title: Increase in mRNA concentrations of pituitary receptors for growth hormone-releasing hormone and growth hormone secretagogues after neonatal monosodium glutamate treatment.
abstract: Previous studies have demonstrated that neonatal monosodium glutamate (MSG) treatment destroys growth hormone releasing-hormone (GHRH) neurones within the hypothalamic arcuate nucleus, decreases serum GH and insulin-like growth factor (IGF-I) concentrations, and retards linear growth. In the present study we investigated whether expression of pituitary GH, GHRH receptors (GHRH-R), growth hormone secretagogue receptors (GHS-R) and liver IGF-I is altered in this model of GHRH deficiency. In addition, we investigated if treatment of MSG-lesioned rats with the GHRH agonist, JI-38, would 'normalise' the GH-axis. Serum GH and IGF-I concentrations were determined by RIA, GH mRNA levels were evaluated by Northern blotting, and GHRH-R, GHS-R and IGF-I mRNA levels were measured by semiquantitative RT-PCR. In accord with previous reports, neonatal MSG treatment caused 50% and 76% decreases in serum GH and IGF-I concentrations, respectively, at 8 weeks of age. The decline in circulating GH was accompanied by a 56% reduction in total pituitary GH content, which was a reflection of the decrease in total pituitary protein. However, GH concentration (per mg protein) was unaltered. Despite the maintenance of a normal GH concentration, GH mRNA concentration (per microg total RNA) was suppressed by 42%, compared to saline-treated controls (P<0.05). These data indicate that a post-transcriptional mechanism, such as a reduction in the GH secretory rate, acts to maintain intracellular GH concentrations. The fall in circulating concentrations of GH leads to a 42% decrease in liver IGF-IB mRNA levels, while liver IGF-IA transcripts showed only a 27% suppression. In contrast, pituitary GHRH-R and GHS-R mRNA levels (per microg total RNA) were increased in MSG-lesioned rats by 96% and 180% of normal values (P<0.01), respectively. Twice daily treatment of MSG-lesioned rats (for 2 weeks) with the GHRH agonist, JI-38, increased serum GH and IGF-I levels, as measured 20 h after the last agonist injection. However, GH, IGF-I, GHRH-R and GHS-R mRNA levels were not altered at this time. These results demonstrate that intermittent GHRH agonist treatment stimulates pituitary GH secretion and GH in turn stimulates hepatic IGF-I but that effects on gene expression are not sustained. Collectively, our observations demonstrate a complex interplay between transcriptional, translational and post-translational mechanisms within each level of the GH-axis following destruction of GHRH neurones by neonatal MSG treatment.
authors.affiliation: Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA. kovacsm@apacs.pote.hu
authors.forename: M
authors.initials: M
authors.lastname: Kovacs
authors.forename: R D
authors.initials: RD
authors.lastname: Kineman
authors.forename: A V
authors.initials: AV
authors.lastname: Schally
authors.forename: B
authors.initials: B
authors.lastname: Flerko
authors.forename: L A
authors.initials: LA
authors.lastname: Frohman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000187:drug effects*; D013006:Growth Hormone / Q000097:blood / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D010902:Pituitary Gland / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018013:Receptors, Neuropeptide / Q000235:genetics*; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000235:genetics*; D011986:Receptors, Somatotropin / Q000235:genetics*; D012970:Sodium Glutamate / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D011986:Receptors, Somatotropin; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C048250:somatotropin releasing hormone receptor; D012970:Sodium Glutamate