Pub Date : 2024-11-23DOI: 10.1016/j.neuint.2024.105907
Martyna Nalepa , Beata Toczyłowska , Aleksandra Owczarek , Aleksandra Skweres , Elżbieta Ziemińska , Michał Węgrzynowicz
Arginase 2 (Arg2) is the predominant arginase isoenzyme in the brain, however its distribution appears to be limited to selected, region-specific subpopulations of cells. Although striatum is highly enriched with Arg2, precise localization and function of striatal Arg2 have never been studied. Here, we confirm that Arg2 is the only arginase isoenzyme in the striatum, and, using genetic model of total Arg2 loss, we show that Arg2 in this region is fully responsible for arginase catalytic activity, and its loss doesn't induce compensatory activation of Arg1. We exhibit that Arg2 is present in medium spiny neurons (MSNs), striatum-specific projecting neurons, where it localizes in soma and neuronal processes, and is absent in astrocytes or microglia. Finally, analysis of NMR spectroscopy-measured metabolic profiles of striata of Arg2-null mice enabled to recognize two metabolites (NADH and malonic acid) to be significantly altered compared to control animals. Multivariate comparison of the data using orthogonal projections to latent structures discriminant analysis, allowed for discrimination between control and Arg2-null mice and identified metabolites that contributed the most to this between-group dissimilarity. Our study reveals for the first time the localization of Arg2 in MSNs and demonstrates significant role of this enzyme in regulating striatal metabolism. These findings may be especially interesting in the context of Huntington's disease (HD), a disorder that specifically affects MSNs and in which, with the use of mouse models, the onset of pathological phenotypes was recently shown to be preceded by progressive impairment of striatal Arg2, a phenomenon of an unknown significance for disease pathogenesis.
{"title":"Striatum-enriched protein, arginase 2 localizes to medium spiny neurons and controls striatal metabolic profile","authors":"Martyna Nalepa , Beata Toczyłowska , Aleksandra Owczarek , Aleksandra Skweres , Elżbieta Ziemińska , Michał Węgrzynowicz","doi":"10.1016/j.neuint.2024.105907","DOIUrl":"10.1016/j.neuint.2024.105907","url":null,"abstract":"<div><div>Arginase 2 (Arg2) is the predominant arginase isoenzyme in the brain, however its distribution appears to be limited to selected, region-specific subpopulations of cells. Although striatum is highly enriched with Arg2, precise localization and function of striatal Arg2 have never been studied. Here, we confirm that Arg2 is the only arginase isoenzyme in the striatum, and, using genetic model of total Arg2 loss, we show that Arg2 in this region is fully responsible for arginase catalytic activity, and its loss doesn't induce compensatory activation of Arg1. We exhibit that Arg2 is present in medium spiny neurons (MSNs), striatum-specific projecting neurons, where it localizes in soma and neuronal processes, and is absent in astrocytes or microglia. Finally, analysis of NMR spectroscopy-measured metabolic profiles of striata of Arg2-null mice enabled to recognize two metabolites (NADH and malonic acid) to be significantly altered compared to control animals. Multivariate comparison of the data using orthogonal projections to latent structures discriminant analysis, allowed for discrimination between control and Arg2-null mice and identified metabolites that contributed the most to this between-group dissimilarity. Our study reveals for the first time the localization of Arg2 in MSNs and demonstrates significant role of this enzyme in regulating striatal metabolism. These findings may be especially interesting in the context of Huntington's disease (HD), a disorder that specifically affects MSNs and in which, with the use of mouse models, the onset of pathological phenotypes was recently shown to be preceded by progressive impairment of striatal Arg2, a phenomenon of an unknown significance for disease pathogenesis.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"182 ","pages":"Article 105907"},"PeriodicalIF":4.4,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708539","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}
Parkinson's disease (PD) is characterized by the formation of α-synuclein (α-syn) aggregates, which lead to dopaminergic neuronal degeneration. The incidence of PD increases with age, and senescence is considered to be a major risk factor for PD. In this study, we evaluated the effect of senescence on PD pathology using α-synuclein preformed fibrils (PFF) injection model in senescence-accelerated mice. We injected PFF into the substantia nigra (SN) of senescence-accelerated prone 8 (SAMP8) mice and senescence-accelerated resistant 1 (SAMR1) mice. At 24 weeks after injection of saline or PFF, we found that SAMP8 mice injected with PFF exhibited robust Lewy pathology and exacerbated degeneration of dopaminergic neurons in the SN compared to PFF-injected SAMR1 mice. We further observed an increase in the number of Iba1-positive cells in the brains of PFF-injected SAMP8 mice. RNA sequencing revealed that several genes related to neuroinflammation were upregulated in the brains of PFF-injected SAMP8 mice compared to SAMR1 mice. Inflammatory chemokine CC-chemokine ligand 21 (CCL21) was upregulated in PFF-injected SAMP8 mice and expressed in the glial cells of these mice. Our research indicates that accelerated senescence leads to persistent neuroinflammation, which plays an important role in the exacerbation of α-synucleinopathy.
{"title":"Accelerated senescence exacerbates α-synucleinopathy in senescence-accelerated prone 8 mice via persistent neuroinflammation","authors":"Hiroshi Sakiyama , Kousuke Baba , Yasuyoshi Kimura , Kotaro Ogawa , Ujiakira Nishiike , Hideki Hayakawa , Miki Yoshida , Cesar Aguirre , Kensuke Ikenaka , Seiichi Nagano , Hideki Mochizuki","doi":"10.1016/j.neuint.2024.105906","DOIUrl":"10.1016/j.neuint.2024.105906","url":null,"abstract":"<div><div>Parkinson's disease (PD) is characterized by the formation of α-synuclein (α-syn) aggregates, which lead to dopaminergic neuronal degeneration. The incidence of PD increases with age, and senescence is considered to be a major risk factor for PD. In this study, we evaluated the effect of senescence on PD pathology using α-synuclein preformed fibrils (PFF) injection model in senescence-accelerated mice. We injected PFF into the substantia nigra (SN) of senescence-accelerated prone 8 (SAMP8) mice and senescence-accelerated resistant 1 (SAMR1) mice. At 24 weeks after injection of saline or PFF, we found that SAMP8 mice injected with PFF exhibited robust Lewy pathology and exacerbated degeneration of dopaminergic neurons in the SN compared to PFF-injected SAMR1 mice. We further observed an increase in the number of Iba1-positive cells in the brains of PFF-injected SAMP8 mice. RNA sequencing revealed that several genes related to neuroinflammation were upregulated in the brains of PFF-injected SAMP8 mice compared to SAMR1 mice. Inflammatory chemokine <em>C</em>C-chemokine ligand 21 (CCL21) was upregulated in PFF-injected SAMP8 mice and expressed in the glial cells of these mice. Our research indicates that accelerated senescence leads to persistent neuroinflammation, which plays an important role in the exacerbation of α-synucleinopathy.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"182 ","pages":"Article 105906"},"PeriodicalIF":4.4,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142705326","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 : 2024-11-19DOI: 10.1016/j.neuint.2024.105905
Muhammad Kamal Hossain , Han Jung Chae
Dysfunctional intraneuronal organelles in Alzheimer's Disease (AD) propel aberrant calcium handling, triggering molecular miscommunication within organelles such as mitochondria, endoplasmic reticulum, and lysosomes. This disruption in organelle function not only impairs cellular homeostasis but also exacerbates neurodegenerative processes involving the accumulation of amyloid-β (Aβ) and hyperphosphorylated tau, amplifying the disease's vicious cycle. In this review, the concept of Mutual Orchestrated Inter-organelle Communication (MOIC) proposes potential therapeutic avenues for restoring Ca2+ homeostasis in AD, offering a theoretical framework for developing disease-modifying treatments. The intricate nature of AD necessitates a shift towards combination therapies targeting MOIC-associated pathways, presenting a more effective approach than monotherapy.
阿尔茨海默病（AD）患者的细胞内细胞器功能失调会导致钙处理失常，引发线粒体、内质网和溶酶体等细胞器内的分子交流失误。这种细胞器功能的紊乱不仅损害了细胞的稳态，还加剧了神经退行性过程，包括淀粉样蛋白-β（Aβ）和高磷酸化tau的积累，扩大了疾病的恶性循环。在这篇综述中，"相互协调的细胞器间通信（MOIC）"这一概念提出了恢复 AD 中 Ca2+ 平衡的潜在治疗途径，为开发改变疾病的治疗方法提供了一个理论框架。由于AD的复杂性，有必要转向针对MOIC相关通路的综合疗法，这是比单一疗法更有效的方法。
{"title":"Calcium balance through mutual orchestrated inter-organelle communication: A pleiotropic target for combating Alzheimer's disease","authors":"Muhammad Kamal Hossain , Han Jung Chae","doi":"10.1016/j.neuint.2024.105905","DOIUrl":"10.1016/j.neuint.2024.105905","url":null,"abstract":"<div><div>Dysfunctional intraneuronal organelles in Alzheimer's Disease (AD) propel aberrant calcium handling, triggering molecular miscommunication within organelles such as mitochondria, endoplasmic reticulum, and lysosomes. This disruption in organelle function not only impairs cellular homeostasis but also exacerbates neurodegenerative processes involving the accumulation of amyloid-β (Aβ) and hyperphosphorylated tau, amplifying the disease's vicious cycle. In this review, the concept of Mutual Orchestrated Inter-organelle Communication (MOIC) proposes potential therapeutic avenues for restoring Ca<sup>2+</sup> homeostasis in AD, offering a theoretical framework for developing disease-modifying treatments. The intricate nature of AD necessitates a shift towards combination therapies targeting MOIC-associated pathways, presenting a more effective approach than monotherapy.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"182 ","pages":"Article 105905"},"PeriodicalIF":4.4,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680422","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}
Traumatic Brain Injury (TBI) is a global healthcare concern with considerable mortality and morbidity. Early diagnosis and timely treatment are critical for optimal clinical prognosis in TBI patients. Injury to the brain tissue following TBI is categorized into primary and secondary injury events, with the former being acute, while the latter evolves over a long period. Although surgical intervention is effective to treat primary injury, secondary injury events that could contribute to long term neurological deterioration, cognitive impairment and neurodegeneration do not have appropriate pharmacotherapy. To address this lacuna, studies based on modern medicine to explore novel drugs in TBI have met with limited success. This has led to focussed efforts to assess natural products capable of targeting multiple pathways in TBI. Complex natural mixtures and isolated phytochemicals capable of targeting redox mechanisms, neuroinflammation, mitochondrial dysfunction, cell death pathways and other specific targets etc. have been characterized. However, the field has met with certain limitations and challenges with inadequate clinical studies and trials being the most important concern. The current review provides an overview of the dietary factors, nutraceuticals, natural extracts, and phytochemicals that could be potentially applied in neuroprotection, TBI therapy and long-term management of cognitive symptoms and other neurological deficits.
{"title":"Neuroprotective effects of nutraceuticals and natural products in traumatic brain injury","authors":"K.M. Bhargavi , Niya Gowthami , G.K. Chetan , M.M. Srinivas Bharath","doi":"10.1016/j.neuint.2024.105904","DOIUrl":"10.1016/j.neuint.2024.105904","url":null,"abstract":"<div><div>Traumatic Brain Injury (TBI) is a global healthcare concern with considerable mortality and morbidity. Early diagnosis and timely treatment are critical for optimal clinical prognosis in TBI patients. Injury to the brain tissue following TBI is categorized into primary and secondary injury events, with the former being acute, while the latter evolves over a long period. Although surgical intervention is effective to treat primary injury, secondary injury events that could contribute to long term neurological deterioration, cognitive impairment and neurodegeneration do not have appropriate pharmacotherapy. To address this lacuna, studies based on modern medicine to explore novel drugs in TBI have met with limited success. This has led to focussed efforts to assess natural products capable of targeting multiple pathways in TBI. Complex natural mixtures and isolated phytochemicals capable of targeting redox mechanisms, neuroinflammation, mitochondrial dysfunction, cell death pathways and other specific targets etc. have been characterized. However, the field has met with certain limitations and challenges with inadequate clinical studies and trials being the most important concern. The current review provides an overview of the dietary factors, nutraceuticals, natural extracts, and phytochemicals that could be potentially applied in neuroprotection, TBI therapy and long-term management of cognitive symptoms and other neurological deficits.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"182 ","pages":"Article 105904"},"PeriodicalIF":4.4,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646555","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 : 2024-11-13DOI: 10.1016/j.neuint.2024.105902
Xue Jiang , Yumei Wang , Zhaochen Lin , Chao Li , Qian Wang , Junyan Zhang , Xiuhua Liu , Ziye Li , Chao Cui
Neurodegenerative diseases (NDDs), as a neurological disorder characterised by neuronal degeneration and death, are a serious threat to human health and have long attracted attention due to their complex pathogenesis and the ineffectiveness of therapeutic drugs. Existing studies have shown that Polygonatum Sibiricum polysaccharides (PSP) have immunoregulatory, antioxidant, anti-inflammatory and other pharmacological effects, and their neuroprotective effects have been demonstrated in several scientific studies. This paper reviews the main pharmacological effects and mechanisms of PSP in the protection and treatment of NDDs, to provide a reference for the clinical application and basic research of PSP in NDDs.
{"title":"Polygonatum sibiricum polysaccharides: A promising strategy in the treatment of neurodegenerative disease","authors":"Xue Jiang , Yumei Wang , Zhaochen Lin , Chao Li , Qian Wang , Junyan Zhang , Xiuhua Liu , Ziye Li , Chao Cui","doi":"10.1016/j.neuint.2024.105902","DOIUrl":"10.1016/j.neuint.2024.105902","url":null,"abstract":"<div><div>Neurodegenerative diseases (NDDs), as a neurological disorder characterised by neuronal degeneration and death, are a serious threat to human health and have long attracted attention due to their complex pathogenesis and the ineffectiveness of therapeutic drugs. Existing studies have shown that <em>Polygonatum Sibiricum</em> polysaccharides (PSP) have immunoregulatory, antioxidant, anti-inflammatory and other pharmacological effects, and their neuroprotective effects have been demonstrated in several scientific studies. This paper reviews the main pharmacological effects and mechanisms of PSP in the protection and treatment of NDDs, to provide a reference for the clinical application and basic research of PSP in NDDs.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"181 ","pages":"Article 105902"},"PeriodicalIF":4.4,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611479","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 : 2024-11-13DOI: 10.1016/j.neuint.2024.105901
Cheng Lei , Jiaqi Wang , Xiaoyu Zhang , Xuemin Ge , Wei Zhao , Xinrong Li , Wei Jiang , Mingyu Ma , Zhenhai Wang , Shanshan Sun , Qingfei Kong , Hulun Li , Lili Mu , Jinghua Wang
Neuronal differentiation and neurite growth are essential processes in nervous system development and are regulated by several factors. Although all-trans retinoic acid (ATRA) has been shown to mediate the differentiation of mouse neuroblastoma cells via the activation of several pathways, including Wnt/β-catenin signaling, the mechanism remains unclear. The pyruvate kinase, muscle (PKM) plays an important role in the glycolysis of neuroblastoma cells and regulates the Wnt signaling pathway in various cancer cells. In this study, we hypothesized that the Wnt/PKM axis regulates the differentiation of neuroblastoma cells (Neuro-2a and N1E-115). To test this hypothesis, we used inhibitors and activators of the Wnt/β-catenin and glycolytic pathways in ATRA-induced differentiated Neuro-2a and N1E-115 cells and established cell lines with silenced or a mutant replacement of Pkm. Western blot and qPCR showed that ATRA treatment activated the Wnt signaling pathway and inhibited PKM-mediated glycolysis. The oxygen consumption rate (indicating oxidative phosphorylation) significantly increased, whereas the extracellular acidification rate (indicating glycolysis) significantly decreased during differentiation; these effects were reversed upon PKM inhibition. The Wnt inhibitor ICG-001 and PKM activator ML-265 inhibited ATRA-induced Neuro-2a and N1E-115 differentiation, whereas RNA interference-mediated Pkm silencing promoted Neuro-2a and N1E-115 differentiation, which was reversed by PKM overexpression. Treatment with the Wnt activator kenpaullone promoted Neuro-2a and N1E-115 differentiation, which was reversed by ML-265 administration. These results indicate that Wnt/β-catenin signaling promotes Neuro-2a and N1E-115 differentiation by inhibiting PKM-mediated glycolysis during ATRA-induced differentiation. These findings may provide a new theoretical basis for the role of glycolysis in nerve differentiation.
{"title":"The wnt/pyruvate kinase, muscle axis plays an essential role in the differentiation of mouse neuroblastoma cells","authors":"Cheng Lei , Jiaqi Wang , Xiaoyu Zhang , Xuemin Ge , Wei Zhao , Xinrong Li , Wei Jiang , Mingyu Ma , Zhenhai Wang , Shanshan Sun , Qingfei Kong , Hulun Li , Lili Mu , Jinghua Wang","doi":"10.1016/j.neuint.2024.105901","DOIUrl":"10.1016/j.neuint.2024.105901","url":null,"abstract":"<div><div>Neuronal differentiation and neurite growth are essential processes in nervous system development and are regulated by several factors. Although all-trans retinoic acid (ATRA) has been shown to mediate the differentiation of mouse neuroblastoma cells via the activation of several pathways, including Wnt/β-catenin signaling, the mechanism remains unclear. The pyruvate kinase, muscle (PKM) plays an important role in the glycolysis of neuroblastoma cells and regulates the Wnt signaling pathway in various cancer cells. In this study, we hypothesized that the Wnt/PKM axis regulates the differentiation of neuroblastoma cells (Neuro-2a and N1E-115). To test this hypothesis, we used inhibitors and activators of the Wnt/β-catenin and glycolytic pathways in ATRA-induced differentiated Neuro-2a and N1E-115 cells and established cell lines with silenced or a mutant replacement of Pkm. Western blot and qPCR showed that ATRA treatment activated the Wnt signaling pathway and inhibited PKM-mediated glycolysis. The oxygen consumption rate (indicating oxidative phosphorylation) significantly increased, whereas the extracellular acidification rate (indicating glycolysis) significantly decreased during differentiation; these effects were reversed upon PKM inhibition. The Wnt inhibitor ICG-001 and PKM activator ML-265 inhibited ATRA-induced Neuro-2a and N1E-115 differentiation, whereas RNA interference-mediated Pkm silencing promoted Neuro-2a and N1E-115 differentiation, which was reversed by PKM overexpression. Treatment with the Wnt activator kenpaullone promoted Neuro-2a and N1E-115 differentiation, which was reversed by ML-265 administration. These results indicate that Wnt/β-catenin signaling promotes Neuro-2a and N1E-115 differentiation by inhibiting PKM-mediated glycolysis during ATRA-induced differentiation. These findings may provide a new theoretical basis for the role of glycolysis in nerve differentiation.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"181 ","pages":"Article 105901"},"PeriodicalIF":4.4,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611483","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 : 2024-11-12DOI: 10.1016/j.neuint.2024.105899
Ingvild E. Bjerke , Harry Carey , Jan G. Bjaalie , Trygve B. Leergaard , Jee Hyun Kim
The dopaminergic system of the brain is involved in complex cognitive functioning and undergoes extensive reorganization during development. Yet, these changes are poorly characterized. We have quantified the density of dopamine 1- and 2-receptor (D1 and D2) positive cells across the forebrain of male and female mice at five developmental stages using validated transgenic mice expressing green fluorescent protein in cells producing D1 or D2 mRNA. After analyzing >4,500 coronal brain images, a cortico-subcortical shift in D1/D2 balance was discovered, with increasing D1 dominance in cortical regions as a maturational pattern that occurs earlier in females. We describe postnatal trajectories of D1 and D2 cell densities across major brain regions and observe increasing regional differentiation of D1 densities through development. Our results provide the most comprehensive overview of the developing dopaminergic system to date, and an empirical foundation for further experimental and computational investigations of dopaminergic signaling.
{"title":"The developing mouse dopaminergic system: Cortical-subcortical shift in D1/D2 receptor balance and increasing regional differentiation","authors":"Ingvild E. Bjerke , Harry Carey , Jan G. Bjaalie , Trygve B. Leergaard , Jee Hyun Kim","doi":"10.1016/j.neuint.2024.105899","DOIUrl":"10.1016/j.neuint.2024.105899","url":null,"abstract":"<div><div>The dopaminergic system of the brain is involved in complex cognitive functioning and undergoes extensive reorganization during development. Yet, these changes are poorly characterized. We have quantified the density of dopamine 1- and 2-receptor (D1 and D2) positive cells across the forebrain of male and female mice at five developmental stages using validated transgenic mice expressing green fluorescent protein in cells producing D1 or D2 mRNA. After analyzing >4,500 coronal brain images, a cortico-subcortical shift in D1/D2 balance was discovered, with increasing D1 dominance in cortical regions as a maturational pattern that occurs earlier in females. We describe postnatal trajectories of D1 and D2 cell densities across major brain regions and observe increasing regional differentiation of D1 densities through development. Our results provide the most comprehensive overview of the developing dopaminergic system to date, and an empirical foundation for further experimental and computational investigations of dopaminergic signaling.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"182 ","pages":"Article 105899"},"PeriodicalIF":4.4,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611482","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 : 2024-11-08DOI: 10.1016/j.neuint.2024.105900
Chusana Mekhora , Daniel J. Lamport , Jeremy P.E. Spencer
Inflammation has been associated with cognitive decline, whether in the peripheral or central nervous systems. The primary mechanism involves the response of microglia, an immune cell in the brain, which generates pro-inflammatory mediators such as cytokines, chemokines, and adhesion molecules. The excessive production of pro-inflammatory mediators may accelerate the damage to neurons, contributing to the development of neurodegenerative diseases such as Alzheimer's disease, mild cognitive impairment, and vascular dementia, as well as a general decline in cognitive function. Various studies have supported the correlation between elevated pro-inflammatory mediators and a decline in cognitive function, particularly in aging and age-related neurodegenerative diseases. Moreover, this association has also been observed in other inflammatory-related conditions, including post-operative cognitive impairment, diabetes, stroke, obesity, and cancer. However, the interaction between inflammatory processes and cognitive function in humans remains unclear and varies according to different health conditions. Therefore, this review aims to consolidate and evaluate the available evidence from original studies as well as meta-analyses in order to provide a greater understanding of the inflammatory process in connection with cognitive function in humans. Furthermore, relevant biological cellular processes, putative inflammatory biomarkers, and the role of nutraceuticals on the interaction between cognitive performance and inflammatory status are outlined.
{"title":"An overview of the relationship between inflammation and cognitive function in humans, molecular pathways and the impact of nutraceuticals","authors":"Chusana Mekhora , Daniel J. Lamport , Jeremy P.E. Spencer","doi":"10.1016/j.neuint.2024.105900","DOIUrl":"10.1016/j.neuint.2024.105900","url":null,"abstract":"<div><div>Inflammation has been associated with cognitive decline, whether in the peripheral or central nervous systems. The primary mechanism involves the response of microglia, an immune cell in the brain, which generates pro-inflammatory mediators such as cytokines, chemokines, and adhesion molecules. The excessive production of pro-inflammatory mediators may accelerate the damage to neurons, contributing to the development of neurodegenerative diseases such as Alzheimer's disease, mild cognitive impairment, and vascular dementia, as well as a general decline in cognitive function. Various studies have supported the correlation between elevated pro-inflammatory mediators and a decline in cognitive function, particularly in aging and age-related neurodegenerative diseases. Moreover, this association has also been observed in other inflammatory-related conditions, including post-operative cognitive impairment, diabetes, stroke, obesity, and cancer. However, the interaction between inflammatory processes and cognitive function in humans remains unclear and varies according to different health conditions. Therefore, this review aims to consolidate and evaluate the available evidence from original studies as well as meta-analyses in order to provide a greater understanding of the inflammatory process in connection with cognitive function in humans. Furthermore, relevant biological cellular processes, putative inflammatory biomarkers, and the role of nutraceuticals on the interaction between cognitive performance and inflammatory status are outlined.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"181 ","pages":"Article 105900"},"PeriodicalIF":4.4,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611486","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 : 2024-11-08DOI: 10.1016/j.neuint.2024.105898
Ediandra Tissot Castro , Rafael Teixeira Ribeiro , Andrey Vinicios Soares Carvalho , Diorlon Nunes Machado , Ângela Beatris Zemniaçak , Rafael Palavro , Sâmela de Azevedo Cunha , Tailine Quevedo Tavares , Diogo Onofre Gomes de Souza , Carlos Alexandre Netto , Guilhian Leipnitz , Alexandre Umpierrez Amaral , Moacir Wajner
Patients with glutaric acidemia type I (GA I) manifest motor and intellectual disabilities whose pathogenesis has been so far poorly explored. Therefore, we evaluated neuromotor and cognitive abilities, as well as histopathological and immunohistochemical features in the cerebral cortex and striatum of glutaryl-CoA dehydrogenase (GCDH) deficient knockout mice (Gcdh−/−), a well-recognized model of GA I. The effects of a single intracerebroventricular glutaric acid (GA) injection in one-day-old pups on the same neurobehavioral and histopathological/immunohistochemical endpoints were also investigated. Seven-day-old Gcdh−/− mice presented altered gait, whereas those receiving a GA neonatal administration manifested other sensorimotor deficits, including an abnormal response to negative geotaxis, cliff aversion and righting reflex, and muscle tone impairment. Compared to the WT mice, adult Gcdh−/− mice exhibited motor impairment, evidenced by poor performance in the Rota-rod test. Furthermore, neonatal GA administration provoked long-standing short- and long-term memory impairment in adult Gcdh−/− mice. Regarding the histopathological features, a significant increase in vacuoles and neurodegenerative cells was observed in both the cerebral cortex and striatum of 15- and 60-day-old Gcdh−/− mice and was more pronounced in mice injected with GA. Neuronal loss (decrease of NeuN staining) was also significantly increased in the cerebral cortex and striatum of Gcdh−/− mice, particularly in those neonatally injected with GA. In contrast, immunohistochemistry of MBP, astrocytic proteins GFAP and S100B, and the microglial marker Iba1 was not changed in 60-day-old Gcdh−/− mice, suggesting no myelination disturbance, reactive astrogliosis, and microglia activation, respectively. These data highlight the neurotoxicity of GA and the importance of early treatment aiming to decrease GA accumulation at early stages of development to prevent brain damage and learning/memory disabilities in GA I patients.
戊二酸血症 I 型（GA I）患者表现为运动和智力障碍，其发病机制迄今为止尚未得到深入研究。因此，我们评估了谷草酰-CoA脱氢酶（GCDH）缺陷基因敲除小鼠（Gcdh-/-）的神经运动和认知能力以及大脑皮层和纹状体的组织病理学和免疫组化特征。我们还研究了对出生一天的幼鼠脑室内注射一次戊二酸（GA）对相同的神经行为和组织病理学/免疫组化终点的影响。七日龄的 Gcdh-/- 小鼠步态发生改变，而那些接受 GA 新生儿给药的小鼠则表现出其他感觉运动缺陷，包括对负向地轴、悬崖厌恶和向右转反射的异常反应，以及肌张力损伤。与 WT 小鼠相比，成年 Gcdh-/- 小鼠表现出运动障碍，这体现在罗盘杆试验中的不良表现。此外，新生儿给予GA会引起成年Gcdh-/-小鼠长期的短期和长期记忆障碍。在组织病理学特征方面，在15天和60天大的Gcdh-/-小鼠的大脑皮层和纹状体中都观察到空泡和神经退行性细胞显著增加，在注射GA的小鼠中更为明显。在 Gcdh-/- 小鼠的大脑皮层和纹状体中，神经元丢失（NeuN 染色减少）也显著增加，尤其是在新生儿注射 GA 的小鼠中。与此相反，在 60 天大的 Gcdh-/- 小鼠中，MBP、星形胶质细胞蛋白 GFAP 和 S100B 以及小胶质细胞标记物 Iba1 的免疫组化结果没有变化，这分别表明没有髓鞘化紊乱、反应性星形胶质细胞增生和小胶质细胞活化。这些数据突显了GA的神经毒性以及早期治疗的重要性，早期治疗旨在减少GA在发育早期的积累，以防止GA I患者的脑损伤和学习/记忆障碍。
{"title":"Impairment of neuromotor development and cognition associated with histopathological and neurochemical abnormalities in the cerebral cortex and striatum of glutaryl-CoA dehydrogenase deficient mice","authors":"Ediandra Tissot Castro , Rafael Teixeira Ribeiro , Andrey Vinicios Soares Carvalho , Diorlon Nunes Machado , Ângela Beatris Zemniaçak , Rafael Palavro , Sâmela de Azevedo Cunha , Tailine Quevedo Tavares , Diogo Onofre Gomes de Souza , Carlos Alexandre Netto , Guilhian Leipnitz , Alexandre Umpierrez Amaral , Moacir Wajner","doi":"10.1016/j.neuint.2024.105898","DOIUrl":"10.1016/j.neuint.2024.105898","url":null,"abstract":"<div><div>Patients with glutaric acidemia type I (GA I) manifest motor and intellectual disabilities whose pathogenesis has been so far poorly explored. Therefore, we evaluated neuromotor and cognitive abilities, as well as histopathological and immunohistochemical features in the cerebral cortex and striatum of glutaryl-CoA dehydrogenase (GCDH) deficient knockout mice (<em>Gcdh</em><sup><em>−/−</em></sup>), a well-recognized model of GA I. The effects of a single intracerebroventricular glutaric acid (GA) injection in one-day-old pups on the same neurobehavioral and histopathological/immunohistochemical endpoints were also investigated. Seven-day-old <em>Gcdh</em><sup><em>−/−</em></sup> mice presented altered gait, whereas those receiving a GA neonatal administration manifested other sensorimotor deficits, including an abnormal response to negative geotaxis, cliff aversion and righting reflex, and muscle tone impairment. Compared to the WT mice, adult <em>Gcdh−/−</em> mice exhibited motor impairment, evidenced by poor performance in the Rota-rod test. Furthermore, neonatal GA administration provoked long-standing short- and long-term memory impairment in adult <em>Gcdh</em><sup><em>−/−</em></sup> mice. Regarding the histopathological features, a significant increase in vacuoles and neurodegenerative cells was observed in both the cerebral cortex and striatum of 15- and 60-day-old Gcd<em>h−/−</em> mice and was more pronounced in mice injected with GA. Neuronal loss (decrease of NeuN staining) was also significantly increased in the cerebral cortex and striatum of <em>Gcdh</em><sup><em>−/−</em></sup> mice, particularly in those neonatally injected with GA. In contrast, immunohistochemistry of MBP, astrocytic proteins GFAP and S100B, and the microglial marker Iba1 was not changed in 60-day-old Gcdh−/− mice, suggesting no myelination disturbance, reactive astrogliosis, and microglia activation, respectively. These data highlight the neurotoxicity of GA and the importance of early treatment aiming to decrease GA accumulation at early stages of development to prevent brain damage and learning/memory disabilities in GA I patients.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"181 ","pages":"Article 105898"},"PeriodicalIF":4.4,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611499","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 : 2024-11-06DOI: 10.1016/j.neuint.2024.105897
Ashmita Das , Vikas Rajput , Durlav Chowdhury , Rajesh Choudhary , Surendra H. Bodakhe
Alzheimer's disease (AD) is a neurodegenerative disorder that is the fifth most common cause of mortality worldwide and the second most common cause of death in developed countries. The etiology of AD remains poorly understood; however, it is correlated with the accumulation of proteins in the brain, ultimately leading to cellular damage. Multiple factors, including genetic and environmental factors such as chemicals or food, have been linked to protein aggregation and cell death in AD. Boron is a vital micronutrient that is necessary for plant growth and is abundantly present in various fruits and nuts. Prior research has emphasized the importance of boron as a neuroprotective agent and necessary component for the preservation of brain health and function. However, the precise function of boron in the brain remains poorly understood. This review elucidates the molecular role of boron in the brain by examining existing information about its impact on neurodegenerative diseases and may provide a deeper understanding of the etiology of AD and, ultimately, lead to the development of novel approaches for its treatment.
{"title":"Boron: An intriguing factor in retarding Alzheimer's progression","authors":"Ashmita Das , Vikas Rajput , Durlav Chowdhury , Rajesh Choudhary , Surendra H. Bodakhe","doi":"10.1016/j.neuint.2024.105897","DOIUrl":"10.1016/j.neuint.2024.105897","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a neurodegenerative disorder that is the fifth most common cause of mortality worldwide and the second most common cause of death in developed countries. The etiology of AD remains poorly understood; however, it is correlated with the accumulation of proteins in the brain, ultimately leading to cellular damage. Multiple factors, including genetic and environmental factors such as chemicals or food, have been linked to protein aggregation and cell death in AD. Boron is a vital micronutrient that is necessary for plant growth and is abundantly present in various fruits and nuts. Prior research has emphasized the importance of boron as a neuroprotective agent and necessary component for the preservation of brain health and function. However, the precise function of boron in the brain remains poorly understood. This review elucidates the molecular role of boron in the brain by examining existing information about its impact on neurodegenerative diseases and may provide a deeper understanding of the etiology of AD and, ultimately, lead to the development of novel approaches for its treatment.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"181 ","pages":"Article 105897"},"PeriodicalIF":4.4,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611497","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}
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