Interleukin-4 mediates the neuroprotective effects of rosiglitazone in the aged brain

Loane, David J.; Deighan, Brian F.; Clarke, Rachael M.; Griffin, Rebecca J.; Lynch, Aileen; Lynch, Marina A.

doi:10.1016/j.neurobiolaging.2007.09.001

Cited by 83 publications

(65 citation statements)

References 61 publications

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“…We report that SIGIRR -/-mice have increased expression of the microglial markers CD40 and ICAM in response to LPS compared to wildtype mice; the co-stimulatory molecules CD80 and CD86 were also upregulated SIGIRR -/-mice in response to LPS and this effect was not observed in wildtype mice. As previously reported, LPS increased IL-6 and TNFα at mRNA and protein levels in hippocampus (Chen et al, 2008;Hellstrom et al, 2005;Loane et al, 2007;Sparkman et al, 2006); significantly, and in parallel with the changes in vitro, the effect of LPS was markedly greater in hippocampus of SIGIRR -/-mice.…”

Section: Discussionsupporting

confidence: 78%

“…In addition to its ability to stimulate cytokine release, LPS upregulates expression of cell surface proteins, considered to be markers of microglial activation (Loane et al, 2007;Qin et al, 2005a). In this study, LPS is shown to increase expression of CD40, as well as another cell surface marker of microglial activation, ICAM-1, but the effect of LPS was several-fold greater in cells prepared from SIGIRR -/-mice.…”

Section: Discussionmentioning

confidence: 49%

“…Previous findings from this laboratory have coupled increased expression of cell surface markers of microglial activation and chemokines with increased production of proinflammatory cytokines (Clarke et al, 2008;Downer et al, 2010;Loane et al, 2007). …”

Section: Lps Induces a More Robust Increase In Proinflammatory Cytokimentioning

confidence: 95%

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SIGIRR modulates the inflammatory response in the brain

Watson

Costello

Carney

et al. 2010

Brain, Behavior, and Immunity

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One of the more recently described members of the interleukin-1 (IL-1) receptor family, single-Ig-Interleukin-1 related receptor (SIGIRR), has been identified as a negative regulator of inflammation in several tissues. It modulates the responses triggered by stimulation of Toll-like receptor (TLR) 4 and IL-1 in several peripheral cell types, possibly in an NFκB-dependent manner. Consistently, responses to lipopolysaccharide (LPS) are exaggerated in SIGIRR-deficient mice and the symptoms of experimental inflammatory conditions are more profound in these animals. Here we set out to establish whether the absence of SIGIRR was associated with inflammatory changes in the brain and report that, LPS induced a greater effect on CD40 and ICAM mRNA in mixed glia prepared from SIGIRR -/-, compared with wildtype mice. This was associated with parallel changes in TNFα and IL-6 at mRNA and protein levels, an effect which was observed in purified microglia but not astrocytes. Similarly, LPS exerted a more profound effect on microglial activation and cytokine production in hippocampal tissue prepared from SIGIRR -/-, compared with wildtype mice. The effect of LPS on exploratory behaviour was also accentuated in SIGIRR -/-mice. The evidence suggests that these changes are a likely consequence of increased hippocampal expression of CD14 and TLR4, and NFκB activation in SIGIRR -/-mice.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 49%

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SIGIRR modulates the inflammatory response in the brain

Watson

Costello

Carney

et al. 2010

Brain, Behavior, and Immunity

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“…Consistent with this is the finding that treatments like eicosapentaenoic acid and the lipid lowering compound, atorvastatin, which attenuate the agerelated increases in microglial activation and IL-1␤ concentration, lead to restoration of LTP (Clarke et al, 2008;. Recent evidence indicates that rosiglitazone, which attenuated the age-related increase in IL-1␤, was also associated with increased ability of aged rats to sustain LTP (Loane et al, 2009). However rosiglitazone did not inhibit the agerelated increase in MHCII mRNA suggesting that it did not affect microglial activation and that its effect on IL-1␤ was a consequence of an effect on another cell type.…”

Section: Introductionmentioning

confidence: 71%

Rosiglitazone attenuates the age-related changes in astrocytosis and the deficit in LTP

Cowley

O'Sullivan

Blau

et al. 2012

Neurobiology of Aging

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Neuroinflammation is a significant and consistent feature of many neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). The greatest risk factor for neurodegenerative disorders is age and a proinflammatory phenotype in the aged brain is believed to contribute to these neurodegenerative conditions. In animal models, neuroinflammatory changes, characterized by increased microglial activation, have been associated with a loss of synaptic plasticity and here we show that treatment of aged rats with the PPAR␥ agonist, rosiglitazone, modulates the inflammatory changes and restores synaptic function. The evidence presented highlights an important role for astrocytes in inducing inflammatory changes and suggests that the age-related astrogliosis and astrocytosis is responsible for the increase in the proinflammatory cytokine, tumor necrosis factor alpha (TNF-␣). Magnetic resonance (MR) imaging revealed an age-related increase in T1 relaxation time and, importantly, treatment of aged rats with rosiglitazone reversed the age-related increases in astrogliosis and astrocytosis, TNF-␣ concentration and T1 relaxation time. The evidence indicates that the site of action for rosiglitazone is endothelial cells, and suggests that its effect on astrocytes is secondary to its effect on endothelial cells.

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“…Animals were anesthetized by intraperitoneal injection of urethane (1.5 g/kg) and, if necessary, a top-up dose of urethane (maximum dose 2.5 g/kg) was given to achieve deep anesthesia as indicated by the absence of a pedal reflex. LTP was assessed in perforant path-granule cell synapses as previously described (Loane et al, 2009). Briefly, a bipolar stimulating electrode and a unipolar recording electrode were positioned in the perforant path (4.4 mm lateral to lambda) and in the dorsal cell body region of the dentate gyrus (2.5 mm lateral and 3.9 mm posterior to bregma).…”

Section: Analysis Of Ltpmentioning

confidence: 99%

The age-related deficit in LTP is associated with changes in perfusion and blood-brain barrier permeability

Blau¹,

Cowley²,

O'Sullivan³

et al. 2012

Neurobiology of Aging

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In view of the increase in the aging population and the unavoidable parallel increase in the incidence of age-related neurodegenerative diseases, a key challenge in neuroscience is the identification of clinical signatures which change with age and impact on neuronal and cognitive function. Early diagnosis offers the possibility of early therapeutic intervention, thus magnetic resonance imaging (MRI) is potentially a powerful diagnostic tool. We evaluated age-related changes in relaxometry, blood flow, and blood-brain barrier (BBB) permeability in the rat by magnetic resonance imaging and assessed these changes in the context of the age-related decrease in synaptic plasticity. We report that T2 relaxation time was decreased with age; this was coupled with a decrease in gray matter perfusion, suggesting that the observed microglial activation, as identified by increased expression of CD11b, MHCII, and CD68 by immunohistochemistry, flow cytometry, or polymerase chain reaction (PCR), might be a downstream consequence of these changes. Increased permeability of the blood-brain barrier was observed in the perivascular area and the hippocampus of aged, compared with young, rats. Similarly there was an age-related increase in CD45-positive cells by flow cytometry, which are most likely infiltrating macrophages, with a parallel increase in the messenger mRNA expression of chemokines IP-10 and MCP-1. These combined changes may contribute to the deficit in long-term potentiation (LTP) in perforant path-granule cell synapses of aged animals.

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Interleukin-4 mediates the neuroprotective effects of rosiglitazone in the aged brain

Cited by 83 publications

References 61 publications

SIGIRR modulates the inflammatory response in the brain

SIGIRR modulates the inflammatory response in the brain

Rosiglitazone attenuates the age-related changes in astrocytosis and the deficit in LTP

The age-related deficit in LTP is associated with changes in perfusion and blood-brain barrier permeability

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