Increased levels of proinflammatory cytokines in the aged rat brain attenuate injury‐induced cytokine response after excitotoxic damage

Abstract

In order to evaluate proinflammatory cytokine levels and their producing cell types in the control aged rat brain and after acute excitotoxic damage, both adult and aged male Wistar rats were injected with N-methyl-D-aspartate in the striatum. At different survival times between 6 hr and 7 days after lesioning, interleukin-1 beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) were analyzed by enzyme-linked immunosorbent assay and by double immunofluorescence of cryostat sections by using cell-specific markers. Basal cytokine expression was attributed to astrocytes and was increased in the normal aged brain showing region specificity: TNF-alpha and IL-6 displayed age-dependent higher levels in the aged cortex, and IL-1beta and IL-6 in the aged striatum. After excitotoxic striatal damage, notable age-dependent differences in cytokine induction in the aged vs. the adult were seen. The adult injured striatum exhibited a rapid induction of all cytokines analyzed, but the aged injured striatum showed a weak induction of cytokine expression: IL-1beta showed no injury-induced changes at any time, TNF-alpha presented a late induction at 5 days after lesioning, and IL-6 was only induced at 6 hr after lesioning. At both ages, in the lesion core, all cytokines were early expressed by neurons and astrocytes, and by microglia/macrophages later on. However, in the adjacent lesion border, cytokines were found in reactive astrocytes. This study highlights the particular inflammatory response of the aged brain and suggests an important role of increased basal levels of proinflammatory cytokines in the reduced ability to induce their expression after damage.

Intestinal ischemia/reperfusion enhances microglial activation and induces cerebral injury and memory dysfunction in rats*

“…TNF-α and IL-6 levels in the serum and brain tissue were measured with enzyme-linked immunosorbent assay kits (Nanjing Jiancheng Corp., Nanjing, China) in accordance with manufacturer's instructions as previously described (2,21,22). The results were expressed as pg/mL.…”

“…Malonaldehyde (MDA) level and superoxide dismutase activity were detected (commercial kits; Nanjing Jiancheng Corp., China) as previously described (2,21,22). The results were expressed as nmol/mg protein and U/mg protein, respectively.…”

Heterogeneous astrocytes: Active players in CNS

“…The senescent astrocytes-released TNF-a, IL-1b and IL-6 clearly increased in rat brain both in the cortex and striatum during aging (Campuzano et al 2009). The proinflammatory phenotype is also observed in the isolated astrocytes from cerebral cortex, hippocampus and striatum of aged rat brain (Garcia-Matas et al 2008;Xie et al 2003).…”

Decreased myeloperoxidase expressing cells in the aged rat brain after excitotoxic damage

“…Aged (22-24 months old) animals display a delay in the neurodegenerative process, tissue damage and edema, concomitant with an earlier astroglial and microglial/macrophagic responses [23,24]. In addition, aged animals display increased basal levels of cytokines, but attenuated post-injury induced cytokine response [24,25], in parallel with reduced expression of the inflammatory enzyme inducible nitric oxide synthase (iNOS) and increased expression of cyclooxygenase-2 (COX2) [24,25]. As neutrophils are important contributors to the production of these inflammatory mediators which show age-related differences, and MPO is an enzyme contributing to oxidative stress, the aim of the present study was to identify and assess putative changes in the presence of MPO expressing cells after acute striatal damage in the aged versus the adult rat brain.…”