Novel glucocorticoid effects on acute inflammation in the CNS

Abstract

The CNS can mount an inflammatory reaction to excitotoxic insults that contributes to the emerging brain damage. Therefore, anti-inflammatory drugs should be beneficial in neurological insults. In contrast, glucocorticoids (GCs), while known for their anti-inflammatory effects, can exacerbate neurotoxicity in the hippocampus after excitotoxic insults. We investigated the effect of GCs on the inflammatory response after a neurological insult. Intact control (INT; intact stress response GC profile), adrenalectomized/GC-supplemented (ADX; low basal GC profile) and GC-treated (COR; chronically high GC profile) rats were injected with kainic acid into the hippocampal CA3 region. Lesion size was determined 8-72 h later. The inflammatory response was characterized using immunohistochemistry, RNAse protection assay and ELISA. The INT and COR rats developed larger CA3 lesions than ADX rats. We found that GCs surprisingly caused an increase in relative numbers of inflammatory cells (granulocytes, monocytes/macrophages and microglia). Additionally, mRNA and protein (IL-1b and TNF-a) levels of the pro-inflammatory cytokines IL-1a, IL-1b and TNF-a were elevated in COR rats compared with INT and ADX rats. These data strongly question the traditional view of GCs being uniformly anti-inflammatory and could further explain how GCs worsen the outcome of neurological insults.

Optimization of multiplexed bead-based cytokine immunoassays for rat serum and brain tissue

“…On the other hand, published ELISA-based values for cytokines in our nine-member panel for brain tissue are even closer to measurements reported here. Dinkel et al (2003) report values for IL-1β, and TNF-α of 25 and 6, respectively, which agree well with our values of 24 and 10 pg/mg protein. Similarly, Allan et al (2001) report IL-1α at 35 pg/mg and IL-6 at 150 pg/mg, while we report these cytokine levels in brain at 64 and 226 pg/mg, respectively.…”

“…Corticosterone can influence expression of cytokines with brain (Dinkel et al, 2003;Goujon et al, 1997;John and Buckingham, 2003;Nadeau and Rivest, 2003) and so can be expected to be a sensitive and general reflection of animal status when serum and tissues are harvested for cytokine analyses. We initially used a standard strategy for processing brain tissue for immunohistochemical analyses of inflammatory markers Kraig, 1996 , 1998;.…”

“…Excessive amounts of corticosterone can be released from rodent adrenal glands in response to stress (for review seeSapolsky, 2003), which can influence cytokine expression in both the blood (Oppenheim and Feldmann, 2001) and brain (Dinkel et al, 2003). Furthermore, rodent corticosterone levels show a diurnal variation (D'Agostino et al, 1982) as do cytokines in humans (Petrovsky and Harrison, 1998) and so, presumably rats.…”

“…For example, injury from brain disease can result in temporally and spatially distinct expression patterns of specific cytokines (Jankowsky and Patterson, 1999;Jean Harry et al, 2003), which can influence their own expression as well as that of counterparts (Oppenheim and Feldmann, 2001). Additionally, other classes of signaling molecules such as glucocorticoids (Dinkel et al, 2003;Goujon et al, 1997;John and Buckingham, 2003;Nadeau and Rivest, 2003) and prostaglandins (del Zoppo et al, 2000;Hori et al, 2000;Vane et al, 1998) can either reduce or promote inflammatory cytokine responses, respectively. Finally, similar scenarios of spatially and temporally distinct, yet interactive and thus complex, behavior can be expected for other intracellular, autocrine, paracrine and endocrine signaling molecule systems.…”

Interleukin-1β Biosynthesis Inhibition Reduces Acute Seizures and Drug Resistant Chronic Epileptic Activity in Mice

“…Besides its established anti-inflammatory properties, dexamethasone anticonvulsant effect may be mediated by its ability to reverse the increased serum corticosterone concentrations, which are elicited by elevated IL-1β brain levels via activation of the hypothalamic-pituitary adrenal axis (HPA) axis [47,48]. Thus, chronic high levels of glucorticoids can produce proinflammatory effects in the brain [49] and increase neuronal vulnerability to injury [50,51]. This mechanism, although still speculative, may also play a role in the anticonvulsant activity of VX-765.…”