Brain inflammation is induced by co-morbidities and risk factors for stroke

Drake, Caroline; Boutin, Hervé; Jones, Matthew; Dénes, Ádám; McColl, Barry W.; Selvarajah, Johann; Hulme, Sharon; Georgiou, Rachel; Hinz, Rainer; Gerhard, Alexander; Vail, Andy; Prenant, C.; Julyan, P. J.; Maroy, Renaud; Brown, Gavin; Smigova, Alison; Herholz, Karl; Kassiou, Michael; Crossman, David C.; Francis, Sheila E.; Proctor, Spencer D.; Russell, James C.; Hopkins, Stephen J.; Tyrrell, Pippa J.; Rothwell, Nancy J.; Allan, Stuart M.

doi:10.1016/j.bbi.2011.02.008

Cited by 180 publications

(146 citation statements)

References 40 publications

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“…One of the pathologic features of obesity and InsRes is inflammation, and it has been described that central inflammation has an impact on brain function possibly through the import of inflammatory cytokines and immune cells into the central nervous system. 31,[36][37][38] Consistent with these reports, we found a significant increase in reactive astrocyte number and size in the hippocampus of HFFD rats, as well as GFAP þ subgranular cells extending vertical processes onto the granular layer of the DG of what we believe, based on morphology and location, is radial glia. In addition, we found slight changes in some microglial cells consistent in increased body size suggesting the onset of a subtle microglial activation.…”

Section: Discussionsupporting

confidence: 87%

Short-Term High-Fat-and-Fructose Feeding Produces Insulin Signaling Alterations Accompanied by Neurite and Synaptic Reduction and Astroglial Activation in the Rat Hippocampus

Calvo-Ochoa

Hernández‐Ortega

Ferrera

et al. 2014

J Cereb Blood Flow Metab

128

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Chronic consumption of high-fat-and-fructose diets (HFFD) is associated with the development of insulin resistance (InsRes) and obesity. Systemic insulin resistance resulting from long-term HFFD feeding has detrimental consequences on cognitive performance, neurogenesis, and long-term potentiation establishment, accompanied by neuronal alterations in the hippocampus. However, diet-induced hippocampal InsRes has not been reported. Therefore, we investigated whether short-term HFFD feeding produced hippocampal insulin signaling alterations associated with neuronal changes in the hippocampus. Rats were fed with a control diet or an HFFD consisting of 10% lard supplemented chow and 20% high-fructose syrup in the drinking water. Our results show that 7 days of HFFD feeding induce obesity and InsRes, associated with the following alterations in the hippocampus: (1) a decreased insulin signaling; (2) a decreased hippocampal weight; (3) a reduction in dendritic arborization in CA1 and microtubule-associated protein 2 (MAP-2) levels; (4) a decreased dendritic spine number in CA1 and synaptophysin content, along with an increase in tau phosphorylation; and finally, (5) an increase in reactive astrocyte associated with microglial changes. To our knowledge, this is the first report addressing hippocampal insulin signaling, as well as morphologic, structural, and functional modifications due to short-term HFFD feeding in the rat.

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Section: Discussionsupporting

confidence: 87%

Short-Term High-Fat-and-Fructose Feeding Produces Insulin Signaling Alterations Accompanied by Neurite and Synaptic Reduction and Astroglial Activation in the Rat Hippocampus

Calvo-Ochoa

Hernández‐Ortega

Ferrera

et al. 2014

J Cereb Blood Flow Metab

128

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“…Although no differences were observed in infarct volume between lean and Cp rats, the latter showed increased BBB damage after stroke. This difference in BBB damage may be explained by increased systemic and cerebrovascular inflammation in the presence of comorbidity (Drake et al, 2011). Indeed, peripheral IL-6 is implicated in atherosclerosis (Schuett et al, 2009), which, together with increased neuroinflammation, may lead to alterations in vascular permeability before stroke and/or influence BBB breakdown after stroke.…”

Section: Discussionmentioning

confidence: 99%

“…Blood-brain barrier (BBB) damage was assessed by immunoglobin G immunostaining, as described previously (Greenhalgh et al, 2010). Double or triple immunofluorescence was performed on free-floating brain sections as previously described (Drake et al, 2011). The primary antibodies used were as follows: goat anti-rat metalloproteinase-9 (MMP-9; 1:100; R&D Systems, UK), rabbit anti-neutrophil serum (1:100; SJC; Anthony et al, 1998), rabbit anti-Iba1 (1:1000; Wako Chemicals, Germany), goat anti-Iba1 (1:1000; Abcam, Cambridge, UK), goat antichemokine (C-X-C motif) ligand (CXCL1; 1:100; R&D Systems, Abingdon, UK), rabbit polyclonal anti-IL-6 (1:100; Abcam).…”

Section: Histology/immunohistochemistrymentioning

confidence: 99%

Delayed Administration of Interleukin-1 Receptor Antagonist Reduces Ischemic Brain Damage and Inflammation in Comorbid Rats

Pradillo

Greenhalgh

Boutin

et al. 2012

J Cereb Blood Flow Metab

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123

108

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Many neuroprotective agents have been effective in experimental stroke, yet few have translated into clinical application. One reason for this may be failure to consider clinical comorbidities/risk factors in experimental models. We have shown that a naturally occurring interleukin-1 receptor antagonist (IL-1Ra) is protective against ischemic brain damage in healthy animals. However, protective effects of IL-1Ra have not been determined in comorbid animals. Thus, we tested whether IL-1Ra protects against brain injury induced by experimental ischemia in aged JCR-LA (corpulent) rats, which have clinically relevant risk factors. Male, aged, lean, and corpulent rats exposed to transient (90 minutes) occlusion of the middle cerebral artery (tMCAO) were administered two doses of IL-1Ra (25 mg/kg, subcutaneously) during reperfusion. Brain injury and neuroinflammatory changes were assessed 24 hours after tMCAO. Our results show that IL-1Ra administered at reperfusion significantly reduced infarct volume measured by magnetic resonance imaging (50%, primary outcome) and blood-brain barrier disruption in these comorbid animals. Interleukin-1Ra also reduced microglial activation, neutrophil infiltration, and cytokines levels in the brain. These data are the first to indicate that IL-1Ra protects against ischemic brain injury when administered via a clinically relevant route and time window in animals with multiple risk factors for stroke.

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“…In hyperlipidemic mice, positron emission tomography imaging and immunostaining confirmed increased microglial phagocytosis, microgliosis, and higher expression of vascular adhesion molecules. In addition, larger numbers of activated myeloid phagocytes, T cells, and granulocytes in the choroid plexus were observed in hyperlipidemic mice [238]. Hyperlipidemia is associated with elevated IL-6, TNF-α, MCP-1, and CCL5 in the periphery [239].…”

Section: Hyperlipidemiamentioning

confidence: 95%

Microglia and Monocyte-Derived Macrophages in Stroke

2016

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Historically, the brain has been considered an immune-privileged organ separated from the peripheral immune system by the blood-brain barrier. However, immune responses do occur in the brain in neurological conditions in which the integrity of the blood-brain barrier is compromised, exposing the brain to peripheral antigens and endogenous danger signals. While most of the associated pathological processes occur in the central nervous system, it is now clear that peripheral immune cells, especially mononuclear phagocytes, that infiltrate into the injury site play a key role in modulating the progression of primary brain injury development. As inflammation is a necessary and critical component for the subsequent injury resolution process, understanding the contribution of mononuclear phagocytes on the regulation of inflammatory responses may provide novel approaches for potential therapies. Furthermore, predisposed comorbid conditions at the time of stroke cause the alteration of stroke-induced immune and inflammatory responses and subsequently influence stroke outcome. In this review, we summarize a role for microglia and monocytes/macrophages in acute ischemic stroke in the context of normal and metabolically compromised conditions.

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Brain inflammation is induced by co-morbidities and risk factors for stroke

Cited by 180 publications

References 40 publications

Short-Term High-Fat-and-Fructose Feeding Produces Insulin Signaling Alterations Accompanied by Neurite and Synaptic Reduction and Astroglial Activation in the Rat Hippocampus

Short-Term High-Fat-and-Fructose Feeding Produces Insulin Signaling Alterations Accompanied by Neurite and Synaptic Reduction and Astroglial Activation in the Rat Hippocampus

Delayed Administration of Interleukin-1 Receptor Antagonist Reduces Ischemic Brain Damage and Inflammation in Comorbid Rats

Microglia and Monocyte-Derived Macrophages in Stroke

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