Abstract:
BACKGROUND:Since HIV-associated neurocognitive disorders (HANDs) occur in up to half of HIV-positive individuals, even with combined antiretroviral therapy (cART), adjunctive therapies are needed. Chronic CNS inflammation contributes to HAND and HIV encephalitis (HIVE). Baricitinib is a JAK 1/2 inhibitor approved in the USA, EU, and Japan for rheumatoid arthritis, demonstrating potent inhibition of IL-6, D-dimer, CRP, TNF-α, IFN-α/β, and other pro-inflammatory cytokines. METHODS:Our modified murine HAND model was used to evaluate the ability of baricitinib to cross the blood-brain barrier (BBB) and modulate monocyte/macrophage-driven HAND. Severity of HAND was measured by assessing cognitive performance of low- and high-dose baricitinib treated versus untreated HAND mice. The severity of brain neuroinflammation was evaluated in these mouse groups after flow cytometric analyses. We also assessed the ability of baricitinib to block events in myeloid and lymphoid cells in vitro that may undergird the persistence of HIV in the central nervous system (CNS) in primary human macrophages (Mϕ) and lymphocytes including HIV replication, HIV-induced activation, reservoir expansion, and reservoir maintenance. RESULTS:In vivo, both doses of 10 and 50 mg/kg qd baricitinib crossed the BBB and reversed behavioral abnormalities conferred by HIV infection. Moreover, baricitinib significantly reduced HIV-induced neuroinflammation marked by glial activation: activated microglia (MHCII+/CD45+) and astrogliosis (GFAP). Baricitinib also significantly reduced the percentage of p24+ human macrophages in mouse brains (p < 0.05 versus HAND mice; t test). In vitro, baricitinib significantly reduced markers of persistence, reservoir size, and reseeding in Mϕ. CONCLUSION:These results show that blocking the JAK/STAT pathway reverses cognitive deficits and curtails inflammatory markers in HAND in mice. Our group recently reported safety and tolerability of ruxolitinib in HIV-infected individuals (Marconi et al., Safety, tolerability and immunologic activity of ruxolitinib added to suppressive ART, 2019), underscoring potential safety and utility of JAK inhibitors for additional human trials. The data reported herein coupled with our recent human trial with JAK inhibitors provide compelling preclinical data and impetus for considering a trial of baricitinib in HAND individuals treated with cART to reverse cognitive deficits and key events driving viral persistence.
journal_name
J Neuroinflammationjournal_title
Journal of neuroinflammationauthors
Gavegnano C,Haile WB,Hurwitz S,Tao S,Jiang Y,Schinazi RF,Tyor WRdoi
10.1186/s12974-019-1565-6subject
Has Abstractpub_date
2019-09-27 00:00:00pages
182issue
1issn
1742-2094pii
10.1186/s12974-019-1565-6journal_volume
16pub_type
杂志文章abstract:BACKGROUND:A dose-limiting side effect of chemotherapeutic agents such as vincristine (VCR) is neuropathic pain, which is poorly managed at present. Chemokine-mediated immune cell/neuron communication in preclinical VCR-induced pain forms an intriguing basis for the development of analgesics. In a murine VCR model, CX3...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/s12974-018-1116-6
更新日期:2018-04-06 00:00:00
abstract:BACKGROUND:Activation of microglia is a part of the inflammatory response in neurodegenerative diseases but its role in the pathophysiology of these diseases is still unclear. The osteopetrotic (op/op) mouse lacks colony-stimulating factor-1 (CSF-1) and thus has a deficiency in microglia and macrophages. Prior reports ...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/1742-2094-4-31
更新日期:2007-12-20 00:00:00
abstract:BACKGROUND:Neuroinflammation often develops in sepsis leading to activation of cerebral endothelium, increased permeability of the blood-brain barrier (BBB), and neutrophil infiltration. We have identified protein kinase C-delta (PKCδ) as a critical regulator of the inflammatory response and demonstrated that pharmacol...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/s12974-018-1342-y
更新日期:2018-11-06 00:00:00
abstract:BACKGROUND:Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory demyelinating and neurodegenerative diseases of the CNS. Although recent studies suggest the neuroprotective effects of oligodendrocytes in neurodegenerative diseases, it remains unknown whether ol...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/s12974-019-1415-6
更新日期:2019-02-01 00:00:00
abstract:BACKGROUND:Experimental autoimmune encephalomyelitis (EAE) is the most commonly used and clinically relevant murine model for human multiple sclerosis (MS), a demyelinating autoimmune disease characterized by mononuclear cell infiltration into the central nervous system (CNS). The aim of the present study was to apprai...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/s12974-020-01936-9
更新日期:2020-09-07 00:00:00
abstract:BACKGROUND:Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders characterized by gradual memory loss and neuropsychiatric symptoms. We have previously demonstrated that the 2-({3-[2-(1-cyclohexene-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanami...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/s12974-020-02022-w
更新日期:2020-11-22 00:00:00
abstract:BACKGROUND:Human marrow stromal cells (hMSCs) injected intrathecally can effectively increase the lifespan and protect motor neurons in a transgenic mouse model of amyotrophic lateral sclerosis. However, how the transplanted cells exert a neuroprotective effect is still unclear. More recently, the anti-inflammation eff...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/1742-2094-10-52
更新日期:2013-04-30 00:00:00
abstract:BACKGROUND:Persistent and/or recurrent inflammatory processes are the main factor leading to multiple sclerosis (MS) lesions. The composite ultramicronized palmitoylethanolamide, an endogenous N-acylethanolamine, combined with the flavonoid luteolin, PEALut, have been found to exert neuroprotective activities in experi...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/s12974-019-1514-4
更新日期:2019-06-20 00:00:00
abstract:BACKGROUND:Atypical chemokine receptor 3 (ACKR3, synonym CXCR7) is increasingly considered relevant in neuroinflammatory conditions, in which its upregulation contributes to compromised endothelial barrier function and may ultimately allow inflammatory brain injury. While an impact of ACKR3 has been recognized in sever...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/s12974-018-1170-0
更新日期:2018-05-23 00:00:00
abstract:BACKGROUND:Recent evidence suggests that reactive astrocytes play an important role in neuroinflammation and neurodegenerative diseases. Thus, controlling astrocyte reactivity has been suggested as a promising strategy for treating neurodegenerative diseases. In the present study, we investigated whether a matrix metal...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/s12974-018-1363-6
更新日期:2018-11-23 00:00:00
abstract:BACKGROUND:Glaucoma is a complex, multifactorial disease where apoptosis, microglia activation, and inflammation have been linked to the death of retinal ganglion cells (RGCs) and axon degeneration. We demonstrated previously that FasL-Fas signaling was required for axon degeneration and death of RGCs in chronic and in...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/s12974-019-1576-3
更新日期:2019-09-30 00:00:00
abstract:BACKGROUND:Rasmussen encephalitis (RE) is a rare neuroinflammatory disease characterized by intractable seizures and progressive atrophy on one side of the cerebrum. Perivascular cuffing and clusters of T cells in the affected cortical hemisphere are indicative of an active cellular immune response. METHODS:Peripheral...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/s12974-015-0352-2
更新日期:2015-07-19 00:00:00
abstract:BACKGROUND:Preconditioning is a phenomenon by which tolerance develops to injury by previous exposure to a stressor of mild severity. Previous studies have shown that single or repeated low dose MDMA can attenuate 5-HT transporter loss produced by a subsequent neurotoxic dose of the drug. We have explored the mechanism...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/1742-2094-8-165
更新日期:2011-11-24 00:00:00
abstract:BACKGROUND:Lyme neuroborreliosis (LNB) can affect both the peripheral (PNS) and the central nervous systems (CNS); it is caused by the spirochete Borrelia burgdorferi. The neuropeptide substance P (SP) is an important mediator of both neuroinflammation and blood-brain barrier dysfunction, through its NK1 receptor. Incr...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/s12974-015-0453-y
更新日期:2015-12-30 00:00:00
abstract:BACKGROUND:Chronic microglia-mediated inflammation and oxidative stress are well-characterized underlying factors in neurodegenerative disease, whereby reactive inflammatory microglia enhance ROS production and impact neuronal integrity. Recently, it has been shown that during chronic inflammation, neuronal integrity i...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/s12974-017-0889-3
更新日期:2017-06-08 00:00:00
abstract::Traumatic brain injury (TBI) is an important cause of disability and mortality in the western world. While the initial injury sustained results in damage, it is the subsequent secondary cascade that is thought to be the significant determinant of subsequent outcomes. The changes associated with the secondary injury do...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章,评审
doi:10.1186/s12974-018-1066-z
更新日期:2018-01-22 00:00:00
abstract:BACKGROUND:White matter injury (WMI) is the major antecedent of cerebral palsy in premature infants, and is often associated with maternal infection and the fetal inflammatory response. The current study explores the therapeutic potential of glutamate receptor blockade or cyclooxygenase-2 (COX-2) inhibition for inflamm...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/1742-2094-10-153
更新日期:2013-12-17 00:00:00
abstract:BACKGROUND:Traumatic brain injury (TBI) is a common pathological condition that presently lacks a specific pharmacological treatment. Adenosine levels rise following TBI, which is thought to be neuroprotective against secondary brain injury. Evidence from stroke and inflammatory disease models suggests that adenosine s...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/s12974-020-02009-7
更新日期:2020-11-12 00:00:00
abstract:BACKGROUND:In sepsis syndromes the severity of the inflammation triggers microvascular dysfunction and early organ failure. We studied the effects of anti-inflammatory vagus nerve stimulation on the cerebral microcirculatory integrity in an endotoxinemic rat model. METHODS:In both control and endotoxinemic (5 mg/kg li...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/1742-2094-9-183
更新日期:2012-07-25 00:00:00
abstract:BACKGROUND:Monocyte infiltration is involved in the pathogenesis of many retinal degenerative conditions. This process traditionally depends on local expression of chemokines, though the roles of many of these in the degenerating retina are unclear. Here, we investigate expression and in situ localization of the broad ...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/s12974-014-0224-1
更新日期:2015-01-17 00:00:00
abstract:BACKGROUND:Excessive inflammation might activate and injure the blood-brain barrier (BBB), a common feature of many central nervous system (CNS) disorders. We previously developed an in vitro BBB injury model in which the organophosphate paraoxon (PX) affects the BBB endothelium by attenuating junctional protein expres...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/s12974-020-01927-w
更新日期:2020-09-09 00:00:00
abstract::Amyotrophic lateral sclerosis (ALS) is a paralyzing disorder characterized by the progressive degeneration and death of motor neurons and occurs both as a sporadic and familial disease. Mutant SOD1 (mtSOD1) in motor neurons induces vulnerability to the disease through protein misfolding, mitochondrial dysfunction, oxi...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/1742-2094-8-69
更新日期:2011-06-20 00:00:00
abstract::Secretory phospholipase A2-IIA (sPLA2-IIA) is an inflammatory protein known to play a role in the pathogenesis of many inflammatory diseases. Although this enzyme has also been implicated in the pathogenesis of neurodegenerative diseases, there has not been a direct demonstration of its expression in diseased human br...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/1742-2094-3-28
更新日期:2006-10-07 00:00:00
abstract:BACKGROUND:Each year in the USA, over 2.4 million people experience mild traumatic brain injury (TBI), which can induce long-term neurological deficits. The dentate gyrus of the hippocampus is notably susceptible to damage following TBI, as hilar mossy cell changes in particular may contribute to post-TBI dysfunction. ...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/s12974-020-1720-0
更新日期:2020-01-31 00:00:00
abstract:BACKGROUND:Low testosterone and obesity are independent risk factors for dysfunction of the nervous system including neurodegenerative disorders such as Alzheimer's disease (AD). In this study, we investigate the independent and cooperative interactions of testosterone and diet-induced obesity on metabolic, inflammator...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/s12974-014-0162-y
更新日期:2014-09-16 00:00:00
abstract:BACKGROUND:Alzheimer's disease (AD) is characterized by extracellular β-amyloid (Aβ) plaques, neurofibrillary tangles (NFTs), and microglia-dominated neuroinflammation. The Nogo/NgR signal pathway is involved in AD pathological features, but the detailed mechanism needs further investigation. Our previous studies have ...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/s12974-016-0522-x
更新日期:2016-03-03 00:00:00
abstract:BACKGROUND:Gliomas are heterogeneous in the tumor immune microenvironment (TIM). However, a classification of gliomas based on immunogenomic profiling remains lacking. METHODS:We hierarchically clustered gliomas based on the enrichment levels of 28 immune cells in the TIM in five datasets and obtained three clusters: ...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/s12974-020-02030-w
更新日期:2020-11-27 00:00:00
abstract::Microglia are the primary immunocompetent cells in brain tissue and microglia-mediated inflammation is associated with the pathogenesis of various neuronal disorders. Recently, many studies have shown that mesenchymal stem cells (MSCs) display a remarkable ability to modulate inflammatory and immune responses through ...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/1742-2094-11-135
更新日期:2014-08-04 00:00:00
abstract:BACKGROUND:The glial response in multiple sclerosis (MS), especially for recruitment and differentiation of oligodendrocyte progenitor cells (OPCs), predicts the success of remyelination of MS plaques and return of function. As a central player in neuroinflammation, activation and polarization of microglia/macrophages ...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/s12974-019-1586-1
更新日期:2019-10-17 00:00:00
abstract:BACKGROUND:Determining the etiology and possible treatment strategies for numerous diseases requires a comprehensive understanding of compensatory mechanisms in physiological systems. The vagus nerve acts as a key interface between the brain and the peripheral internal organs. We set out to identify mechanisms compensa...
journal_title:Journal of neuroinflammation
pub_type: 杂志文章
doi:10.1186/s12974-019-1544-y
更新日期:2019-07-19 00:00:00