3β) stands out due to its multifaced nature, as it contributes to the promotion of amyloid β and tau protein accumulation, as well as neuroinflammatory processes. Therefore, in the present study, we have designed, synthesized, and evaluated a new series of GSK-3β inhibitors based on the <i>N</i>-(pyridin-2-yl)cyclopropanecarboxamide scaffold. We identified compound <b>36</b>, demonstrating an IC<sub>50</sub> of 70 nM against GSK-3β. Subsequently, through crystallography studies and quantum mechanical analysis, we elucidated its binding mode and identified the structural features crucial for interactions with the active site of GSK-3β, thereby understanding its inhibitory potency. Compound <b>36</b> was effective in the cellular model of hyperphosphorylated tau-induced neurodegeneration, where it restored cell viability after okadaic acid treatment and showed anti-inflammatory activity in the LPS model, significantly reducing NO, IL-6, and TNF-α release. In ADME-tox in vitro studies, we confirmed the beneficial profile of <b>36,</b> including high permeability in PAMPA (<i>Pe</i> equals 9.4) and high metabolic stability in HLMs as well as lack of significant interactions with isoforms of the CYP enzymes and lack of considerable cytotoxicity on selected cell lines (IC<sub>50</sub> > 100 μM on HT-22 cells and 89.3 μM on BV-2 cells). Based on promising pharmacological activities and favorable ADME-tox properties, compound <b>36</b> may be considered a promising candidate for in vivo research as well as constitute a reliable starting point for further studies.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.4c00365","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142135221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-19DOI: 10.1021/acschemneuro.4c0025310.1021/acschemneuro.4c00253
Arushi Dabas, and , Bhupesh Goyal*,
The inhibition of amyloid-β (Aβ) fibrillation and clearance of Aβ aggregates have emerged as a potential pharmacological strategy to alleviate Aβ aggregate-induced neurotoxicity in Alzheimer’s disease (AD). Maity et al. shortlisted ADH-353 from a small library of positively charged N-substituted oligopyrrolamides for its notable ability to inhibit Aβ fibrillation, disintegrate intracellular cytotoxic Aβ oligomers, and alleviate Aβ-induced cytotoxicity in the SH-SY5Y and N2a cells. However, the molecular mechanism through which ADH-353 interacts with the Aβ42 fibrils, leading to their disruption and subsequent clearance, remains unclear. Thus, a detailed molecular mechanism underlying the disruption of neurotoxic Aβ42 fibrils (PDB ID 2NAO) by ADH-353 has been illuminated in this work using molecular dynamics simulations. Interestingly, conformational snapshots during simulation depicted the shortening and disappearance of β-strands and the emergence of a helix conformation, indicating a loss of the well-organized β-sheet-rich structure of the disease-relevant Aβ42 fibril on the incorporation of ADH-353. ADH-353 binds strongly to the Aβ42 fibril (ΔGbinding= −142.91 ± 1.61 kcal/mol) with a notable contribution from the electrostatic interactions between positively charged N-propylamine side chains of ADH-353 with the glutamic (Glu3, Glu11, and Glu22) and aspartic (Asp7 and Asp23) acid residues of the Aβ42 fibril. This aligns well with heteronuclear single quantum coherence NMR studies, which depict that the binding of ADH-353 with the Aβ peptide is driven by electrostatic and hydrophobic contacts. Furthermore, a noteworthy decrease in the binding affinity of Aβ42 fibril chains on the incorporation of ADH-353 indicates the weakening of interchain interactions leading to the disruption of the double-horseshoe conformation of the Aβ42 fibril. The illumination of key interactions responsible for the destabilization of the Aβ42 fibril by ADH-353 in this work will greatly aid in designing new chemical scaffolds with enhanced efficacy for the clearance of Aβ aggregates in AD.
{"title":"Structural Reorganization Mechanism of the Aβ42 Fibril Mediated by N-Substituted Oligopyrrolamide ADH-353","authors":"Arushi Dabas, and , Bhupesh Goyal*, ","doi":"10.1021/acschemneuro.4c0025310.1021/acschemneuro.4c00253","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00253https://doi.org/10.1021/acschemneuro.4c00253","url":null,"abstract":"<p >The inhibition of amyloid-β (Aβ) fibrillation and clearance of Aβ aggregates have emerged as a potential pharmacological strategy to alleviate Aβ aggregate-induced neurotoxicity in Alzheimer’s disease (AD). Maity et al. shortlisted ADH-353 from a small library of positively charged <i>N</i>-substituted oligopyrrolamides for its notable ability to inhibit Aβ fibrillation, disintegrate intracellular cytotoxic Aβ oligomers, and alleviate Aβ-induced cytotoxicity in the SH-SY5Y and N2a cells. However, the molecular mechanism through which ADH-353 interacts with the Aβ<sub>42</sub> fibrils, leading to their disruption and subsequent clearance, remains unclear. Thus, a detailed molecular mechanism underlying the disruption of neurotoxic Aβ<sub>42</sub> fibrils (PDB ID 2NAO) by ADH-353 has been illuminated in this work using molecular dynamics simulations. Interestingly, conformational snapshots during simulation depicted the shortening and disappearance of β-strands and the emergence of a helix conformation, indicating a loss of the well-organized β-sheet-rich structure of the disease-relevant Aβ<sub>42</sub> fibril on the incorporation of ADH-353. ADH-353 binds strongly to the Aβ<sub>42</sub> fibril (Δ<i>G</i><sub>binding</sub>= −142.91 ± 1.61 kcal/mol) with a notable contribution from the electrostatic interactions between positively charged <i>N</i>-propylamine side chains of ADH-353 with the glutamic (Glu3, Glu11, and Glu22) and aspartic (Asp7 and Asp23) acid residues of the Aβ<sub>42</sub> fibril. This aligns well with heteronuclear single quantum coherence NMR studies, which depict that the binding of ADH-353 with the Aβ peptide is driven by electrostatic and hydrophobic contacts. Furthermore, a noteworthy decrease in the binding affinity of Aβ<sub>42</sub> fibril chains on the incorporation of ADH-353 indicates the weakening of interchain interactions leading to the disruption of the double-horseshoe conformation of the Aβ<sub>42</sub> fibril. The illumination of key interactions responsible for the destabilization of the Aβ<sub>42</sub> fibril by ADH-353 in this work will greatly aid in designing new chemical scaffolds with enhanced efficacy for the clearance of Aβ aggregates in AD.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142135140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}