Age exaggerates proinflammatory cytokine signaling and truncates signal transducers and activators of transcription 3 signaling following ischemic stroke in the rat

Abstract

Neuroinflammation is associated with glial activation following a variety of brain injuries, including stroke. While activation of perilesional astrocytes and microglia following ischemic brain injury is well documented, the influence of age on these cellular responses after stroke is unclear. This study investigated the influence of advanced age on neuronal degeneration, neuroinflammation, and glial activation in female Sprague-Dawley rats after reversible embolic occlusion of the middle cerebral artery (MCAO). Results indicate that in comparison to young adult rats (3 months), aged rats (18 months) showed enhanced neuronal degeneration, altered microglial response, and a markedly increased expression of proinflammatory cytokines/ chemokines following MCAO. In addition, the time-course for activation of STAT3, the signaling mechanism that regulates astrocyte reactivity, was truncated in the aged rats after MCAO. Moreover, the expression of SOCS3, which is associated with termination of astrogliosis, was enhanced as a function of age after MCAO. These findings are suggestive of an enhanced proinflammatory response and a truncated astroglial response as a function of advanced age following MCAO. These data provide further evidence of the prominent role played by age in the molecular and cellular responses to ischemic stroke and suggest that astrocytes may represent targets for future therapies aimed at improving stroke outcome.Keywords neurovascular unit; neuropoietic; IL6; SOCS3; astrocyte; microglia Treatment of acute ischemic stroke injury is hampered by the inability to translate successful animal studies into clinically effective therapies. Despite considerable research interest in specific cardiovascular risk factors for stroke, such as hypertension, hypercholesterolemia, and diabetes, data from the Framingham Heart study demonstrate that age is the single greatest risk factor for stroke (Grossi, 2008). Aging results in enhanced basal expression of proinflammatory cytokines and these same proinflammatory mediators often are associated Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2011 October 13. with neural injury-related activation of microglia and astroglia. Taken together, the aging, inflammation and glial activation phenotypes serve as the basis for the "inflam-aging" hypothesis (Salvioli et al., 2006;Franceschi et al., 2007;Giunta, 2008). According to this hypothesis, increased inflammation during the aging process results from dysregulation of the immune system and a...

Aging aggravates ischemic stroke-induced brain damage in mice with chronic peripheral infection

“…It is thus still unclear whether aging exerts its effects via stimulation of excessive or dysregulated inflammatory responses. This hypothesis is supported by previous studies showing that aged animals have altered immune responses resulting from ischemic insult (Kharlamov et al, 2000;PopaWagner et al, 2007;Dinapoli et al, 2010;Sieber et al, 2011), intracerebral hemorrhage (Lee et al, 2009) or mechanical injury (Kyrkanides et al, 2001). However, mechanisms through which aging interacts with systemic inflammation to influence cerebrovascular pathologies remain unclear.…”

“…Cerebral inflammation is elevated with aging (Sieber et al, 2011), and aged animals have been reported to show an increase in proinflammatory mediators after ischemia (Dinapoli et al, 2010), intracerebral hemorrhage (Lee et al, 2009), or mechanical injury (Kyrkanides et al, 2001). In the current study, the brain peri-infarct levels of MCP-1, KC, IL-1a, and RANTES were elevated after brain ischemia in aged mice compared with their young counterparts.…”

Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy

“…10 Hippocampal protein samples were dissolved in 0.5 ml hot (85°-95°C) 1% sodium dodecyl sulfate, sonicated, and assayed with a bicinchoninic acid protein assay kit (Thermo Fisher Scientific). Thirty micrograms of protein per well was run with 2× Laemmli buffer on precast Bolt Bis-Tris Plus 10% 12-well gels (Life Technologies) using a Bolt Mini tank system (Life Technologies).…”

Regulation of Basal and Injury-Induced Fate Decisions of Adult Neural Precursor Cells: Focus on SOCS2 and Related Signalling Pathways

“…SOCS3 expression is induced or upregulated in various brain regions including hippocampus and lateral ventricles in response to CNTF administration [197], ischemic stroke [198,199] and seizure, which also showed transient downregulation of hippocampal SOCS2 expression but no upregulation of SOCS1 [200]. Conversely, after transient forebrain ischemia, SOCS2 expression was upregulated in the hippocampus, not only in astrocytes but also a subset of nestin positive NPCs [201].…”