Objective
The present study was undertaken to determine the efficacy of coadministration of fingolimod with alteplase in acute ischemic stroke patients in a delayed time window.
Methods
This was a ...prospective, randomized, open‐label, blinded endpoint clinical trial, enrolling patients with internal carotid artery or middle cerebral artery proximal occlusion within 4.5 to 6 hours from symptom onset. Patients were randomly assigned to receive alteplase alone or alteplase with fingolimod. All patients underwent pretreatment and 24‐hour noncontrast computed tomography (CT)/perfusion CT/CT angiography. The coprimary endpoints were the decrease of National Institutes of Health Stroke Scale scores over 24 hours and the favorable shift of modified Rankin Scale score (mRS) distribution at day 90. Exploratory outcomes included vessel recanalization, anterograde reperfusion, and retrograde reperfusion of collateral flow.
Results
Each treatment group included 23 patients. Compared with alteplase alone, patients receiving fingolimod plus alteplase exhibited better early clinical improvement at 24 hours and a favorable shift of mRS distribution at day 90. In addition, patients who received fingolimod and alteplase exhibited a greater reduction in the perfusion lesion accompanied by suppressed infarct growth by 24 hours. Fingolimod in conjunction with alteplase significantly improved anterograde reperfusion of downstream territory and prevented the failure of retrograde reperfusion from collateral circulation.
Interpretation
Fingolimod may enhance the efficacy of alteplase administration in the 4.5‐ to 6‐hour time window in patients with a proximal cerebral arterial occlusion and salvageable penumbral tissue by promoting both anterograde reperfusion and retrograde collateral flow. These findings are instructive for the design of future trials of recanalization therapies in extended time windows. Ann Neurol 2018;84:725–736
Microglia, the resident inflammatory cells of the CNS, are the only CNS cells that express the fractalkine receptor (CX3CR1). Using three different in vivo models, we show that CX3CR1 deficiency ...dysregulates microglial responses, resulting in neurotoxicity. Following peripheral lipopolysaccharide injections, Cx3cr1-/- mice showed cell-autonomous microglial neurotoxicity. In a toxic model of Parkinson disease and a transgenic model of amyotrophic lateral sclerosis, Cx3cr1-/- mice showed more extensive neuronal cell loss than Cx3cr1+ littermate controls. Augmenting CX3CR1 signaling may protect against microglial neurotoxicity, whereas CNS penetration by pharmaceutical CX3CR1 antagonists could increase neuronal vulnerability.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Oxidative stress plays an important role in cerebral ischemia–reperfusion injury. Dimethyl fumarate (DMF) and its primary metabolite monomethyl fumarate (MMF) are antioxidant agents that can activate ...the nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway and induce the expression of antioxidant proteins. Here, we evaluated the impact of DMF and MMF on ischemia-induced brain injury and whether the Nrf2 pathway mediates the effects provided by DMF and MMF in cerebral ischemia–reperfusion injury. Using a mouse model of transient focal brain ischemia, we show that DMF and MMF significantly reduce neurological deficits, infarct volume, brain edema, and cell death. Further, DMF and MMF suppress glial activation following brain ischemia. Importantly, the protection of DMF and MMF was mostly evident during the subacute stage and was abolished in Nrf2
−/−
mice, indicating that the Nrf2 pathway is required for the beneficial effects of DMF and MMF. Together, our data indicate that DMF and MMF have therapeutic potential in cerebral ischemia–reperfusion injury and their protective role is likely mediated by the Nrf2 pathway.
The remarkable global development of disease-modifying therapies （DMTs） specific for multiple sclerosis （MS） has significantly reduced the frequency of relapse, slowed the progression of disability, ...and improved the quality of life in patients with MS. With increasing numbers of approved DMTs, neurologists in North America and Europe are able to present multiple treatment options to their patients to achieve a better therapeutic outcome, and in many cases, no evidence of disease activity. MS patients have improved accessibility to various DMTs at no or minimal out-of-pocket cost. The ethical guidelines defined by the Edinburgh revision of the Declaration of Helsinki strongly discourage the use of placebo control groups in modern MS clinical trials. The use of an active comparator control group increases the number of participants in each group that is essential to achieve statistical significance, thus further increasing the difficulty of completing randomized controlled trials （RCTs） for the development of new MS therapies. There is evidence of a high prevalence of MS and a large number of patients in Asia. The belief of the existence of Asian types of MS that are distinct from Western types, and regulatory policies are among the reasons why DMTs are limited in most Asian countries. Lack of access to approved DMTs provides a good opportunity for clinical trials that are designed for the development of new MS therapies. Recently, data from RCTs have demonstrated excellent recruitment of participants and the completion of multi-nation and single-nation MS trials within this region. Recent studies using the McDonald MS diagnostic criteria carefully excluded patients with neuromyelitis optica （NMO） and NMO spectrum disorder, and demonstrated that patients with MS in Asia have clinical characteristics and treatment responses similar to those in Western countries.
There is increasing interest in the isolation of adult microglia to study their functions at a morphological and molecular level during normal and neuroinflammatory conditions. Microglia have ...important roles in brain homeostasis, and in disease states they exert neuroprotective or neurodegenerative functions. To assay expression profiles or functions of microglia, we have developed a method to isolate microglial cells and infiltrating leukocytes from adult mouse brain. This protocol uses a digestion cocktail containing collagenase and dispase, and it involves separation over discontinuous percoll gradients. Isolated cells can be used for RNA analysis, including RNase protection analysis (RPA), quantitative RT-PCR, high-density microarray, proteomic or flow cytometric characterization of cell surface markers or adoptive transfer. Cell isolation can be completed in less than 4 h.
Multiple sclerosis (MS), a leading nontraumatic cause of neurologic disability,1 is an inflammatory disorder involving autoreactive T cells attacking myelin sheaths in the CNS, resulting in ...demyelination and axonal loss. The development of disease-modifying therapies (DMTs) for MS has been remarkable in recent years. Many approved DMTs for MS are parenteral. Oral fingolimod2,3 (Gilenya, Novartis, Basel, Switzerland) was approved by the US Food and Drug Administration (FDA) in 2010. Immunomodulation including sequestration of lymphocytes in the secondary lymphoid organs is the main proposed mechanism of action. In a phase 3 trial, rare but fatal viral infections were observed.2 One patient with MS developed disseminated primary varicella-zoster virus infection. Another patient had herpes simplex encephalitis. Both patients received fingolimod 1.25 mg once daily, a dose that is higher than the currently FDA-approved dose. Although fingolimod at 0.5 mg once daily did not show increased infection incidence in individual trials that led to FDA approval, a recent analysis of pooled trial data demonstrated a relatively higher rate of varicellazoster virus infections in patients treated with fingolimod 0.5 mg daily than in placebo recipients.4 Disseminated cryptococcosis is a rare opportunistic infection reported in immunocompromised individuals such as patients with AIDS.5 In this report, we describe a patient with MS who received fingolimod therapy and subsequently developed disseminated cryptococcal infection.
CXCR3, the receptor for CXCL9/MIG, CXCL10/IP-10, and CXCL11/I-TAC, is preferentially expressed on activated Th1 T cells and has been predicted to play an important role in their trafficking. However, ...this simplistic view of the function of CXCR3 and its ligands has not been borne out by studies of disease models, including experimental autoimmune encephalomyelitis (EAE), using varied methods of receptor blockade, as well as knockout or transgenic mice. This review focuses on the current understanding of the enigmatic role of CXCR3 and its ligands in CNS inflammatory/autoimmune disorders. The conflicting results among varied models of CNS inflammation suggest complex and multiple roles for CXCR3 and its ligands in the pathogenesis of CNS inflammatory/autoimmune diseases. Thus, further study is needed to determine how CXCL10 neutralizing agents or CXCR3 receptor antagonists might be applied to treating human disease.
Objective
Inflammatory progressive multifocal leukoencephalopathy (iPML) with enhancing magnetic resonance imaging (MRI) lesions and leukocyte infiltration occurs in human immunodeficiency virus ...(HIV)–infected individuals after highly active antiretroviral therapy (HAART) treatment. MRI diagnostic criteria for PML suggest that iPML does not occur in HIV‐negative individuals.
Methods
We studied pathologically proved PML (12 by biopsy, 9 with MRI, 32 at autopsy).
Results
HIV‐negative (2/5) and ‐positive (2/4) PML patients had enhancing MRI lesions, correlated with CD3+ lymphocyte infiltration. Inflammatory infiltrates occurred in the majority of HIV‐negative (7/8) and HIV‐positive/HAART (17/20) cases (p > 0.2), but in only 2 of 16 HIV‐positive/non‐HAART cases (p < 0.001).
Interpretation
iPML showed radiographic and pathological similarity in HIV‐positive/HAART and HIV‐negative patients. HIV‐negative iPML necessitates further consideration of MRI criteria for PML. Ann Neurol 2007
The development and function of Th17 cells are influenced in part by the cytokines TGF-β, IL-23 and IL-6, but the mechanisms that govern recruitment and activity of Th17 cells during initiation of ...autoimmunity remain poorly defined. We show here that the development of autoreactive Th17 cells in secondary lymphoid organs in experimental autoimmune myasthenia gravis - an animal model of human myasthenia gravis - is modulated by IL-6-producing CD11b⁺ cells via the CC chemokine ligand 2 (CCL2). Notably, acetylcholine receptor (AChR)-reactive Th17 cells provide help for the B cells to produce anti-AChR antibodies, which are responsible for the impairment of the neuromuscular transmission that contributes to the clinical manifestations of autoimmunity, as indicated by a lack of disease induction in IL-17-deficient mice. Thus, Th17 cells can promote humoral autoimmunity via a novel mechanism that involves CCL2.Supporting Information for this article is available at www.wiley-vch.de/contents/jc_2040/2008/37973_s.pdf
This article focuses on the production of chemokines by resident glial cells of the nervous system. We describe studies in two distinct categories of inflammation within the nervous system: ...immune-mediated inflammation as seen in experimental autoimmune encephalomyelitis (EAE) or multiple sclerosis (MS) and post-traumatic inflammation. We provide evidence that chemokines play a role in amplifying the inflammatory reaction in EAE (and, probably, MS). In the context of neural trauma, chemokines appear to be primary stimuli for leukocyte recruitment. Strikingly, expression of monocyte chemoattractant protein (MCP)-1 and interferon-gamma-inducible protein-10 (IP-10) are largely restricted to astrocytes or other glial cells in these diverse pathological states. The remainder of the review focuses on studies that address the molecular mechanisms which underlie transcriptional regulation of three astrocyte-derived chemokines: MCP-1, IP-10 and beta-R1/interferon-gamma-inducible T-cell chemoattractant (I-TAC). Based on these studies, we propose that the complex promoters of these genes are marvelously organized for flexible and efficient response to challenge. In the case of MCP-1, several different stimuli can elicit gene transcription, acting through a conserved mechanism that includes binding of inducible transcription factors and recruitment of the constitutive factor Sp1. For IP-10 and beta-R1/I-TAC, it appears that efficient gene transcription occurs only in highly inflammatory circumstances that produce aggregates of simultaneous stimuli. These characteristics, in turn, mirror the expression patterns of the endogenous genes: MCP-1 is expressed under a variety of circumstances, while IP-10 appears primarily during immune-mediated processes that feature exposure of resident neuroglia to high levels of inflammatory cytokines.
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