Novel glucocorticoid effects on acute inflammation in the CNS.
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-1beta and TNF-alpha) levels of the pro-inflammatory cytokines IL-1alpha, IL-1beta and TNF-alpha 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.
Dinkel
Klaus
K
Department of Biological Sciences, Gilbert Hall, Stanford University, Stanford, CA 94305-5020, USA. kdinkel12@hotmail.com
MacPherson
Anna
A
Sapolsky
Robert M
RM
D000208:Acute Disease; D000315:Adrenalectomy; D000818:Animals; D002452:Cell Count; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004679:Encephalomyelitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D018690:Excitatory Amino Acid Agonists; D005938:Glucocorticoids / Q000494:pharmacology*; D006098:Granulocytes / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D007608:Kainic Acid; D008264:Macrophages / Q000473:pathology; D008297:Male; D017628:Microglia / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013256:Steroids / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D018690:Excitatory Amino Acid Agonists; D005938:Glucocorticoids; D007375:Interleukin-1; D012333:RNA, Messenger; D013256:Steroids; D014409:Tumor Necrosis Factor-alpha; D007608:Kainic Acid