Michael Stangis, Daniel Adesse, Bhavya Sharma, Eduardo Castro, Kush Kumar, Neil Kumar, Masha Minevich, Michal Toborek
{"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}
Haylee R. Hammond, S. Eans, Thomas J. Cirino, S. Ananthan, Ana Catya Jimenez-Torres, Jun Zhu, J. McLaughlin
{"title":"SRI-30827, a novel allosteric modulator of the dopamine transporter, alleviates HIV-1 Tat-induced potentiation of cocaine conditioned place preference in mice","authors":"Haylee R. Hammond, S. Eans, Thomas J. Cirino, S. Ananthan, Ana Catya Jimenez-Torres, Jun Zhu, J. McLaughlin","doi":"10.1515/nipt-2023-0022","DOIUrl":"https://doi.org/10.1515/nipt-2023-0022","url":null,"abstract":"Abstract Objectives HIV-1 Tat (transactivator of transcription) protein disrupts dopaminergic transmission and potentiates the rewarding effects of cocaine. Allosteric modulators of the dopamine transporter (DAT) have been shown to reverse Tat-induced DAT dysfunction. We hypothesized that a novel DAT allosteric modulator, SRI-30827, would counteract Tat-induced potentiation of cocaine reward. Methods Doxycycline (Dox)-inducible Tat transgenic (iTat-tg) mice and their G-tg (Tat-null) counterparts were tested in a cocaine conditioned place preference (CPP) paradigm. Mice were treated 14 days with saline, or Dox (100 mg/kg/day, i.p.) to induce Tat protein. Upon induction, mice were place conditioned two days with cocaine (10 mg/kg/day) after a 1-h daily intracerebroventricular (i.c.v.) pretreatment with SRI-30827 (1 nmol) or a vehicle control, and final place preference assessed as a measure of cocaine reward. Results Dox-treatment significantly potentiated cocaine-CPP in iTat-tg mice over the response of saline-treated control littermates. SRI-30827 treatment eliminated Tat-induced potentiation without altering normal cocaine-CPP in saline-treated mice. Likewise, SRI-30827 did not alter cocaine-CPP in both saline- and Dox-treated G-tg mice incapable of expressing Tat protein. Conclusions These findings add to a growing body of evidence that allosteric modulation of DAT could provide a promising therapeutic intervention for patients with comorbid HIV-1 and cocaine use disorder (CUD).","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":" 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138617882","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}
{"title":"Developmental outcomes with perinatal exposure (DOPE) to prescription opioids.","authors":"Adrian Flores, Nghi M Nguyen, Gurudutt Pendyala","doi":"10.1515/nipt-2023-0017","DOIUrl":"10.1515/nipt-2023-0017","url":null,"abstract":"<p><p>Researchers have found considerable evidence in the past 20 years that perinatal opioid exposure leads to an increased risk of developmental disorders in offspring that persist into adulthood. The use of opioids to treat pain concerning pregnancy, delivery, and postpartum complications has been rising. As a result, communities have reported a 300-400 % increase in Neonatal Opioid Withdrawal Syndrome (NOWS). NOWS represents the initial stage of several behavioral, phenotypic, and synaptic deficits. This review article summarizes the Developmental Outcomes of Perinatal Exposure (DOPE) to prescription opioids. Moreover, we also seek to connect these findings to clinical research that describes DOPE at multiple stages of life. Since specific mechanisms that underlie DOPE remain unclear, this article aims to provide a framework for conceptualizing across all ages and highlight the implications they may have for longevity.</p>","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"2 4","pages":"339-351"},"PeriodicalIF":0.0,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10696573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138500419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Harmonizing science with music: a novel approach in AIDS research dissemination","authors":"Kevin Hanrahan","doi":"10.1515/nipt-2023-0023","DOIUrl":"https://doi.org/10.1515/nipt-2023-0023","url":null,"abstract":"","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"679 ","pages":"331 - 332"},"PeriodicalIF":0.0,"publicationDate":"2023-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139240477","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}
{"title":"Blood-brain barrier breakdown in COVID-19 ICU survivors: an MRI pilot study.","authors":"Wen Shi, Dengrong Jiang, Hannah Rando, Shivalika Khanduja, Zixuan Lin, Kaisha Hazel, George Pottanat, Ebony Jones, Cuimei Xu, Doris Lin, Sevil Yasar, Sung-Min Cho, Hanzhang Lu","doi":"10.1515/nipt-2023-0018","DOIUrl":"10.1515/nipt-2023-0018","url":null,"abstract":"<p><strong>Objectives: </strong>Coronavirus disease 2019 (COVID-19) results in severe inflammation at the acute stage. Chronic neuroinflammation and abnormal immunological response have been suggested to be the contributors to neuro-long-COVID, but direct evidence has been scarce. This study aims to determine the integrity of the blood-brain barrier (BBB) in COVID-19 intensive care unit (ICU) survivors using a novel MRI technique.</p><p><strong>Methods: </strong>COVID-19 ICU survivors (n=7) and age and sex-matched control participants (n=17) were recruited from June 2021 to March 2023. None of the control participants were hospitalized due to COVID-19 infection. The COVID-19 ICU survivors were studied at 98.6 ± 14.9 days after their discharge from ICU. A non-invasive MRI technique was used to assess the BBB permeability to water molecules, in terms of permeability surface area-product (PS) in the units of mL/100 g/min.</p><p><strong>Results: </strong>PS was significantly higher in COVID-19 ICU survivors (p=0.038) when compared to the controls, with values of 153.1 ± 20.9 mL/100 g/min and 132.5 ± 20.7 mL/100 g/min, respectively. In contrast, there were no significant differences in whole-brain cerebral blood flow (p=0.649) or brain volume (p=0.471) between the groups.</p><p><strong>Conclusions: </strong>There is preliminary evidence of a chronic BBB breakdown in COVID-19 survivors who had a severe acute infection, suggesting a plausible contributor to neurological long-COVID symptoms.</p>","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"2 4","pages":"333-338"},"PeriodicalIF":0.0,"publicationDate":"2023-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10696574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138500418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Trent A. Bullock, Kalpani N. Udeni Galpayage Dona, Jonathan F. Hale, Paula Morales, Nadine Jagerovic, Allison M. Andrews, Servio H. Ramirez
{"title":"Activation of CB2R by synthetic CB2R agonist, PM289, improves brain endothelial barrier properties, decreases inflammatory response and enhances endothelial repair","authors":"Trent A. Bullock, Kalpani N. Udeni Galpayage Dona, Jonathan F. Hale, Paula Morales, Nadine Jagerovic, Allison M. Andrews, Servio H. Ramirez","doi":"10.1515/nipt-2023-0016","DOIUrl":"https://doi.org/10.1515/nipt-2023-0016","url":null,"abstract":"Abstract The Cannabinoid 2 Receptor (CB2R) has been found to provide immunological modulation in different cell types. More recently, detection of CB2R in the cerebral endothelium suggests a possible role in the resolution of inflammation at the level of the blood–brain–barrier (BBB). Here, the notion that CB2R upregulation in brain endothelial cells could be exploited to promote vascular protection and BBB integrity was evaluated. Targeting and activation of CB2R was accomplished by a novel and highly specific chromenopyrazole based CB2R agonist, PM289. This study demonstrates that CB2R upregulation is induced as early as 8 h in the cortical vasculature in an experimental mouse model of TBI. Unlike CB2R, CB1R was marginally detected and not significantly induced. In the human brain endothelial cell line, hCMEC/D3 cells, similar induction of CB2R was observed upon stimulation with TNFα. Analysis of transendothelial electrical resistance shows that PM289 markedly prevented the barrier-leakiness induced by TNFα. The BBB is also responsible for maintaining an immunological barrier. The five-fold increase in ICAM1 expression in stimulated endothelial cells was significantly diminished due to CB2R activation. Utilizing wounding assays, results showed that wound repair could be accomplished in nearly half the time when the novel CB2R agonist is present compared to the untreated control. Lastly, mechanistically, the effects of CB2R may be explained by the observed inhibition of the p65 NFκB subunit. Overall, these studies support the notion that targeting and activating CB2R in the brain vasculature could aid in BBB and vascular protection in the context of neuroinflammation.","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"10 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136078247","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}
{"title":"Prenatal and adolescent alcohol exposure, neuroinflammation, and Alzheimer’s disease: a network meta analysis approach","authors":"Lazer Gerlikhman, Ujjal Das, Dipak K. Sarkar","doi":"10.1515/nipt-2023-0003","DOIUrl":"https://doi.org/10.1515/nipt-2023-0003","url":null,"abstract":"Abstract Objectives This review aims to determine the connection between developmental alcohol exposure and its potential impact on Alzheimer's disease (AD) later in life. We employ a network meta-analysis approach and examine gene fold changes from literature and Gene Expression Omnibus (GEO) datasets. Our goal is to investigate whether prenatal alcohol exposure (PAE) and/or adolescent alcohol exposure (AAE) could activate specific neuroinflammatory genes, potentially increasing the risk of AD development. Content We conducted a comprehensive analysis of brain datasets using a network meta-analysis approach. By synthesizing gene fold changes from literature and GEO datasets, we examined the potential impact of developmental alcohol exposure on increased risk of developing AD in the future. Summary Our findings reveal significant associations between alcohol exposure and critical functional categories and diseases in the brain. Alcohol exposure was strongly linked to the “Inflammatory Response” and “Nervous System Development and Function” categories, indicative of inflammatory reactions in the brain and detrimental effects on nervous system integrity. Furthermore, we observed links with “Organismal Injury and Abnormalities” and “Cell Death and Survival.” Pathway analysis revealed dysregulation in neuroinflammatory, ERK/MAPK signaling, amyloid processing, IL-1 signaling and calcium signaling pathways, suggesting their potential involvement in alcohol-induced neurotoxicity. Outlook This review highlights the necessity of recognizing developmental alcohol exposure as a potential risk factor for AD and shed light on the underlying mechanisms that may contribute to alcohol-induced neurotoxicity. By expanding our understanding of these mechanisms, we can better address the complex relationship between developmental alcohol exposure and neurodegenerative disorders like AD.","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43310333","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}
Mai M Abdelmoaty, Pravin Yeapuri, Jatin Machhi, Yaman Lu, Krista L Namminga, Rana Kadry, Eugene Lu, Shaurav Bhattarai, Rodney Lee Mosley, Howard E Gendelman
{"title":"Immune senescence in aged APP/PS1 mice.","authors":"Mai M Abdelmoaty, Pravin Yeapuri, Jatin Machhi, Yaman Lu, Krista L Namminga, Rana Kadry, Eugene Lu, Shaurav Bhattarai, Rodney Lee Mosley, Howard E Gendelman","doi":"10.1515/nipt-2023-0015","DOIUrl":"10.1515/nipt-2023-0015","url":null,"abstract":"<p><strong>Objectives: </strong>To evaluate the linkage between age and deficits in innate and adaptive immunity which heralds both Alzheimer's disease (AD) onset and progression. The pathobiological events which underlie and tie these outcomes remain not fully understood.</p><p><strong>Methods: </strong>To investigate age-dependent immunity in AD, we evaluated innate and adaptive immunity in coordinate studies of regulatory T cell (Treg) function, T cell frequencies, and microglial integrity. These were assessed in blood, peripheral lymphoid tissues, and the hippocampus of transgenic (Tg) amyloid precursor protein/presenilin 1 (APP/PS1) against non-Tg mice. Additionally, immune arrays of hippocampal tissue were performed at 4, 6, 12, and 20 months of age.</p><p><strong>Results: </strong>APP/PS1 mice showed progressive impairment of Treg immunosuppressive function with age. There was partial restoration of Treg function in 20-month-old mice. Ingenuity pathway analyses of hippocampal tissues were enriched in inflammatory, oxidative, and cellular activation pathways that paralleled advancing age and AD-pathobiology. Operative genes in those pathways included, but were not limited to triggering receptor on myeloid cells 1 (TREM1), T helper type 1 (Th1), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways. Interleukin-17 (IL-17), nitric oxide, acute phase, and T cell receptor signaling pathways were also perturbed. Significant inflammation was observed at 6- and 12-months. However, at 20-months, age associated partial restoration of Treg function reduced inflammatory phenotype.</p><p><strong>Conclusions: </strong>Impaired Treg function, inflammation and oxidative stress were associated with AD pathology. Age associated partial restoration of Treg function in old mice reduced the hippocampal inflammatory phenotype. Restoring Treg suppressive function can be a therapeutic modality for AD.</p>","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":" ","pages":"317-330"},"PeriodicalIF":0.0,"publicationDate":"2023-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10659760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46909718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sudipta Chakrabarti, Sukhamoy Gorai, Kalipada Pahan
{"title":"A simple protocol for isolating microglia from adult mouse brain.","authors":"Sudipta Chakrabarti, Sukhamoy Gorai, Kalipada Pahan","doi":"10.1515/nipt-2023-0014","DOIUrl":"10.1515/nipt-2023-0014","url":null,"abstract":"<p><strong>Objectives: </strong>Although microglia are activated in adult and aged brains resulting in neurodegenerative and neuroinflammatory disorders, most of the cell culture studies on microglia deal with neonatal microglia because of ease of isolation. Microglia could be isolated from adult brains, but it requires separation by density gradient centrifugation, magnetic beads, etc. Here, we describe a simple protocol of isolating highly purified microglia from adult mouse brains.</p><p><strong>Methods: </strong>Our protocol involves dilution with sterile PBS or media, regular centrifugation, and plating on poly-D-lysine-coated flasks.</p><p><strong>Results: </strong>These adult microglia expressed the inducible nitric oxide synthase in response to preformed α-syn fibril, an etiological reagent of Parkinson's disease, and bacterial lipopolysaccharides, one of the prototype proinflammatory stimuli. Moreover, these adult microglia exhibited phagocytosis, which was stimulated by LPS treatment.</p><p><strong>Conclusions: </strong>These results suggest that adult microglia isolated by our procedure are functional and that these adult microglia could be used for studies related to neurodegenerative disorders.</p>","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"2 1","pages":"293-300"},"PeriodicalIF":0.0,"publicationDate":"2023-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10474378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48987881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}