-
Sajjad Muhammad,
Emanuel Haasbach,
Maria Kotchourko,
Anne Strigli,
Antje Krenz,
Dirk A Ridder,
Annette B Vogel,
Hugo H Marti,
Yousef Al-Abed,
Oliver Planz,
Markus Schwaninger
[show abstract]
[hide abstract]
ABSTRACT: Stroke is triggered by several risk factors, including influenza and other respiratory tract infections. However, it is unknown how and in which way influenza infection affects stroke outcome.
We infected mice intranasally with human influenza A (H1N1) virus and occluded the middle cerebral artery to induce ischemic strokes. Infarct volume and intracerebral hemorrhage were determined by histology. To evaluate the integrity of the blood-brain barrier and inflammation, we measured various cytokines in vivo and in vitro and performed immunohistochemistry of leukocyte markers, collagen IV, immunoglobulins, and matrix metalloproteinase-9.
Influenza virus infection increased infarct size. Whereas changes in cardiovascular parameters did not explain this effect, we found evidence for an inflammatory mechanism. In influenza virus infection, the respiratory tract released cytokines into the blood, such as RANTES that induced macrophage inflammatory protein-2 and other inflammatory mediators in the ischemic brain. In infected mice, there was an increased number of neutrophils expressing the matrix metalloproteinase-9 in the ischemic brain. This was accompanied by severe disruption of the blood-brain barrier and an increased rate of intracerebral hemorrhages after tissue plasminogen activator treatment. To investigate the role of cytokines, we blocked cytokine release by using GTS-21, a selective agonist of the α7 nicotinic acetylcholine receptor. GTS-21 ameliorated ischemic brain damage and improved survival.
Influenza virus infection triggers a cytokine cascade that aggravates ischemic brain damage and increases the risk of intracerebral hemorrhage after tissue plasminogen activator treatment. Blockade of cytokine production by α7 nicotinic acetylcholine receptor agonists is a novel therapeutic option to treat stroke in a proinflammatory context.
Stroke 03/2011; 42(3):783-91. · 5.73 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 17β-Estradiol (E2) was shown to exert neuroprotective effects both in in vitro and in vivo models of stroke. Although these effects of E2 are known to require estrogen receptor-α (ERα), the cellular target of estrogen-mediated neuroprotection remains unknown. Using cell type-specific ER mutant mice in an in vivo model of stroke, we specifically investigated the role of ERα in neuronal cells versus its role in the microglia in the mediation of neuroprotection by estrogens. We generated and analyzed two different tissue-specific knockout mouse lines lacking ERα either in cells of myeloid lineage, including microglia, or in the neurons of the forebrain. Both E2-treated and E2-untreated mutant and control mice were subjected to a permanent middle cerebral artery occlusion for 48 h, and the infarct volume was quantified. Although the infarct volume of E2-treated female myeloid-specific ERα knockout mice was similar to that of E2-treated control mice, both male and female neuron-specific ERα mutant mice had larger infarcts than did control mice after E2 treatment. We conclude that neuronal ERα in female and male mice mediates neuroprotective estrogen effects in an in vivo mouse model of stroke, whereas microglial ERα is dispensable.Keywords: cerebral ischemia; estrogen receptor-α; microglia; neuron
Journal of Cerebral Blood Flow & Metabolism 12/2009; 30(5):935-942. · 5.01 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 17beta-Estradiol (E(2)) was shown to exert neuroprotective effects both in in vitro and in vivo models of stroke. Although these effects of E(2) are known to require estrogen receptor-alpha (ER alpha), the cellular target of estrogen-mediated neuroprotection remains unknown. Using cell type-specific ER mutant mice in an in vivo model of stroke, we specifically investigated the role of ER alpha in neuronal cells versus its role in the microglia in the mediation of neuroprotection by estrogens. We generated and analyzed two different tissue-specific knockout mouse lines lacking ER alpha either in cells of myeloid lineage, including microglia, or in the neurons of the forebrain. Both E(2)-treated and E(2)-untreated mutant and control mice were subjected to a permanent middle cerebral artery occlusion for 48 h, and the infarct volume was quantified. Although the infarct volume of E(2)-treated female myeloid-specific ER alpha knockout mice was similar to that of E(2)-treated control mice, both male and female neuron-specific ER alpha mutant mice had larger infarcts than did control mice after E(2) treatment. We conclude that neuronal ER alpha in female and male mice mediates neuroprotective estrogen effects in an in vivo mouse model of stroke, whereas microglial ER alpha is dispensable.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 12/2009; 30(5):935-42. · 5.46 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Activation of the cannabinoid 2 receptor (CB(2)) reduces ischemic injury in several organs. However, the mechanisms underlying this protective action are unclear. In a mouse model of ischemic stroke, we show that the CB(2) agonist JWH-133 (1 mg . kg(-1) . d(-1)) decreases the infarct size measured 3 d after onset of ischemia. The neuroprotective effect of JWH-133 was lost in CB(2)-deficient mice, confirming the specificity of JWH-133. Analysis of bone marrow chimeric mice revealed that bone marrow-derived cells mediate the CB(2) effect on ischemic brain injury. CB(2) activation reduced the number of neutrophils in the ischemic brain as shown by FACS analysis and by measuring the levels of the neutrophil marker enzyme myeloperoxidase. Indeed, we found in vitro that CB(2) activation inhibits adherence of neutrophils to brain endothelial cells. JWH-133 (1 microM) also interfered with the migration of neutrophils induced by the endogenous chemokine CXCL2 (30 ng/ml) through activation of the MAP kinase p38. This effect on neutrophils is likely responsible for the neuroprotection mediated by JWH-133 because JWH-133 was no longer protective when neutrophils were depleted. In conclusion, our data demonstrate that by activating p38 in neutrophils, CB(2) agonists inhibit neutrophil recruitment to the brain and protect against ischemic brain injury.-Murikinati, S., Jüttler, E., Keinert, T., Ridder, D. A., Muhammad, S., Waibler, Z., Ledent, C., Zimmer, A., Kalinke, U., Schwaninger, M. Activation of cannabinoid 2 receptors protects against cerebral ischemia by inhibiting neutrophil recruitment.
The FASEB Journal 11/2009; 24(3):788-98. · 5.71 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A morphological hallmark of Alzheimer's disease (AD) is the deposition of amyloid-beta peptide in plaques and along blood vessels. As several lines of evidence suggest that vascular dysfunction contributes to AD, the pathophysiology of diabetic vasculopathy and stroke may cast light on the vascular component of AD. In this review, we compile some recent findings on the role of reactive oxygen species in diabetes-induced vascular dysfunction and the consequent cerebral ischemia and compare them with key findings in AD. Overall, there is compelling evidence that reactive oxygen species play a key role in the pathophysiology of AD. Unfortunately, this insight has not yet led to a new treatment of AD.
Journal of Alzheimer's disease: JAD 02/2009; 16(4):775-85. · 3.74 Impact Factor
-
Sajjad Muhammad,
Waleed Barakat,
Stoyan Stoyanov,
Sasidhar Murikinati,
Huan Yang,
Kevin J Tracey,
Martin Bendszus,
Grazisa Rossetti,
Peter P Nawroth,
Angelika Bierhaus,
Markus Schwaninger
[show abstract]
[hide abstract]
ABSTRACT: In ischemic stroke, the necrotic core is surrounded by a zone of inflammation, in which delayed cell death aggravates the initial insult. Here, we provide evidence that the receptor for advanced glycation end products (RAGE) functions as a sensor of necrotic cell death and contributes to inflammation and ischemic brain damage. The RAGE ligand high mobility group box 1 (HMGB1) was elevated in serum of stroke patients and was released from ischemic brain tissue in a mouse model of cerebral ischemia. A neutralizing anti-HMGB1 antibody and HMGB1 box A, an antagonist of HMGB1 at the receptor RAGE, ameliorated ischemic brain damage. Interestingly, genetic RAGE deficiency and the decoy receptor soluble RAGE reduced the infarct size. In vitro, expression of RAGE in (micro)glial cells mediated the toxic effect of HMGB1. Addition of macrophages to neural cultures further enhanced the toxic effect of HMGB1. To test whether immigrant macrophages in the ischemic brain mediate the RAGE effect, we generated chimeric mice by transplanting RAGE(-/-) bone marrow to wild-type mice. RAGE deficiency in bone marrow-derived cells significantly reduced the infarct size. Thus, HMGB1-RAGE signaling links necrosis with macrophage activation and may provide a target for anti-inflammatory therapy in stroke.
Journal of Neuroscience 12/2008; 28(46):12023-31. · 7.11 Impact Factor
-
Ioana Inta,
Stephan Paxian,
Ira Maegele,
Wen Zhang,
Marina Pizzi,
PierFranco Spano,
Ilenia Sarnico, Sajjad Muhammad,
Oliver Herrmann,
Dragos Inta,
Bernd Baumann,
Hsiou-Chi Liou,
Roland M Schmid,
Markus Schwaninger
[show abstract]
[hide abstract]
ABSTRACT: The transcription factor nuclear factor kappaB (NF-kappaB) is well known for its antiapoptotic action. However, in some disorders, such as cerebral ischemia, a proapoptotic function of NF-kappaB has been demonstrated. To analyze which subunit of NF-kappaB is functional in cerebral ischemia, we induced focal cerebral ischemia in mice with a germline deletion of the p52 or c-Rel gene or with a conditional deletion of RelA in the brain. Only RelA deficiency reduced infarct size. Interestingly, expression of the proapoptotic BH3 (Bcl-2 homology domain 3)-only genes Bim and Noxa in cerebral ischemia depended on RelA and the upstream kinase IKK (IkappaB kinase). RelA stimulated Bim and Noxa gene transcription in primary cortical neurons and bound to the promoter of both genes. Thus, the deleterious function in cerebral ischemia is specific for the NF-kappaB subunit RelA and may be mediated through Bim and Noxa.
Journal of Neuroscience 01/2007; 26(50):12896-903. · 7.11 Impact Factor
-
Oliver Herrmann,
Bernd Baumann,
Rossana de Lorenzi, Sajjad Muhammad,
Wen Zhang,
Jens Kleesiek,
Max Malfertheiner,
Martin Köhrmann,
Ioana Potrovita,
Ira Maegele,
Cordian Beyer,
James R Burke,
Mazahir T Hasan,
Hermann Bujard,
Thomas Wirth,
Manolis Pasparakis,
Markus Schwaninger
[show abstract]
[hide abstract]
ABSTRACT: The IkappaB kinase complex IKK is a central component of the signaling cascade that controls NF-kappaB-dependent gene transcription. So far, its function in the brain is largely unknown. Here, we show that IKK is activated in a mouse model of stroke. To investigate the function of IKK in brain ischemia we generated mice that contain a targeted deletion of Ikbkb (which encodes IKK2) in mouse neurons and mice that express a dominant inhibitor of IKK in neurons. In both lines, inhibition of IKK activity markedly reduced infarct size. In contrast, constitutive activation of IKK2 enlarged the infarct size. A selective small-molecule inhibitor of IKK mimicked the effect of genetic IKK inhibition in neurons, reducing the infarct volume and cell death in a therapeutic time window of 4.5 h. These data indicate a key function of IKK in ischemic brain damage and suggest a potential role for IKK inhibitors in stroke therapy.
Nature Medicine 01/2006; 11(12):1322-9. · 22.46 Impact Factor
