SYSTEMIC ENDOTOXIN INCREASES STEADY-STATE GENE-EXPRESSION OF HYPOTHALAMIC NITRIC-OXIDE SYNTHASE - COMPARISON WITH CORTICOTROPIN-RELEASING FACTOR AND VASOPRESSIN GENE TRANSCRIPTS

Citation
S. Lee et al., SYSTEMIC ENDOTOXIN INCREASES STEADY-STATE GENE-EXPRESSION OF HYPOTHALAMIC NITRIC-OXIDE SYNTHASE - COMPARISON WITH CORTICOTROPIN-RELEASING FACTOR AND VASOPRESSIN GENE TRANSCRIPTS, Brain research, 705(1-2), 1995, pp. 136-148
Citations number
86
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Neurosciences
Journal title
ISSN journal
0006-8993
Volume
705
Issue
1-2
Year of publication
1995
Pages
136 - 148
Database
ISI
SICI code
0006-8993(1995)705:1-2<136:SEISGO>2.0.ZU;2-9
Abstract
The enzyme responsible for nitric oxide (NO) formation, NO synthase (N OS), is found in hypothalamic neurons that control ACTH secretion. Thi s led to the hypothesis that brain NO may modulate the response of the hypothalamic-pituitary (HP) axis to various stimuli. We tested this h ypothesis by measuring changes in constitutive (c) NOS mRNA levels in the hypothalamus of rats systemically injected with endotoxin, a lipop olysaccharide (LPS) that releases endogenous cytokines, and analyzed t hese results in the context of the appearance of ACTH-releasing secret agogues such as corticotropin-releasing factor (CRF) and vasopressin ( VP), as well as CRF receptors type A (CRF-R(A)). We purposefully chose doses of LPS thought to only minimally disrupt the blood-brain barrie r and not be accompanied by an endotoxin shock, so that the results we obtained did not primarily stem from abnormal passage of compounds in to the brain, or non-specific stress. Three to four hours following LP S injection (100 mu g/kg, i.v.), cNOS mRNA levels increased in the par aventricular nucleus (PVN) of the hypothalamus. LPS treatment also upr egulated PVN CRF gene transcription (measured by CRF heteronuclear RNA ) and increased steady-state gene expression of the immediate early ge nes (LEG) c-fos and NGFI-B, with the first changes noted 1-2 h after t reatment. Transcripts of CRF receptors type A were present in the hypo thalamus 6 h after endotoxin treatment. On the other hand, no alterati ons in cytoplasmic VP mRNA levels were noted in rats injected with LPS . Because the dose of LPS we used stimulates ACTH secretion within 30 min, our results suggest that systemic LPS acts first within the media n eminence, where it stimulates peptidic nerve terminals. Neuronal act ivation of hypothalamic cell bodies takes place later, and whether thi s phenomenon is due to the production of brain neurotransmitters and/o r cytokines, or whether it primarily results from increased demand on the synthetic machinery, remains to be established. These studies exte nd prior work showing that systemic LPS increases the neuronal activit y of hypothalamic regions known for their involvement in the responses of the HP axis, and bring forth two important additional points. Firs t, increases in CRF primary nuclear transcripts are delayed with regar d to the temporal release of ACTH. This suggests, though it does not d emonstrate, that under the experimental conditions we used, the first site of action of LPS is the median eminence. Second, the observation of increased cNOS gene expression following LPS treatment, and the pre sence of this enzyme in neurons that regulate ACTH secretion, bring su pport to the hypothesis that this gas plays an important function in m ediating the HP axis response to an immune challenge.