Miguel Perez-Pouchoulen, Amanda S. Holley, E. Reinl, J. VanRyzin, Amir Mehrabani, Christie Dionisos, Muhammed Mirza, Margaret M. McCarthy
To study the effect of viral inflammation induced by Polyinosinic:polycytidylic acid (PIC) on the cerebellum during a critical period of development in rats. Neonatal rat pups were treated with PIC on postnatal days (PN) 8 and 10 after which we quantified RNA using Nanostring, qRT-PCR and RNAscope and analyzed immune cells through flow cytometry and immunohistochemistry on PN11. Using the same paradigm, we also analyzed play juvenile behavior, anxiety-like behavior, motor balance using the balance beam and the rotarod assays as well as fine motor behavior using the sunflower seed opening test. We determined that male and female pups treated with PIC reacted with a significant increase in CCL5, a chemotactic cytokine that attracts T-cells, eosinophils and basophils to the site of inflammation, at PN11. PIC treatment also increased the expression of two receptors for CCL5, CCR1 and CCR5 in the cerebellar vermis in both males and females at PN11. In-situ hybridization (RNAscope®) for specific transcripts revealed that microglia express both CCL5 receptors under inflammatory and non-inflammatory conditions in both males and females. PIC treatment also increased the total number of CCL5+ cells in the developing cerebellum which were determined to be both natural killer cells and T-cells. There were modest but significant impacts of PIC treatment on large and fine motor skills and juvenile play behavior. Our findings suggest an important role for CCL5 and other immune cells in mediating inflammation in the developing cerebellum that potentially impact the maturation of cerebellar neurons during a critical period of development.
{"title":"Viral-mediated inflammation by Poly I:C induces the chemokine CCL5 in NK cells and its receptors CCR1 and CCR5 in microglia in the neonatal rat cerebellum","authors":"Miguel Perez-Pouchoulen, Amanda S. Holley, E. Reinl, J. VanRyzin, Amir Mehrabani, Christie Dionisos, Muhammed Mirza, Margaret M. McCarthy","doi":"10.1515/nipt-2024-0002","DOIUrl":"https://doi.org/10.1515/nipt-2024-0002","url":null,"abstract":"\u0000 \u0000 \u0000 To study the effect of viral inflammation induced by Polyinosinic:polycytidylic acid (PIC) on the cerebellum during a critical period of development in rats.\u0000 \u0000 \u0000 \u0000 Neonatal rat pups were treated with PIC on postnatal days (PN) 8 and 10 after which we quantified RNA using Nanostring, qRT-PCR and RNAscope and analyzed immune cells through flow cytometry and immunohistochemistry on PN11. Using the same paradigm, we also analyzed play juvenile behavior, anxiety-like behavior, motor balance using the balance beam and the rotarod assays as well as fine motor behavior using the sunflower seed opening test.\u0000 \u0000 \u0000 \u0000 We determined that male and female pups treated with PIC reacted with a significant increase in CCL5, a chemotactic cytokine that attracts T-cells, eosinophils and basophils to the site of inflammation, at PN11. PIC treatment also increased the expression of two receptors for CCL5, CCR1 and CCR5 in the cerebellar vermis in both males and females at PN11. In-situ hybridization (RNAscope®) for specific transcripts revealed that microglia express both CCL5 receptors under inflammatory and non-inflammatory conditions in both males and females. PIC treatment also increased the total number of CCL5+ cells in the developing cerebellum which were determined to be both natural killer cells and T-cells. There were modest but significant impacts of PIC treatment on large and fine motor skills and juvenile play behavior.\u0000 \u0000 \u0000 \u0000 Our findings suggest an important role for CCL5 and other immune cells in mediating inflammation in the developing cerebellum that potentially impact the maturation of cerebellar neurons during a critical period of development.\u0000","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"58 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140666895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Laird, Alexandra Anh Le, J. Kulbe, A. Umlauf, Melody Sagarian, Matthew Spencer, Anish Sathe, D. Grelotti, J. Iudicello, Brook Henry, Ronald J. Ellis, J. Fields
People with HIV (PWH) have high rates of depression and neurocognitive impairment (NCI) despite viral suppression on antiretroviral therapy (ART). Mounting evidence suggests that immunometabolic disruptions may contribute to these conditions in some PWH. We hypothesized that metabolic dysfunction in astrocytes is associated with depressive symptoms and cognitive function in PWH. Human astrocytes were exposed to sera from PWH (n=40) with varying degrees of depressive symptomatology and cognitive function. MitoTrackerTM Deep Red FM (MT) was used to visualize mitochondrial activity and glial fibrillary acidic protein (GFAP) as an indicator of astrocyte reactivity using the high-throughput fluorescent microscopy and image analyses platform, CellInsight CX5 (CX5). The Seahorse platform was used to assess glycolytic and mitochondrial metabolism. More severe depression, as indexed by higher Beck's Depression Inventory (BDI-II) scores, was associated with lower MT signal measures. Better cognitive function, as assessed by neuropsychiatric testing t-scores, was associated with increased MT signal measures. GFAP intensity negatively correlated with several cognitive t-scores. Age positively correlated with (higher) MT signal measures and GFAP intensity. Worse depressive symptoms (higher BDI-II scores) were associated with decreased oxygen consumption rate and spare respiratory capacity, concomitant with increased extracellular acidification rate in astrocytes. These findings show that factors in the sera of PWH alter mitochondrial activity in cultured human astrocytes, suggesting that mechanisms that alter mitochondrial and astrocyte homeostasis can be detected peripherally. Thus, in vitro cultures may provide a model to identify neuropathogenic mechanisms of depression or neurocognitive impairment in PWH and test personalized therapeutics for neurologic and psychiatric disorders.
尽管抗逆转录病毒疗法（ART）能抑制病毒，但艾滋病病毒感染者（PWH）的抑郁症和神经认知障碍（NCI）发病率很高。越来越多的证据表明，免疫代谢紊乱可能是导致一些艾滋病病毒感染者出现这些症状的原因。我们假设星形胶质细胞的代谢功能障碍与 PWH 的抑郁症状和认知功能有关。 我们将人类星形胶质细胞暴露于有不同程度抑郁症状和认知功能的 PWH（40 人）的血清中。利用高通量荧光显微镜和图像分析平台 CellInsight CX5 (CX5)，使用 MitoTrackerTM Deep Red FM (MT) 观察线粒体活性和作为星形胶质细胞反应性指标的胶质纤维酸性蛋白 (GFAP)。海马平台用于评估糖酵解和线粒体代谢。 贝克抑郁量表（BDI-II）评分越高，抑郁程度越严重，MT信号测量值越低。通过神经精神测试 t 分数评估的较好认知功能与 MT 信号测量值的增加有关。GFAP 强度与几项认知能力 t 分数呈负相关。年龄与（较高的）MT 信号测量值和 GFAP 强度呈正相关。抑郁症状加重（BDI-II 评分升高）与耗氧量和剩余呼吸量减少有关，同时与星形胶质细胞细胞外酸化率升高有关。 这些研究结果表明，PWH 血清中的因子会改变培养的人类星形胶质细胞的线粒体活性，这表明可以从外围检测到改变线粒体和星形胶质细胞平衡的机制。因此，体外培养可为确定 PWH 抑郁症或神经认知障碍的神经致病机制提供模型，并测试神经和精神疾病的个性化疗法。
{"title":"Sera from people with HIV and depression induce commensurate metabolic alterations in astrocytes: toward precision diagnoses and therapies","authors":"A. Laird, Alexandra Anh Le, J. Kulbe, A. Umlauf, Melody Sagarian, Matthew Spencer, Anish Sathe, D. Grelotti, J. Iudicello, Brook Henry, Ronald J. Ellis, J. Fields","doi":"10.1515/nipt-2024-0001","DOIUrl":"https://doi.org/10.1515/nipt-2024-0001","url":null,"abstract":"\u0000 \u0000 \u0000 People with HIV (PWH) have high rates of depression and neurocognitive impairment (NCI) despite viral suppression on antiretroviral therapy (ART). Mounting evidence suggests that immunometabolic disruptions may contribute to these conditions in some PWH. We hypothesized that metabolic dysfunction in astrocytes is associated with depressive symptoms and cognitive function in PWH.\u0000 \u0000 \u0000 \u0000 Human astrocytes were exposed to sera from PWH (n=40) with varying degrees of depressive symptomatology and cognitive function. MitoTrackerTM Deep Red FM (MT) was used to visualize mitochondrial activity and glial fibrillary acidic protein (GFAP) as an indicator of astrocyte reactivity using the high-throughput fluorescent microscopy and image analyses platform, CellInsight CX5 (CX5). The Seahorse platform was used to assess glycolytic and mitochondrial metabolism. \u0000 \u0000 \u0000 \u0000 More severe depression, as indexed by higher Beck's Depression Inventory (BDI-II) scores, was associated with lower MT signal measures. Better cognitive function, as assessed by neuropsychiatric testing t-scores, was associated with increased MT signal measures. GFAP intensity negatively correlated with several cognitive t-scores. Age positively correlated with (higher) MT signal measures and GFAP intensity. Worse depressive symptoms (higher BDI-II scores) were associated with decreased oxygen consumption rate and spare respiratory capacity, concomitant with increased extracellular acidification rate in astrocytes.\u0000 \u0000 \u0000 \u0000 These findings show that factors in the sera of PWH alter mitochondrial activity in cultured human astrocytes, suggesting that mechanisms that alter mitochondrial and astrocyte homeostasis can be detected peripherally. Thus, in vitro cultures may provide a model to identify neuropathogenic mechanisms of depression or neurocognitive impairment in PWH and test personalized therapeutics for neurologic and psychiatric disorders.\u0000","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"62 26","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140376610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tay-Sachs disease (TSD) and its severe form Sandhoff disease (SD) are autosomal recessive lysosomal storage metabolic disorders, which often result into excessive GM2 ganglioside accumulation predominantly in lysosomes of nerve cells. Although patients with these diseases appear normal at birth, the progressive accumulation of undegraded GM2 gangliosides in neurons leads to early death accompanied by manifestation of motor difficulties and gradual loss of behavioral skills. Unfortunately, there is still no effective treatment available for TSD/SD. The present study highlights the importance of cinnamic acid (CA), a naturally occurring aromatic fatty acid present in a number of plants, in inhibiting the disease process in a transgenic mouse model of SD. Oral administration of CA significantly attenuated glial activation and inflammation and reduced the accumulation of GM2 gangliosides/glycoconjugates in the cerebral cortex of Sandhoff mice. Besides, oral CA also improved behavioral performance and increased the survival of Sandhoff mice. While assessing the mechanism, we found that oral administration of CA increased the level of peroxisome proliferator-activated receptor α (PPARα) in the brain of Sandhoff mice and that oral CA remained unable to reduce glycoconjugates, improve behavior and increase survival in Sandhoff mice lacking PPARα. Our results indicate a beneficial function of CA that utilizes a PPARα-dependent mechanism to halt the progression of SD and thereby increase the longevity of Sandhoff mice.
{"title":"Cinnamic acid, a natural plant compound, exhibits neuroprotection in a mouse model of Sandhoff disease via PPARα","authors":"S. Raha, Ramesh K Paidi, Debashis Dutta, K. Pahan","doi":"10.1515/nipt-2023-0027","DOIUrl":"https://doi.org/10.1515/nipt-2023-0027","url":null,"abstract":"\u0000 Tay-Sachs disease (TSD) and its severe form Sandhoff disease (SD) are autosomal recessive lysosomal storage metabolic disorders, which often result into excessive GM2 ganglioside accumulation predominantly in lysosomes of nerve cells. Although patients with these diseases appear normal at birth, the progressive accumulation of undegraded GM2 gangliosides in neurons leads to early death accompanied by manifestation of motor difficulties and gradual loss of behavioral skills. Unfortunately, there is still no effective treatment available for TSD/SD. The present study highlights the importance of cinnamic acid (CA), a naturally occurring aromatic fatty acid present in a number of plants, in inhibiting the disease process in a transgenic mouse model of SD. Oral administration of CA significantly attenuated glial activation and inflammation and reduced the accumulation of GM2 gangliosides/glycoconjugates in the cerebral cortex of Sandhoff mice. Besides, oral CA also improved behavioral performance and increased the survival of Sandhoff mice. While assessing the mechanism, we found that oral administration of CA increased the level of peroxisome proliferator-activated receptor α (PPARα) in the brain of Sandhoff mice and that oral CA remained unable to reduce glycoconjugates, improve behavior and increase survival in Sandhoff mice lacking PPARα. Our results indicate a beneficial function of CA that utilizes a PPARα-dependent mechanism to halt the progression of SD and thereby increase the longevity of Sandhoff mice.","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"14 30","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140240491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. M. Abdelmoaty, Rana Kadry, R. Mosley, H. Gendelman
Alternative medicines commonly supplement or, at times, replace standard medical treatment. One area of increasing attention is disease-modifying medicines for neurodegenerative diseases. However, few such alternatives have been investigated thoroughly with an eye towards understanding mechanisms of action for clinical use. Medicinal mushrooms have important health benefits and pharmacological activities with anti-inflammatory, antioxidant, antibacterial, antiviral, immunomodulatory, digestive, cytoprotective, homeostatic, and neuroprotective activities. Edible mushrooms are known to play roles in preventing age-related diseases. Several studies have revealed that polysaccharides, terpenes, and phenolic compounds are chemical components derived from mushrooms with pharmacological activities. Due to limited effective protocols for mushroom protein extraction for proteomic studies, information about these medicinally related proteins and their biological functions remains enigmatic. Herein, we have performed proteomic studies of two mushroom species Laricifomes officinalis (agarikon) and Grifola frondosa (maitake). These studies serve to uncover a foundation for putative proteome-associated neuroprotective processes. The recovered proteins from both species show multiple cell-specific signaling pathways including unfolded protein response, and mitochondrial protein import as well as those linked to BAG2, ubiquitination, apoptosis, microautophagy, glycolysis, SNARE, and immunogenic cell signaling pathways. This study uncovered mushroom proteome-associated proteins which serve to better understand the structural and functional properties of mushrooms used as alternative medicines for broad potential health benefits.
{"title":"Neuroprotective mushrooms","authors":"M. M. Abdelmoaty, Rana Kadry, R. Mosley, H. Gendelman","doi":"10.1515/nipt-2024-0004","DOIUrl":"https://doi.org/10.1515/nipt-2024-0004","url":null,"abstract":"\u0000 \u0000 \u0000 Alternative medicines commonly supplement or, at times, replace standard medical treatment. One area of increasing attention is disease-modifying medicines for neurodegenerative diseases. However, few such alternatives have been investigated thoroughly with an eye towards understanding mechanisms of action for clinical use. Medicinal mushrooms have important health benefits and pharmacological activities with anti-inflammatory, antioxidant, antibacterial, antiviral, immunomodulatory, digestive, cytoprotective, homeostatic, and neuroprotective activities. Edible mushrooms are known to play roles in preventing age-related diseases. Several studies have revealed that polysaccharides, terpenes, and phenolic compounds are chemical components derived from mushrooms with pharmacological activities. Due to limited effective protocols for mushroom protein extraction for proteomic studies, information about these medicinally related proteins and their biological functions remains enigmatic.\u0000 \u0000 \u0000 \u0000 Herein, we have performed proteomic studies of two mushroom species Laricifomes officinalis (agarikon) and Grifola frondosa (maitake).\u0000 \u0000 \u0000 \u0000 These studies serve to uncover a foundation for putative proteome-associated neuroprotective processes. The recovered proteins from both species show multiple cell-specific signaling pathways including unfolded protein response, and mitochondrial protein import as well as those linked to BAG2, ubiquitination, apoptosis, microautophagy, glycolysis, SNARE, and immunogenic cell signaling pathways.\u0000 \u0000 \u0000 \u0000 This study uncovered mushroom proteome-associated proteins which serve to better understand the structural and functional properties of mushrooms used as alternative medicines for broad potential health benefits.\u0000","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"27 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140261737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Human immunodeficiency virus 1 (HIV-1) can invade the central nervous system (CNS) early during infection and persist in the CNS for life despite effective antiretroviral treatment. Infection and activation of residential glial cells lead to low viral replication and chronic inflammation, which damage neurons contributing to a spectrum of HIV-associated neurocognitive disorders (HAND). Substance use, including methamphetamine (METH), can increase one’s risk and severity of HAND. Here, we investigate HIV-1/METH co-treatment in a key neurosupportive glial cell, astrocytes. Specifically, mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) signaling pathways, such as calcium and the unfolded protein response (UPR), are key mechanisms underlying HAND pathology and arise as potential targets to combat astrocyte dysfunction. Primary human astrocytes were transduced with a pseudotyped HIV-1 model and exposed to low-dose METH for seven days. We assessed changes in astrocyte HIV-1 infection, inflammation, mitochondrial antioxidant and dynamic protein expression, respiratory acitivity, mitochondrial calcium flux, and UPR/MAM mediator expression. We then tested a selective antagonist for METH-binding receptor, trace amine-associated receptor 1 (TAAR1) as a potetnial upstream regulator of METH-induced calcium flux and UPR/MAM mediator expression. Chronic METH exposure increased astrocyte HIV-1 infection. Moreover, HIV-1/METH co-treatment suppressed astrocyte antioxidant and metabolic capacity while increasing mitochondrial calcium load and protein expression of UPR messengers and MAM mediators. Notably, HIV-1 increases astrocyte TAAR1 expression, thus, could be a critical regulator of HIV-1/METH co-treatment in astrocytes. Indeed, selective antagonism of TAAR1 significantly inhibited cytosolic calcium flux and induction of UPR/MAM protein expression. Altogether, our findings demonstrate HIV-1/METH-induced ER-mitochondrial dysfunction in astrocytes, whereas TAAR1 may be an upstream regulator for HIV-1/METH-mediated astrocyte dysfunction.
{"title":"HIV-1 and methamphetamine co-treatment in primary human astrocytes: TAARgeting ER/UPR dysfunction","authors":"J. Proulx, In-Woo Park, K. Borgmann","doi":"10.1515/nipt-2023-0020","DOIUrl":"https://doi.org/10.1515/nipt-2023-0020","url":null,"abstract":"\u0000 \u0000 \u0000 Human immunodeficiency virus 1 (HIV-1) can invade the central nervous system (CNS) early during infection and persist in the CNS for life despite effective antiretroviral treatment. Infection and activation of residential glial cells lead to low viral replication and chronic inflammation, which damage neurons contributing to a spectrum of HIV-associated neurocognitive disorders (HAND). Substance use, including methamphetamine (METH), can increase one’s risk and severity of HAND. Here, we investigate HIV-1/METH co-treatment in a key neurosupportive glial cell, astrocytes. Specifically, mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) signaling pathways, such as calcium and the unfolded protein response (UPR), are key mechanisms underlying HAND pathology and arise as potential targets to combat astrocyte dysfunction.\u0000 \u0000 \u0000 \u0000 Primary human astrocytes were transduced with a pseudotyped HIV-1 model and exposed to low-dose METH for seven days. We assessed changes in astrocyte HIV-1 infection, inflammation, mitochondrial antioxidant and dynamic protein expression, respiratory acitivity, mitochondrial calcium flux, and UPR/MAM mediator expression. We then tested a selective antagonist for METH-binding receptor, trace amine-associated receptor 1 (TAAR1) as a potetnial upstream regulator of METH-induced calcium flux and UPR/MAM mediator expression.\u0000 \u0000 \u0000 \u0000 Chronic METH exposure increased astrocyte HIV-1 infection. Moreover, HIV-1/METH co-treatment suppressed astrocyte antioxidant and metabolic capacity while increasing mitochondrial calcium load and protein expression of UPR messengers and MAM mediators. Notably, HIV-1 increases astrocyte TAAR1 expression, thus, could be a critical regulator of HIV-1/METH co-treatment in astrocytes. Indeed, selective antagonism of TAAR1 significantly inhibited cytosolic calcium flux and induction of UPR/MAM protein expression.\u0000 \u0000 \u0000 \u0000 Altogether, our findings demonstrate HIV-1/METH-induced ER-mitochondrial dysfunction in astrocytes, whereas TAAR1 may be an upstream regulator for HIV-1/METH-mediated astrocyte dysfunction.\u0000","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"11 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139958777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Mondal, Shelby Prieto, Suresh B. Rangasamy, Debashis Dutta, K. Pahan
Huntington Disease (HD), a devastating hereditary neurodegenerative disorder, is caused by expanded CAG trinucleotide repeats in the huntingtin gene (Htt) on chromosome 4. Currently, there is no effective therapy for HD. Although aspirin, acetylsalicylic acid, is one of the most widely-used analgesics throughout the world, it has some side effects. Even at low doses, oral aspirin can cause gastrointestinal symptoms, such as heartburn, upset stomach, or pain. Therefore, to bypass the direct exposure of aspirin to stomach, here, we described a new mode of use of aspirin and demonstrated that nebulization of low-dose of aspirin (10 μg/mouse/d=0.4 mg/kg body wt/d roughly equivalent to 28 mg/adult human/d) alleviated HD pathology in N171-82Q transgenic mice. Our immunohistochemical and western blot studies showed that daily aspirin nebulization significantly reduced glial activation, inflammation and huntingtin pathology in striatum and cortex of N171-82Q mice. Aspirin nebulization also protected transgenic mice from brain volume shrinkage and improved general motor behaviors. Collectively, these results highlight that nebulization of low-dose aspirin may have therapeutic potential in the treatment of HD.
亨廷顿舞蹈症（Huntington Disease，HD）是一种严重的遗传性神经退行性疾病，由第 4 号染色体上的亨廷丁基因（Hunt）中的 CAG 三核苷酸重复序列扩增引起。目前，HD 尚无有效的治疗方法。虽然阿司匹林（乙酰水杨酸）是世界上使用最广泛的镇痛药之一，但它也有一些副作用。即使剂量很小，口服阿司匹林也会引起胃肠道症状，如胃灼热、胃部不适或疼痛。因此，为了避免阿司匹林直接暴露于胃部，我们在此描述了一种新的阿司匹林使用模式，并证明低剂量阿司匹林（10 μg/小鼠/天=0.4 mg/kg体重/天，大致相当于28 mg/成人/天）雾化可减轻N171-82Q转基因小鼠的HD病理变化。我们的免疫组化和 Western 印迹研究表明，每日雾化吸入阿司匹林可显著减少 N171-82Q 小鼠纹状体和皮层中的神经胶质活化、炎症和亨廷蛋白病理变化。阿司匹林雾化治疗还能保护转基因小鼠免于脑容量缩小，并改善一般运动行为。总之，这些结果突出表明，雾化吸入低剂量阿司匹林可能具有治疗 HD 的潜力。
{"title":"Nebulization of low-dose aspirin ameliorates Huntington’s pathology in N171-82Q transgenic mice","authors":"S. Mondal, Shelby Prieto, Suresh B. Rangasamy, Debashis Dutta, K. Pahan","doi":"10.1515/nipt-2023-0026","DOIUrl":"https://doi.org/10.1515/nipt-2023-0026","url":null,"abstract":"\u0000 Huntington Disease (HD), a devastating hereditary neurodegenerative disorder, is caused by expanded CAG trinucleotide repeats in the huntingtin gene (Htt) on chromosome 4. Currently, there is no effective therapy for HD. Although aspirin, acetylsalicylic acid, is one of the most widely-used analgesics throughout the world, it has some side effects. Even at low doses, oral aspirin can cause gastrointestinal symptoms, such as heartburn, upset stomach, or pain. Therefore, to bypass the direct exposure of aspirin to stomach, here, we described a new mode of use of aspirin and demonstrated that nebulization of low-dose of aspirin (10 μg/mouse/d=0.4 mg/kg body wt/d roughly equivalent to 28 mg/adult human/d) alleviated HD pathology in N171-82Q transgenic mice. Our immunohistochemical and western blot studies showed that daily aspirin nebulization significantly reduced glial activation, inflammation and huntingtin pathology in striatum and cortex of N171-82Q mice. Aspirin nebulization also protected transgenic mice from brain volume shrinkage and improved general motor behaviors. Collectively, these results highlight that nebulization of low-dose aspirin may have therapeutic potential in the treatment of HD.","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":" 53","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139788038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Mondal, Shelby Prieto, Suresh B. Rangasamy, Debashis Dutta, K. Pahan
Huntington Disease (HD), a devastating hereditary neurodegenerative disorder, is caused by expanded CAG trinucleotide repeats in the huntingtin gene (Htt) on chromosome 4. Currently, there is no effective therapy for HD. Although aspirin, acetylsalicylic acid, is one of the most widely-used analgesics throughout the world, it has some side effects. Even at low doses, oral aspirin can cause gastrointestinal symptoms, such as heartburn, upset stomach, or pain. Therefore, to bypass the direct exposure of aspirin to stomach, here, we described a new mode of use of aspirin and demonstrated that nebulization of low-dose of aspirin (10 μg/mouse/d=0.4 mg/kg body wt/d roughly equivalent to 28 mg/adult human/d) alleviated HD pathology in N171-82Q transgenic mice. Our immunohistochemical and western blot studies showed that daily aspirin nebulization significantly reduced glial activation, inflammation and huntingtin pathology in striatum and cortex of N171-82Q mice. Aspirin nebulization also protected transgenic mice from brain volume shrinkage and improved general motor behaviors. Collectively, these results highlight that nebulization of low-dose aspirin may have therapeutic potential in the treatment of HD.
亨廷顿舞蹈症（Huntington Disease，HD）是一种严重的遗传性神经退行性疾病，由第 4 号染色体上的亨廷丁基因（Hunt）中的 CAG 三核苷酸重复序列扩增引起。目前，HD 尚无有效的治疗方法。虽然阿司匹林（乙酰水杨酸）是世界上使用最广泛的镇痛药之一，但它也有一些副作用。即使剂量很小，口服阿司匹林也会引起胃肠道症状，如胃灼热、胃部不适或疼痛。因此，为了避免阿司匹林直接暴露于胃部，我们在此描述了一种新的阿司匹林使用模式，并证明低剂量阿司匹林（10 μg/小鼠/天=0.4 mg/kg体重/天，大致相当于28 mg/成人/天）雾化可减轻N171-82Q转基因小鼠的HD病理变化。我们的免疫组化和 Western 印迹研究表明，每日雾化吸入阿司匹林可显著减少 N171-82Q 小鼠纹状体和皮层中的神经胶质活化、炎症和亨廷蛋白病理变化。阿司匹林雾化治疗还能保护转基因小鼠免于脑容量缩小，并改善一般运动行为。总之，这些结果突出表明，雾化吸入低剂量阿司匹林可能具有治疗 HD 的潜力。
{"title":"Nebulization of low-dose aspirin ameliorates Huntington’s pathology in N171-82Q transgenic mice","authors":"S. Mondal, Shelby Prieto, Suresh B. Rangasamy, Debashis Dutta, K. Pahan","doi":"10.1515/nipt-2023-0026","DOIUrl":"https://doi.org/10.1515/nipt-2023-0026","url":null,"abstract":"\u0000 Huntington Disease (HD), a devastating hereditary neurodegenerative disorder, is caused by expanded CAG trinucleotide repeats in the huntingtin gene (Htt) on chromosome 4. Currently, there is no effective therapy for HD. Although aspirin, acetylsalicylic acid, is one of the most widely-used analgesics throughout the world, it has some side effects. Even at low doses, oral aspirin can cause gastrointestinal symptoms, such as heartburn, upset stomach, or pain. Therefore, to bypass the direct exposure of aspirin to stomach, here, we described a new mode of use of aspirin and demonstrated that nebulization of low-dose of aspirin (10 μg/mouse/d=0.4 mg/kg body wt/d roughly equivalent to 28 mg/adult human/d) alleviated HD pathology in N171-82Q transgenic mice. Our immunohistochemical and western blot studies showed that daily aspirin nebulization significantly reduced glial activation, inflammation and huntingtin pathology in striatum and cortex of N171-82Q mice. Aspirin nebulization also protected transgenic mice from brain volume shrinkage and improved general motor behaviors. Collectively, these results highlight that nebulization of low-dose aspirin may have therapeutic potential in the treatment of HD.","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"412 27","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139847619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. de Mendoza, Graham Taylor, A. Gessain, Andrea K. Thoma-Kress, Charles R. M. Bangham, Jan Vesterbacka, Roberto Accolla, Ali Bazarbachi, Jan van Weyenbergh, Lucy Cook, Jorge Casseb, Juan Carlos Ramos, Carolina Rosadas, Beatrice Macchi, O. Cassar, V. Soriano
Abstract The 30th workshop of the HTLV European Research Network (HERN) was held in Madrid on September 15–16, 2023. Over fifty researchers from Europe and America convened for a two-day conference to update and discuss basic science, epidemiology, clinical management and therapeutics for patients with HTLV-1 infection. Scientific topics addressed included new estimates for HTLV-1 in Europe; impact of antenatal screening on mother-to-child HTLV-1 infections; new insights into the molecular epidemiology of HTLV-1; reports of elite controllers for HTLV-1 infection; role of antiretrovirals as HTLV-1 pre-exposure prophylaxis; and prospects for a HTLV-1 vaccine. The group agreed to submit a formal request to WHO for increasing the global surveillance and awareness of HTLV-1. This viral infection is a potentially life-threatening, neglected condition with neither treatment nor vaccine. At this time, expanding HTLV-1 screening is the most effective way to reduce viral dissemination.
{"title":"Virology, pathogenesis, epidemiology and clinical management of HTLV-1 infection. Proceedings of the 30th HTLV European research network (HERN 2023)","authors":"C. de Mendoza, Graham Taylor, A. Gessain, Andrea K. Thoma-Kress, Charles R. M. Bangham, Jan Vesterbacka, Roberto Accolla, Ali Bazarbachi, Jan van Weyenbergh, Lucy Cook, Jorge Casseb, Juan Carlos Ramos, Carolina Rosadas, Beatrice Macchi, O. Cassar, V. Soriano","doi":"10.1515/nipt-2023-0025","DOIUrl":"https://doi.org/10.1515/nipt-2023-0025","url":null,"abstract":"Abstract The 30th workshop of the HTLV European Research Network (HERN) was held in Madrid on September 15–16, 2023. Over fifty researchers from Europe and America convened for a two-day conference to update and discuss basic science, epidemiology, clinical management and therapeutics for patients with HTLV-1 infection. Scientific topics addressed included new estimates for HTLV-1 in Europe; impact of antenatal screening on mother-to-child HTLV-1 infections; new insights into the molecular epidemiology of HTLV-1; reports of elite controllers for HTLV-1 infection; role of antiretrovirals as HTLV-1 pre-exposure prophylaxis; and prospects for a HTLV-1 vaccine. The group agreed to submit a formal request to WHO for increasing the global surveillance and awareness of HTLV-1. This viral infection is a potentially life-threatening, neglected condition with neither treatment nor vaccine. At this time, expanding HTLV-1 screening is the most effective way to reduce viral dissemination.","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"3 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139438119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
P. Halcrow, Darius N. K. Quansah, Nirmal Kumar, Rebecca L. Solloway, Kayla M. Teigen, Kasumi A. Lee, Braelyn Liang, Jonathan D. Geiger
Abstract Objectives Approximately 75 % of marketed drugs have the physicochemical property of being weak bases. Weak-base drugs with relatively high pKa values enter acidic organelles including endosomes and lysosomes (endolysosomes), reside in and de-acidify endolysosomes, and induce cytotoxicity. Divalent cations within endolysosomes, including iron, are released upon endolysosome de-acidification. Endolysosomes are “master regulators of iron homeostasis”, and neurodegeneration is linked to ferrous iron (Fe2+)-induced reactive oxygen species (ROS) generation via Fenton chemistry. Because endolysosome de-acidification-induced lysosome-stress responses release endolysosome Fe2+, it was crucial to determine the mechanisms by which a functionally and structurally diverse group of weak base drugs including atropine, azithromycin, fluoxetine, metoprolol, and tamoxifen influence endolysosomes and cause cell death. Methods Using U87MG astrocytoma and SH-SY5Y neuroblastoma cells, we conducted concentration-response relationships for 5 weak-base drugs to determine EC50 values. From these curves, we chose pharmacologically and therapeutically relevant concentrations to determine if weak-base drugs induced lysosome-stress responses by de-acidifying endolysosomes, releasing endolysosome Fe2+ in sufficient levels to increase cytosolic and mitochondria Fe2+ and ROS levels and cell death. Results Atropine (anticholinergic), azithromycin (antibiotic), fluoxetine (antidepressant), metoprolol (beta-adrenergic), and tamoxifen (anti-estrogen) at pharmacologically and therapeutically relevant concentrations (1) de-acidified endolysosomes, (2) decreased Fe2+ levels in endolysosomes, (3) increased Fe2+ and ROS levels in cytosol and mitochondria, (4) induced mitochondrial membrane potential depolarization, and (5) increased cell death; effects prevented by the endocytosed iron-chelator deferoxamine. Conclusions Weak-base pharmaceuticals induce lysosome-stress responses that may affect their safety profiles; a better understanding of weak-base drugs on Fe2+ interorganellar signaling may improve pharmacotherapeutics.
{"title":"Weak base drug-induced endolysosome iron dyshomeostasis controls the generation of reactive oxygen species, mitochondrial depolarization, and cytotoxicity","authors":"P. Halcrow, Darius N. K. Quansah, Nirmal Kumar, Rebecca L. Solloway, Kayla M. Teigen, Kasumi A. Lee, Braelyn Liang, Jonathan D. Geiger","doi":"10.1515/nipt-2023-0021","DOIUrl":"https://doi.org/10.1515/nipt-2023-0021","url":null,"abstract":"Abstract Objectives Approximately 75 % of marketed drugs have the physicochemical property of being weak bases. Weak-base drugs with relatively high pKa values enter acidic organelles including endosomes and lysosomes (endolysosomes), reside in and de-acidify endolysosomes, and induce cytotoxicity. Divalent cations within endolysosomes, including iron, are released upon endolysosome de-acidification. Endolysosomes are “master regulators of iron homeostasis”, and neurodegeneration is linked to ferrous iron (Fe2+)-induced reactive oxygen species (ROS) generation via Fenton chemistry. Because endolysosome de-acidification-induced lysosome-stress responses release endolysosome Fe2+, it was crucial to determine the mechanisms by which a functionally and structurally diverse group of weak base drugs including atropine, azithromycin, fluoxetine, metoprolol, and tamoxifen influence endolysosomes and cause cell death. Methods Using U87MG astrocytoma and SH-SY5Y neuroblastoma cells, we conducted concentration-response relationships for 5 weak-base drugs to determine EC50 values. From these curves, we chose pharmacologically and therapeutically relevant concentrations to determine if weak-base drugs induced lysosome-stress responses by de-acidifying endolysosomes, releasing endolysosome Fe2+ in sufficient levels to increase cytosolic and mitochondria Fe2+ and ROS levels and cell death. Results Atropine (anticholinergic), azithromycin (antibiotic), fluoxetine (antidepressant), metoprolol (beta-adrenergic), and tamoxifen (anti-estrogen) at pharmacologically and therapeutically relevant concentrations (1) de-acidified endolysosomes, (2) decreased Fe2+ levels in endolysosomes, (3) increased Fe2+ and ROS levels in cytosol and mitochondria, (4) induced mitochondrial membrane potential depolarization, and (5) increased cell death; effects prevented by the endocytosed iron-chelator deferoxamine. Conclusions Weak-base pharmaceuticals induce lysosome-stress responses that may affect their safety profiles; a better understanding of weak-base drugs on Fe2+ interorganellar signaling may improve pharmacotherapeutics.","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"9 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139438962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Michael Stangis, Daniel Adesse, Bhavya Sharma, Eduardo Castro, Kush Kumar, Neil Kumar, Masha Minevich, Michal Toborek
Abstract Objectives Cerebrovascular complications are prevalent in COVID-19 infection and post-COVID conditions; therefore, interactions of SARS-CoV-2 with cerebral microvascular cells became an emerging concern. Methods We examined the inflammatory responses of human brain microvascular endothelial cells (HBMEC), the main structural element of the blood–brain barrier (BBB), following exposure to the S1 subunit of the spike protein of different SARS-CoV-2 variants. Specifically, we used the S1 subunit derived from the D614 variant of SARS-CoV-2, which started widely circulating in March of 2020, and from the Delta variant, which started widely circulating in early 2021. We then further examined the impact of the HBMEC secretome, produced in response to the S1 exposure, on microglial proinflammatory responses. Results Treatment with S1 derived from the D614 variant and from the Delta variant resulted in differential alterations of the IL-6 signaling pathway. Moreover, the HBMEC secretome obtained after exposure to the S1 subunit of the D614 variant activated STAT3 in microglial cells, indicating that proinflammatory signals from endothelial cells can propagate to other cells of the neurovascular unit. Overall, these results indicate the potential for different SARS-CoV-2 variants to induce unique cellular signatures and warrant individualized treatment strategies. The findings from this study also bring further awareness to proinflammatory responses involving brain microvasculature in COVID-19 and demonstrate how the surrounding microglia react to each unique variant derived response.
{"title":"The S1 subunits of SARS-CoV-2 variants differentially trigger the IL-6 signaling pathway in human brain endothelial cells and downstream impact on microglia activation","authors":"Michael Stangis, Daniel Adesse, Bhavya Sharma, Eduardo Castro, Kush Kumar, Neil Kumar, Masha Minevich, Michal Toborek","doi":"10.1515/nipt-2023-0024","DOIUrl":"https://doi.org/10.1515/nipt-2023-0024","url":null,"abstract":"Abstract Objectives Cerebrovascular complications are prevalent in COVID-19 infection and post-COVID conditions; therefore, interactions of SARS-CoV-2 with cerebral microvascular cells became an emerging concern. Methods We examined the inflammatory responses of human brain microvascular endothelial cells (HBMEC), the main structural element of the blood–brain barrier (BBB), following exposure to the S1 subunit of the spike protein of different SARS-CoV-2 variants. Specifically, we used the S1 subunit derived from the D614 variant of SARS-CoV-2, which started widely circulating in March of 2020, and from the Delta variant, which started widely circulating in early 2021. We then further examined the impact of the HBMEC secretome, produced in response to the S1 exposure, on microglial proinflammatory responses. Results Treatment with S1 derived from the D614 variant and from the Delta variant resulted in differential alterations of the IL-6 signaling pathway. Moreover, the HBMEC secretome obtained after exposure to the S1 subunit of the D614 variant activated STAT3 in microglial cells, indicating that proinflammatory signals from endothelial cells can propagate to other cells of the neurovascular unit. Overall, these results indicate the potential for different SARS-CoV-2 variants to induce unique cellular signatures and warrant individualized treatment strategies. The findings from this study also bring further awareness to proinflammatory responses involving brain microvasculature in COVID-19 and demonstrate how the surrounding microglia react to each unique variant derived response.","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"48 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139380067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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