Pub Date : 2024-01-01Epub Date: 2024-09-09DOI: 10.1080/17590914.2024.2394352
Makenzie Nolt, James Connor
Iron is a critical transition metal required to sustain a healthy central nervous system. Iron is involved in metabolic reactions, enzymatic activity, myelinogenesis, and oxygen transport. However, in several pathological conditions such as cancer, neurodegeneration, and neurotrauma iron becomes elevated. Excessive iron can have deleterious effects leading to reactive oxygen species (ROS) via the Fenton reaction. Iron-derived ROS are known to drive several mechanisms such as cell death pathways including ferroptosis, necroptosis, and pyroptosis. Excessive iron present in the post-traumatic brain could trigger these harmful pathways potentiating the high rates of morbidity and mortality. In the present review, we will discuss how iron plays an intricate role in initiating ferroptosis, necroptosis, and pyroptosis, examine their potential link to traumatic brain injury morbidity and mortality, and suggest therapeutic targets.
{"title":"Implications of Iron in Ferroptosis, Necroptosis, and Pyroptosis as Potential Players in TBI Morbidity and Mortality.","authors":"Makenzie Nolt, James Connor","doi":"10.1080/17590914.2024.2394352","DOIUrl":"https://doi.org/10.1080/17590914.2024.2394352","url":null,"abstract":"<p><p>Iron is a critical transition metal required to sustain a healthy central nervous system. Iron is involved in metabolic reactions, enzymatic activity, myelinogenesis, and oxygen transport. However, in several pathological conditions such as cancer, neurodegeneration, and neurotrauma iron becomes elevated. Excessive iron can have deleterious effects leading to reactive oxygen species (ROS) via the Fenton reaction. Iron-derived ROS are known to drive several mechanisms such as cell death pathways including ferroptosis, necroptosis, and pyroptosis. Excessive iron present in the post-traumatic brain could trigger these harmful pathways potentiating the high rates of morbidity and mortality. In the present review, we will discuss how iron plays an intricate role in initiating ferroptosis, necroptosis, and pyroptosis, examine their potential link to traumatic brain injury morbidity and mortality, and suggest therapeutic targets.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2024-07-16DOI: 10.1080/17590914.2024.2371164
Price Obot, Antonio Cibelli, Jian Pan, Libor Velíšek, Jana Velíšková, Eliana Scemes
There is a high co-morbidity between childhood epilepsy and autism spectrum disorder (ASD), with age of seizure onset being a critical determinant of behavioral outcomes. The interplay between these comorbidities has been investigated in animal models with results showing that the induction of seizures at early post-natal ages leads to learning and memory deficits and to autistic-like behavior in adulthood. Modifications of the excitation/inhibition (glutamate/GABA, ATP/adenosine) balance that follows early-life seizures (ELS) are thought to be the physiological events that underlie neuropsychiatric and neurodevelopmental disorders. Although alterations in purinergic/adenosinergic signaling have been implicated in seizures and ASD, it is unknown whether the ATP release channels, Pannexin1 (Panx1), contribute to ELS-induced behavior changes. To tackle this question, we used the ELS-kainic acid model in transgenic mice with global and cell type specific deletion of Panx1 to evaluate whether these channels were involved in behavioral deficits that occur later in life. Our studies show that ELS results in Panx1 dependent social behavior deficits and also in poor performance in a spatial memory test that does not involve Panx1. These findings provide support for a link between ELS and adult behavioral deficits. Moreover, we identify neuronal and not astrocyte Panx1 as a potential target to specifically limit astrogliosis and social behavioral deficits resultant from early-life seizures.
儿童癫痫与自闭症谱系障碍(ASD)的共病率很高,而癫痫发作的年龄是行为结果的关键决定因素。人们在动物模型中研究了这些并发症之间的相互作用,结果表明,在出生后早期诱导癫痫发作会导致学习和记忆障碍,并在成年后出现类似自闭症的行为。早期癫痫发作(ELS)后兴奋/抑制(谷氨酸/GABA、ATP/腺苷)平衡的改变被认为是导致神经精神和神经发育障碍的生理事件。虽然嘌呤能/腺苷能信号的改变与癫痫发作和 ASD 有关联,但 ATP 释放通道 Pannexin1(Panx1)是否有助于 ELS 诱导的行为变化,目前尚不清楚。为了解决这个问题,我们在转基因小鼠中使用了 ELS-凯尼酸模型,并对 Panx1 进行了全局性和细胞类型特异性缺失,以评估这些通道是否参与了日后出现的行为缺陷。我们的研究表明,ELS 会导致依赖于 Panx1 的社会行为缺陷,并在不涉及 Panx1 的空间记忆测试中表现不佳。这些发现为 ELS 与成年行为缺陷之间的联系提供了支持。此外,我们还发现神经元而非星形胶质细胞的 Panx1 是一个潜在的靶点,可专门限制星形胶质细胞增生和早期癫痫发作导致的社会行为缺陷。
{"title":"Pannexin1 Mediates Early-Life Seizure-Induced Social Behavior Deficits.","authors":"Price Obot, Antonio Cibelli, Jian Pan, Libor Velíšek, Jana Velíšková, Eliana Scemes","doi":"10.1080/17590914.2024.2371164","DOIUrl":"10.1080/17590914.2024.2371164","url":null,"abstract":"<p><p>There is a high co-morbidity between childhood epilepsy and autism spectrum disorder (ASD), with age of seizure onset being a critical determinant of behavioral outcomes. The interplay between these comorbidities has been investigated in animal models with results showing that the induction of seizures at early post-natal ages leads to learning and memory deficits and to autistic-like behavior in adulthood. Modifications of the excitation/inhibition (glutamate/GABA, ATP/adenosine) balance that follows early-life seizures (ELS) are thought to be the physiological events that underlie neuropsychiatric and neurodevelopmental disorders. Although alterations in purinergic/adenosinergic signaling have been implicated in seizures and ASD, it is unknown whether the ATP release channels, Pannexin1 (Panx1), contribute to ELS-induced behavior changes. To tackle this question, we used the ELS-kainic acid model in transgenic mice with global and cell type specific deletion of Panx1 to evaluate whether these channels were involved in behavioral deficits that occur later in life. Our studies show that ELS results in Panx1 dependent social behavior deficits and also in poor performance in a spatial memory test that does not involve Panx1. These findings provide support for a link between ELS and adult behavioral deficits. Moreover, we identify neuronal and not astrocyte Panx1 as a potential target to specifically limit astrogliosis and social behavioral deficits resultant from early-life seizures.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11262470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141722921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2024-07-15DOI: 10.1080/17590914.2024.2371163
Hebe M Guardiola-Diaz, Brett T DiBenedictis, Erealda Prendaj, Rashmi Bansal
The fifteen canonical paracrine fibroblast growth factors (FGFs) are organized in five subfamilies that interact with four FGF-receptors (FGFRs) and heparan sulfate proteoglycan (HSPG) co-receptors. Many of these FGFs are expressed in CNS regions where oligodendrocyte (OL) progenitors originate, migrate or differentiate. FGF2 (basic FGF) is considered a prototype FGF and the information about the effects of FGF signaling on OL-lineage cells has evolved largely from the study of FGF2. However, other FGFs from four subfamilies ((FGF1 (FGF1,-2), FGF4 (FGF4,-5,-6), FGF8 (FGF8,-17,-18) and FGF9 (FGF9,-16,-20)) that can interact with the isoforms of FGFRs expressed in OL-lineage cells may also play important roles. We previously reported OL-responses to FGF8 family members. Here, we investigate the effects of members of the FGF1,-4, and -9 subfamilies on proliferation and differentiation of OL progenitors (OPCs), and on cell cycle re-entry and down-regulation of myelin proteins by mature OLs. We found that while FGF2 induced all these responses strongly, FGF4,-6,-9 could do so only transiently and in the presence of exogenous HSPGs, and that FGF5,-16,-20 could not do so even in the presence of heparin or at higher concentrations. Furthermore, we noted that structurally similar FGFs within subfamilies did not always show similarities in their biological effects on OL-lineage cells. Taken together, these studies reveal that FGFs differ in the way they regulate the OL-lineage cells, emphasizes the selectivity and importance of HSPGs as FGF co-receptors in OL-lineage cells and suggests that structural similarity among FGF-subfamily members may not always predict their overlapping biological functions.
15 种典型的旁分泌型成纤维细胞生长因子(FGFs)分为 5 个亚族,它们与 4 种 FGF 受体(FGFRs)和硫酸肝素蛋白聚糖(HSPG)共受体相互作用。其中许多生长因子在中枢神经系统区域表达,少突胶质细胞(OL)祖细胞在这些区域起源、迁移或分化。FGF2(基本 FGF)被认为是 FGF 的原型,有关 FGF 信号对 OL 系细胞影响的信息主要来自对 FGF2 的研究。然而,来自四个亚家族(FGF1 (FGF1,-2)、FGF4 (FGF4,-5,-6)、FGF8 (FGF8,-17,-18) 和 FGF9 (FGF9,-16,-20))、能与 OL 系细胞中表达的 FGFR 异构体相互作用的其他 FGF 也可能发挥重要作用。我们以前曾报道过 OL 对 FGF8 家族成员的反应。在这里,我们研究了 FGF1、-4 和 -9 亚家族成员对 OL 祖细胞(OPCs)增殖和分化的影响,以及对成熟 OLs 重新进入细胞周期和下调髓鞘蛋白的影响。我们发现,虽然 FGF2 能强烈诱导所有这些反应,但 FGF4、-6、-9 只能在外源性 HSPG 存在的情况下短暂诱导这些反应,而 FGF5、-16、-20 即使在肝素存在或浓度较高的情况下也不能诱导这些反应。此外,我们还注意到,亚家族中结构相似的 FGFs 对 OL 系细胞的生物效应并不总是相似的。总之,这些研究揭示了 FGFs 在调控 OL 系细胞的方式上存在差异,强调了 HSPGs 作为 FGF 共受体在 OL 系细胞中的选择性和重要性,并表明 FGF 亚家族成员之间的结构相似性并不总能预示它们的生物功能重叠。
{"title":"Diverse Responses of Oligodendrocytes to Different FGF-Family Members: Uncoupling Structure-Function Relationship Within FGF Subfamilies.","authors":"Hebe M Guardiola-Diaz, Brett T DiBenedictis, Erealda Prendaj, Rashmi Bansal","doi":"10.1080/17590914.2024.2371163","DOIUrl":"10.1080/17590914.2024.2371163","url":null,"abstract":"<p><p>The fifteen canonical paracrine fibroblast growth factors (FGFs) are organized in five subfamilies that interact with four FGF-receptors (FGFRs) and heparan sulfate proteoglycan (HSPG) co-receptors. Many of these FGFs are expressed in CNS regions where oligodendrocyte (OL) progenitors originate, migrate or differentiate. FGF2 (basic FGF) is considered a prototype FGF and the information about the effects of FGF signaling on OL-lineage cells has evolved largely from the study of FGF2. However, other FGFs from four subfamilies ((FGF1 (FGF1,-2), FGF4 (FGF4,-5,-6), FGF8 (FGF8,-17,-18) and FGF9 (FGF9,-16,-20)) that can interact with the isoforms of FGFRs expressed in OL-lineage cells may also play important roles. We previously reported OL-responses to FGF8 family members. Here, we investigate the effects of members of the FGF1,-4, and -9 subfamilies on proliferation and differentiation of OL progenitors (OPCs), and on cell cycle re-entry and down-regulation of myelin proteins by mature OLs. We found that while FGF2 induced all these responses strongly, FGF4,-6,-9 could do so only transiently and in the presence of exogenous HSPGs, and that FGF5,-16,-20 could not do so even in the presence of heparin or at higher concentrations. Furthermore, we noted that structurally similar FGFs within subfamilies did not always show similarities in their biological effects on OL-lineage cells. Taken together, these studies reveal that FGFs differ in the way they regulate the OL-lineage cells, emphasizes the selectivity and importance of HSPGs as FGF co-receptors in OL-lineage cells and suggests that structural similarity among FGF-subfamily members may not always predict their overlapping biological functions.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11262039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141722920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2024-09-09DOI: 10.1080/17590914.2024.2386884
Douglas L Feinstein
{"title":"Editorial.","authors":"Douglas L Feinstein","doi":"10.1080/17590914.2024.2386884","DOIUrl":"https://doi.org/10.1080/17590914.2024.2386884","url":null,"abstract":"","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2024-07-16DOI: 10.1080/17590914.2024.2371162
Yonglin Gao, Lukasz P Slomnicki, Ewa Kilanczyk, Michael D Forston, Maciej Pietrzak, Eric C Rouchka, Russell M Howard, Scott R Whittemore, Michal Hetman
Endoplasmic reticulum (ER) stress in oligodendrocyte (OL) linage cells contributes to several CNS pathologies including traumatic spinal cord injury (SCI) and multiple sclerosis. Therefore, primary rat OL precursor cell (OPC) transcriptomes were analyzed using RNASeq after treatments with two ER stress-inducing drugs, thapsigargin (TG) or tunicamycin (TM). Gene ontology term (GO) enrichment showed that both drugs upregulated mRNAs associated with the general stress response. The GOs related to ER stress were only enriched for TM-upregulated mRNAs, suggesting greater ER stress selectivity of TM. Both TG and TM downregulated cell cycle/cell proliferation-associated transcripts, indicating the anti-proliferative effects of ER stress. Interestingly, many OL lineage-enriched mRNAs were downregulated, including those for transcription factors that drive OL identity such as Olig2. Moreover, ER stress-associated decreases of OL-specific gene expression were found in mature OLs from mouse models of white matter pathologies including contusive SCI, toxin-induced demyelination, and Alzheimer's disease-like neurodegeneration. Taken together, the disrupted transcriptomic fingerprint of OL lineage cells may facilitate myelin degeneration and/or dysfunction when pathological ER stress persists in OL lineage cells.
少突胶质细胞(OL)系细胞中的内质网(ER)应激是包括创伤性脊髓损伤(SCI)和多发性硬化症在内的多种中枢神经系统疾病的诱因。因此,在使用两种ER应激诱导药物--thapsigargin(TG)或tunicamycin(TM)--处理后,使用RNASeq分析了原代大鼠OL前体细胞(OPC)转录组。基因本体术语(GO)富集显示,两种药物都上调了与一般应激反应相关的mRNA。只有 TM 上调的 mRNA 富集了与 ER 应激有关的 GO,这表明 TM 对 ER 应激具有更大的选择性。TG和TM都能下调细胞周期/细胞增殖相关的转录本,表明ER应激具有抗增殖作用。有趣的是,许多 OL 系富集的 mRNA 被下调,包括那些驱动 OL 特性的转录因子,如 Olig2。此外,在白质病理学小鼠模型(包括挫伤性 SCI、毒素诱导的脱髓鞘和阿尔茨海默病样神经变性)的成熟 OL 中,也发现了与 ER 应激相关的 OL 特异性基因表达下降。综上所述,当病理性ER应激在OL系细胞中持续存在时,OL系细胞的转录组指纹紊乱可能会促进髓鞘变性和/或功能障碍。
{"title":"Reduced Expression of Oligodendrocyte Linage-Enriched Transcripts During the Endoplasmic Reticulum Stress/Integrated Stress Response.","authors":"Yonglin Gao, Lukasz P Slomnicki, Ewa Kilanczyk, Michael D Forston, Maciej Pietrzak, Eric C Rouchka, Russell M Howard, Scott R Whittemore, Michal Hetman","doi":"10.1080/17590914.2024.2371162","DOIUrl":"10.1080/17590914.2024.2371162","url":null,"abstract":"<p><p>Endoplasmic reticulum (ER) stress in oligodendrocyte (OL) linage cells contributes to several CNS pathologies including traumatic spinal cord injury (SCI) and multiple sclerosis. Therefore, primary rat OL precursor cell (OPC) transcriptomes were analyzed using RNASeq after treatments with two ER stress-inducing drugs, thapsigargin (TG) or tunicamycin (TM). Gene ontology term (GO) enrichment showed that both drugs upregulated mRNAs associated with the general stress response. The GOs related to ER stress were only enriched for TM-upregulated mRNAs, suggesting greater ER stress selectivity of TM. Both TG and TM downregulated cell cycle/cell proliferation-associated transcripts, indicating the anti-proliferative effects of ER stress. Interestingly, many OL lineage-enriched mRNAs were downregulated, including those for transcription factors that drive OL identity such as <i>Olig2</i>. Moreover, ER stress-associated decreases of OL-specific gene expression were found in mature OLs from mouse models of white matter pathologies including contusive SCI, toxin-induced demyelination, and Alzheimer's disease-like neurodegeneration. Taken together, the disrupted transcriptomic fingerprint of OL lineage cells may facilitate myelin degeneration and/or dysfunction when pathological ER stress persists in OL lineage cells.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11262469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141722922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2024-07-16DOI: 10.1080/17590914.2024.2371160
Lili Veronika Nagy, Zsolt Kristóf Bali, István Ledneczki, Zsolt Némethy, Balázs Lendvai, István Hernádi
Promising new pharmacological strategies for the enhancement of cognition target either nicotinic acetylcholine receptors (nAChR) or N-methyl-D-aspartate receptors (NMDAR). There is also an increasing interest in low-dose combination therapies co-targeting the above neurotransmitter systems to reach greater efficacy over the monotreatments and to reduce possible side effects of high-dose monotreatments. In the present study, we assessed modulatory effects of the α7 nAChR-selective agonist PHA-543613 (PHA), a novel α7 nAChR positive allosteric modulator compound (CompoundX) and the NMDAR antagonist memantine on the in vivo firing activity of CA1 pyramidal neurons in the rat hippocampus. Three different test conditions were applied: spontaneous firing activity, NMDA-evoked firing activity and ACh-evoked firing activity. Results showed that high but not low doses of memantine decreased NMDA-evoked firing activity, and low doses increased the spontaneous and ACh-evoked firing activity. Systemically applied PHA robustly potentiated ACh-evoked firing activity with having no effect on NMDA-evoked activity. In addition, CompoundX increased both NMDA- and ACh-evoked firing activity, having no effects on spontaneous firing of the neurons. A combination of low doses of memantine and PHA increased firing activity in all test conditions and similar effects were observed with memantine and CompoundX but without spontaneous firing activity increasing effects. Our present results demonstrate that α7 nAChR agents beneficially interact with Alzheimer's disease medication memantine. Moreover, positive allosteric modulators potentiate memantine effects on the right time and the right place without affecting spontaneous firing activity. All these data confirm previous behavioral evidence for the viability of combination therapies for cognitive enhancement.
针对烟碱乙酰胆碱受体(nAChR)或N-甲基-D-天冬氨酸受体(NMDAR)的新药理学策略在提高认知能力方面大有可为。此外,人们对联合靶向上述神经递质系统的低剂量联合疗法也越来越感兴趣,以达到比单一疗法更高的疗效,并减少高剂量单一疗法可能产生的副作用。在本研究中,我们评估了α7 nAChR选择性激动剂PHA-543613(PHA)、新型α7 nAChR正异位调节剂化合物(CompoundX)和NMDAR拮抗剂美金刚对大鼠海马CA1锥体神经元体内发射活动的调节作用。实验采用了三种不同的测试条件:自发发射活动、NMDA诱发发射活动和ACh诱发发射活动。结果显示,高剂量而非低剂量的美金刚能降低NMDA诱发的发射活动,而低剂量的美金刚能提高自发发射活动和ACh诱发的发射活动。全身应用 PHA 可显著增强 ACh 诱导的发射活动,而对 NMDA 诱导的活动没有影响。此外,CompoundX 还能增强 NMDA 和 ACh 诱发的发射活动,但对神经元的自发发射没有影响。在所有测试条件下,低剂量美金刚和 PHA 的组合都能增加发射活动,美金刚和 CompoundX 也有类似的效果,但没有增加自发发射活动的效果。我们目前的研究结果表明,α7 nAChR 药物能与阿尔茨海默病药物美金刚产生有益的相互作用。此外,正性异位调节剂能在正确的时间和正确的地点增强美金刚的作用,而不会影响自发发射活动。所有这些数据都证实了之前的行为学证据,证明了联合疗法在增强认知能力方面的可行性。
{"title":"Cellular Mechanisms of Cognitive Enhancement: The <i>In Vivo</i> Modulation of the Firing Activity and the Responsiveness of Rat Hippocampal Neurons by Memantine and Alpha7 Nicotinic Acetylcholine Receptor Ligands.","authors":"Lili Veronika Nagy, Zsolt Kristóf Bali, István Ledneczki, Zsolt Némethy, Balázs Lendvai, István Hernádi","doi":"10.1080/17590914.2024.2371160","DOIUrl":"10.1080/17590914.2024.2371160","url":null,"abstract":"<p><p>Promising new pharmacological strategies for the enhancement of cognition target either nicotinic acetylcholine receptors (nAChR) or N-methyl-D-aspartate receptors (NMDAR). There is also an increasing interest in low-dose combination therapies co-targeting the above neurotransmitter systems to reach greater efficacy over the monotreatments and to reduce possible side effects of high-dose monotreatments. In the present study, we assessed modulatory effects of the α7 nAChR-selective agonist PHA-543613 (PHA), a novel α7 nAChR positive allosteric modulator compound (CompoundX) and the NMDAR antagonist memantine on the <i>in vivo</i> firing activity of CA1 pyramidal neurons in the rat hippocampus. Three different test conditions were applied: spontaneous firing activity, NMDA-evoked firing activity and ACh-evoked firing activity. Results showed that high but not low doses of memantine decreased NMDA-evoked firing activity, and low doses increased the spontaneous and ACh-evoked firing activity. Systemically applied PHA robustly potentiated ACh-evoked firing activity with having no effect on NMDA-evoked activity. In addition, CompoundX increased both NMDA- and ACh-evoked firing activity, having no effects on spontaneous firing of the neurons. A combination of low doses of memantine and PHA increased firing activity in all test conditions and similar effects were observed with memantine and CompoundX but without spontaneous firing activity increasing effects. Our present results demonstrate that α7 nAChR agents beneficially interact with Alzheimer's disease medication memantine. Moreover, positive allosteric modulators potentiate memantine effects on the right time and the right place without affecting spontaneous firing activity. All these data confirm previous behavioral evidence for the viability of combination therapies for cognitive enhancement.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11262468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141722919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2024-07-15DOI: 10.1080/17590914.2024.2368382
Subash Sapkota, Sagor C Roy, Rami Shrestha, Karen P Briski
Ventromedial hypothalamic nucleus (VMN) growth hormone-releasing hormone (Ghrh) neurotransmission shapes counterregulatory hormone secretion. Dorsomedial VMN Ghrh neurons express the metabolic-sensitive transcription factor steroidogenic factor-1/NR5A1 (SF-1). In vivo SF-1 gene knockdown tools were used here to address the premise that in male rats, SF-1 may regulate basal and/or hypoglycemic patterns of Ghrh, co-transmitter biosynthetic enzyme, and estrogen receptor (ER) gene expression in these neurons. Single-cell multiplex qPCR analyses showed that SF-1 regulates basal profiles of mRNAs that encode Ghrh and protein markers for neurochemicals that suppress (γ-aminobutyric acid) or enhance (nitric oxide; glutamate) counterregulation. SF-1 siRNA pretreatment respectively exacerbated or blunted hypoglycemia-associated inhibition of glutamate decarboxylase67 (GAD67/GAD1) and -65 (GAD65/GAD2) transcripts. Hypoglycemia augmented or reduced nitric oxide synthase and glutaminase mRNAs, responses that were attenuated by SF-1 gene silencing. Ghrh and Ghrh receptor transcripts were correspondingly refractory to or increased by hypoglycemia, yet SF-1 knockdown decreased both gene profiles. Hypoglycemic inhibition of ER-alpha and G protein-coupled-ER gene expression was amplified by SF-1 siRNA pretreatment, whereas as ER-beta mRNA was amplified. SF-1 knockdown decreased (corticosterone) or elevated [glucagon, growth hormone (GH)] basal counterregulatory hormone profiles, but amplified hypoglycemic hypercorticosteronemia and -glucagonemia or prevented elevated GH release. Outcomes document SF-1 control of VMN Ghrh neuron counterregulatory neurotransmitter and ER gene transcription. SF-1 likely regulates Ghrh nerve cell receptivity to estradiol and release of distinctive neurochemicals during glucose homeostasis and systemic imbalance. VMN Ghrh neurons emerge as a likely substrate for SF-1 control of glucose counterregulation in the male rat.
{"title":"Steroidogenic Factor-1 Regulation of Dorsomedial Ventromedial Hypothalamic Nucleus Ghrh Neuron Transmitter Marker and Estrogen Receptor Gene Expression in Male Rat.","authors":"Subash Sapkota, Sagor C Roy, Rami Shrestha, Karen P Briski","doi":"10.1080/17590914.2024.2368382","DOIUrl":"10.1080/17590914.2024.2368382","url":null,"abstract":"<p><p>Ventromedial hypothalamic nucleus (VMN) growth hormone-releasing hormone (Ghrh) neurotransmission shapes counterregulatory hormone secretion. Dorsomedial VMN Ghrh neurons express the metabolic-sensitive transcription factor steroidogenic factor-1/NR5A1 (SF-1). <i>In vivo</i> SF-1 gene knockdown tools were used here to address the premise that in male rats, SF-1 may regulate basal and/or hypoglycemic patterns of Ghrh, co-transmitter biosynthetic enzyme, and estrogen receptor (ER) gene expression in these neurons. Single-cell multiplex qPCR analyses showed that SF-1 regulates basal profiles of mRNAs that encode Ghrh and protein markers for neurochemicals that suppress (γ-aminobutyric acid) or enhance (nitric oxide; glutamate) counterregulation. SF-1 siRNA pretreatment respectively exacerbated or blunted hypoglycemia-associated inhibition of glutamate decarboxylase<sub>67</sub> (GAD<sub>67</sub>/GAD1) and -<sub>65</sub> (GAD<sub>65</sub>/GAD2) transcripts. Hypoglycemia augmented or reduced nitric oxide synthase and glutaminase mRNAs, responses that were attenuated by SF-1 gene silencing. Ghrh and Ghrh receptor transcripts were correspondingly refractory to or increased by hypoglycemia, yet SF-1 knockdown decreased both gene profiles. Hypoglycemic inhibition of ER-alpha and G protein-coupled-ER gene expression was amplified by SF-1 siRNA pretreatment, whereas as ER-beta mRNA was amplified. SF-1 knockdown decreased (corticosterone) or elevated [glucagon, growth hormone (GH)] basal counterregulatory hormone profiles, but amplified hypoglycemic hypercorticosteronemia and -glucagonemia or prevented elevated GH release. Outcomes document SF-1 control of VMN Ghrh neuron counterregulatory neurotransmitter and ER gene transcription. SF-1 likely regulates Ghrh nerve cell receptivity to estradiol and release of distinctive neurochemicals during glucose homeostasis and systemic imbalance. VMN Ghrh neurons emerge as a likely substrate for SF-1 control of glucose counterregulation in the male rat.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11262038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141722923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01DOI: 10.1177/17590914231157974
Isadora Matias, Luan Pereira Diniz, Ana Paula Bergamo Araujo, Isabella Vivarini Damico, Pâmella de Moura, Felipe Cabral-Miranda, Fabiola Diniz, Belisa Parmeggiani, Valeria de Mello Coelho, Renata E P Leite, Claudia K Suemoto, Gustavo Costa Ferreira, Regina Célia Cussa Kubrusly, Flávia Carvalho Alcantara Gomes
Aging is marked by complex and progressive physiological changes, including in the glutamatergic system, that lead to a decline of brain function. Increased content of senescent cells in the brain, such as glial cells, has been reported to impact cognition both in animal models and human tissue during normal aging and in the context of neurodegenerative disease. Changes in the glutamatergic synaptic activity rely on the glutamate-glutamine cycle, in which astrocytes handle glutamate taken up from synapses and provide glutamine for neurons, thus maintaining excitatory neurotransmission. However, the mechanisms of glutamate homeostasis in brain aging are still poorly understood. Herein, we showed that mouse senescent astrocytes in vitro undergo upregulation of GLT-1, GLAST, and glutamine synthetase (GS), along with the increased enzymatic activity of GS and [3H]-D-aspartate uptake. Furthermore, we observed higher levels of GS and increased [3H]-D-aspartate uptake in the hippocampus of aged mice, although the activity of GS was similar between young and old mice. Analysis of a previously available RNAseq dataset of mice at different ages revealed upregulation of GLAST and GS mRNA levels in hippocampal astrocytes during aging. Corroborating these rodent data, we showed an increased number of GS + cells, and GS and GLT-1 levels/intensity in the hippocampus of elderly humans. Our data suggest that aged astrocytes undergo molecular and functional changes that control glutamate-glutamine homeostasis upon brain aging.
{"title":"Age-Associated Upregulation of Glutamate Transporters and Glutamine Synthetase in Senescent Astrocytes In Vitro and in the Mouse and Human Hippocampus.","authors":"Isadora Matias, Luan Pereira Diniz, Ana Paula Bergamo Araujo, Isabella Vivarini Damico, Pâmella de Moura, Felipe Cabral-Miranda, Fabiola Diniz, Belisa Parmeggiani, Valeria de Mello Coelho, Renata E P Leite, Claudia K Suemoto, Gustavo Costa Ferreira, Regina Célia Cussa Kubrusly, Flávia Carvalho Alcantara Gomes","doi":"10.1177/17590914231157974","DOIUrl":"https://doi.org/10.1177/17590914231157974","url":null,"abstract":"<p><p>Aging is marked by complex and progressive physiological changes, including in the glutamatergic system, that lead to a decline of brain function. Increased content of senescent cells in the brain, such as glial cells, has been reported to impact cognition both in animal models and human tissue during normal aging and in the context of neurodegenerative disease. Changes in the glutamatergic synaptic activity rely on the glutamate-glutamine cycle, in which astrocytes handle glutamate taken up from synapses and provide glutamine for neurons, thus maintaining excitatory neurotransmission. However, the mechanisms of glutamate homeostasis in brain aging are still poorly understood. Herein, we showed that mouse senescent astrocytes <i>in vitro</i> undergo upregulation of GLT-1, GLAST, and glutamine synthetase (GS), along with the increased enzymatic activity of GS and [<sup>3</sup>H]-D-aspartate uptake. Furthermore, we observed higher levels of GS and increased [<sup>3</sup>H]-D-aspartate uptake in the hippocampus of aged mice, although the activity of GS was similar between young and old mice. Analysis of a previously available RNAseq dataset of mice at different ages revealed upregulation of GLAST and GS mRNA levels in hippocampal astrocytes during aging. Corroborating these rodent data, we showed an increased number of GS + cells, and GS and GLT-1 levels/intensity in the hippocampus of elderly humans. Our data suggest that aged astrocytes undergo molecular and functional changes that control glutamate-glutamine homeostasis upon brain aging.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/af/85/10.1177_17590914231157974.PMC9950616.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9363191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01DOI: 10.1177/17590914231167230
Karen P Briski, Prabhat R Napit, Abdulrahman Alhamyani, Jérôme Leprince, A S M Hasan Mahmood
Central endozepinergic signaling is implicated in glucose homeostasis. Ventromedial hypothalamic nucleus (VMN) metabolic monitoring governs glucose counter-regulation. VMN glucose-stimulatory nitric oxide (NO) and glucose-inhibitory γ-aminobutyric acid (GABA) neurons express the energy gauge 5'-AMP-activated protein kinase (AMPK). Current research addresses the premise that the astrocyte glio-peptide octadecaneuropeptide (ODN) imposes sex-dimorphic control of metabolic sensor activity and neurotransmitter signaling in these neurons. The ODN G-protein coupled-receptor antagonist cyclo(1-8)[DLeu5]OP (LV-1075) was administered intracerebroventricularly (icv) to euglycemic rats of each sex; additional groups were pretreated icv with the ODN isoactive surrogate ODN11-18 (OP) before insulin-induced hypoglycemia. Western blotting of laser-catapult-microdissected VMN NO and GABA neurons showed that hypoglycemia caused OP-reversible augmentation of phospho-, e.g., activated AMPK and nitric oxide synthase (nNOS) expression in rostral (female) or middle (male) VMN segments or ODN-dependent suppression of nNOS in male caudal VMN. OP prevented hypoglycemic down-regulation of glutamate decarboxylase profiles in female rat rostral VMN, without affecting AMPK activity. LV-1075 treatment of male, not female rats elevated plasma glucagon and corticosterone concentrations. Moreover, OP attenuated hypoglycemia-associated augmentation of these hormones in males only. Results identify, for each sex, regional VMN metabolic transmitter signals that are subject to endozepinergic regulation. Directional shifts and gain-or-loss of ODN control during eu- versus hypoglycemia infer that VMN neuron receptivity to or post-receptor processing of this stimulus may be modulated by energy state. In male, counter-regulatory hormone secretion may be governed principally by ODN-sensitive neural pathways, whereas this endocrine outflow may be controlled by parallel, redundant ODN-dependent and -independent mechanisms in female.
{"title":"Sex-Dimorphic Octadecaneuropeptide (ODN) Regulation of Ventromedial Hypothalamic Nucleus Glucoregulatory Neuron Function and Counterregulatory Hormone Secretion.","authors":"Karen P Briski, Prabhat R Napit, Abdulrahman Alhamyani, Jérôme Leprince, A S M Hasan Mahmood","doi":"10.1177/17590914231167230","DOIUrl":"10.1177/17590914231167230","url":null,"abstract":"<p><p>Central endozepinergic signaling is implicated in glucose homeostasis. Ventromedial hypothalamic nucleus (VMN) metabolic monitoring governs glucose counter-regulation. VMN glucose-stimulatory nitric oxide (NO) and glucose-inhibitory γ-aminobutyric acid (GABA) neurons express the energy gauge 5'-AMP-activated protein kinase (AMPK). Current research addresses the premise that the astrocyte glio-peptide octadecaneuropeptide (ODN) imposes sex-dimorphic control of metabolic sensor activity and neurotransmitter signaling in these neurons. The ODN G-protein coupled-receptor antagonist cyclo<sub>(1-8)</sub>[DLeu<sup>5</sup>]OP (LV-1075) was administered intracerebroventricularly (<i>icv</i>) to euglycemic rats of each sex; additional groups were pretreated <i>icv</i> with the ODN isoactive surrogate ODN<sub>11-18</sub> (OP) before insulin-induced hypoglycemia. Western blotting of laser-catapult-microdissected VMN NO and GABA neurons showed that hypoglycemia caused OP-reversible augmentation of phospho-, e.g., activated AMPK and nitric oxide synthase (nNOS) expression in rostral (female) or middle (male) VMN segments or ODN-dependent suppression of nNOS in male caudal VMN. OP prevented hypoglycemic down-regulation of glutamate decarboxylase profiles in female rat rostral VMN, without affecting AMPK activity. LV-1075 treatment of male, not female rats elevated plasma glucagon and corticosterone concentrations. Moreover, OP attenuated hypoglycemia-associated augmentation of these hormones in males only. Results identify, for each sex, regional VMN metabolic transmitter signals that are subject to endozepinergic regulation. Directional shifts and gain-or-loss of ODN control during eu- versus hypoglycemia infer that VMN neuron receptivity to or post-receptor processing of this stimulus may be modulated by energy state. In male, counter-regulatory hormone secretion may be governed principally by ODN-sensitive neural pathways, whereas this endocrine outflow may be controlled by parallel, redundant ODN-dependent and -independent mechanisms in female.</p>","PeriodicalId":8616,"journal":{"name":"ASN NEURO","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c9/f9/10.1177_17590914231167230.PMC10196551.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9515615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}