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Systemic Adrenocorticotropic Hormone Administration 0031-3998/04/5504-0604 PEDIATRIC RESEARCH Vol. 55, No. 4, 2004 Copyright © 2004 International Pediatric Research Foundation, Inc. Printed in U.S.A. Systemic Adrenocorticotropic Hormone Administration Down-Regulates the Expression of Corticotropin-Releasing Hormone (CRH) and CRH-Binding Protein in Infant Rat Hippocampus WEI WANG, BRIDGID MURPHY, KIMBERLY E. DOW, R. DAVID ANDREW, AND DOUGLAS D. FRASER Department of Paediatrics [W.W., K.E.D.], Kingston General Hospital, Queen’s University, Kingston, Ontario, Canada, K7L 1N6; Department of Anatomy and Cell Biology [B.M., R.D.A.], Botterell Hall Queen’s University, Kingston, Ontario, Canada, K7L 3N6; Department of Paediatrics and Clinical Neurological Sciences [D.D.F.], Children’s Hospital of Western Ontario, London, Ontario Canada, N6C 2V5; Child Health Research Institute [D.D.F.], London, Ontario, Canada, N6C 2V5; and Clinical Trials Group, Canadian Paediatric Epilepsy Network (CPEN) ABSTRACT Systemic adrenocorticotropic hormone (ACTH) administra- altered by ACTH treatment, relative to saline-injected rats. This tion is a first-line therapy for the treatment of infantile spasms, an latter finding was confirmed electrophysiologically by measuring age-specific seizure disorder of infancy. It is proposed that the enhancement of hippocampal population spikes by exoge- exogenous ACTH acts via negative feedback to suppress the nous CRH, also showing no differences between ACTH- and synthesis of corticotropin-releasing hormone (CRH), a possible saline-injected rats. The results of this study support the proposal endogenous convulsant in infant brain tissue. The aim of this that systemic ACTH treatment down-regulates CRH expression study was to determine whether systemic ACTH treatment in in infant brain, perhaps contributing to the therapeutic efficacy infant rats down-regulates the hippocampal CRH system, includ- observed during treatment of infantile spasms. (Pediatr Res 55: ing CRH, CRH-binding protein (CRH-BP), and CRH receptors 604–610, 2004) (CRH-R1 and CRH-R2). Daily i.p. injection of ACTH for 7 consecutive days (postnatal days 3–9) elevated serum corticoste- rone levels 20-fold measured on postnatal day 10, indicating Abbreviations systemic absorption and circulation of the ACTH. Semiquanti- aCSF, artificial cerebrospinal fluid tative reverse transcriptase–PCR demonstrated that both CRH ACTH, adrenocorticotropic hormone and CRH-BP mRNA obtained from the hippocampi of ACTH- CRH, corticotropin-releasing hormone injected infant rats was significantly depressed relative to saline- CRH-BP, corticotrophin-releasing hormone–binding protein injected animals. Comparable reductions in both CRH and CRH-R1, corticotropin-releasing hormone–receptor 1 CRH-BP synthesis were further demonstrated with radioimmuno- CRH-R2, corticotropin releasing hormone–receptor 2 assay. In contrast, neither CRH-R1 nor CRH-R2 mRNA was RT-PCR, reverse transcriptase–PCR Adrenocorticotropic hormone (ACTH) is a 39–amino acid both stress and immune responses via stimulation of the adre- peptide released into circulation by the anterior pituitary in nal glands (2). In neonates, the adrenal glands are relatively response to corticotropin-releasing hormone (CRH) stimula- insensitive to ACTH stimulation, and corticosterone release tion from the hypothalamic paraventricular nuclei (1). Among occurs primarily via constitutive secretion (3). Although this its various physiologic effects, ACTH is known to regulate period of adrenal hyporesponsiveness is proposed to be pro- tective under normal circumstances (4), excessive activity of the hypothalamic-pituitary axis (i.e. CRH release) may result in Received February 21, 2003; accepted November 20, 2003. Correspondence: Douglas D. Fraser, M.D., Ph.D., FRCPC, Paediatric Critical Care an attempt to elevate circulating levels of adrenal steroids after Unit, Children’s Hospital of Western Ontario, 800 Commissioners Road East, London, stressful events (1, 5). Excess synthesis and release of CRH Ontario, Canada, N6C 2V5; e-mail: [email protected] during the neonatal period may also have detrimental effects on Financial support to D.D.F. includes Queen’s University (Botterell Foundation, Advi- sory Research Council, and Angada Foundation), the Savoy Foundation for Epilepsy neuronal excitability and development during infancy (6). Research, and the Physicians’ Services Incorporated Foundation. Infantile spasms are an age-dependent epileptic syndrome DOI: 10.1203/01.PDR.0000112105.33521.DC associated with developmental delay and hypsarrhythmia (7). 604 ACTH DOWN-REGULATES CRH/CRH-BP 605 The cause of infantile spasms has been attributed to a wide tubes with antibody to rat corticosterone for2hatroom variety of brain insults occurring during antenatal/perinatal temperature. After incubation, the solution was decanted and development (1, 8). At present, infantile spasms are treated radioactivity was counted for 1 min in a gamma counter. primarily with systemic ACTH administration. It is proposed RT-PCR. Total RNA isolation and RT-PCR were performed that ACTH suppresses endogenous release of the excitatory as previously described (18). Briefly, total RNA was obtained neuropeptide CRH via a negative feedback mechanism (1, 9). from the isolated CA1 region of rat hippocampus by the acid CRH is elevated during periods of physiologic stress [i.e. guanidinium thiocyanate-phenol-chloroform method (19). One antenatal and/or perinatal insults (10)] and possesses consid- microgram of total RNA was reverse transcribed by the AMV erable convulsant activity if injected into the CNS of immature reverse transcriptase. The reaction was performed in the ab- rats (6). These observations have led to the hypothesis that sence of reverse transcriptase or RNA as negative controls. For CRH is an endogenous convulsant in infant brain tissue, sec- amplification of cDNA, an aliquot of reverse transcription ondary to stress-induced alterations in the brain-adrenal axis. mixture (2.0 ␮L) was amplified with the following cycle The alterations in the CRH system [CRH, CRH-binding pro- parameters: 94°C for 45 s, 55°C for 45 s, and 72°C for 90 s. tein (CRH-BP), and/or CRH receptors] by ACTH treatment, After 28 and 26 (␤-actin) cycles of amplification, a final however, are unknown. Identification of the cellular mecha- extension cycle was performed at 72°C for 5 min. PCR pro- nisms underlying ACTH modulation of the CRH system may ducts were visualized by electrophoresis using a 1.5% agarose allow for the development of novel therapeutic agents for the gel containing ethidium bromide. A negative control was treatment of infantile spasms (i.e. CRH receptor antagonists). performed using PCR amplification without cDNA. No prod- The aim of this study, therefore, was to determine whether ucts were detected from these control experiments. Kinetic systemic ACTH therapy down-regulates the CRH system. studies of each gene were performed to give a linear range of More specific, we measured the expression levels of CRH, amplification before semiquantitative analysis. PCR products CRH-BP, and CRH receptors (CRH-R1 and/or CRH-R2) using obtained under the linear range were analyzed and visualized. reverse transcriptase–PCR (RT-PCR), RIA and, electrophysi- A photograph of the gel was scanned in reflectance mode using ologic techniques. The data for this study were obtained from computer-assisted linear scanning densitometer (Digitizer- rats that were killed on postnatal day 10. This age was specif- Matrox IM 1280). The optical intensities of the PCR products ically investigated as postnatal days 10–13 are reported to were quantified and analyzed by the software package MCID correspond with human infancy based on similarities in syn- M2 (Imaging Research Inc.). The data were expressed as mean aptic maturation, myelination, and evolving expression of re- Ϯ SE. Differences between groups were compared by ANOVA ceptor and second messenger systems (11, 12). The hippocam- or by Kruskal-Wallis one-way ANOVA on ranks using pus was chosen for study as previous investigations, both in SigmaStat software (Jandel Scientific). vivo (6) and in vitro (13–16), have shown that this structure is The primers chosen to assess mRNA were as follows: CRH responsive to CRH application. The data presented in this (360 bp) 5'-CAA CTT TTT CCG CGT GTT GCT-3' and study support the hypothesis that systemic ACTH administra- 5'-ATG GCA TAA GAG CAG CGC TAT-3'; CRH-R1 (476 tion alters the nonhypothalamic CRH system and may contrib- bp) 5'-ACA AAC AAT GGC TAC CGG GAG-3' and 5'-ACA ute to the therapeutic efficacy of ACTH treatment of infantile CCC CAG CCA ATG CAG AC-3'; CRH-R2 (615 bp) 5'-TGT spasms. GGA AGG CTG CTA CCT G-3' and 5'-GTC TGC TTG ATG CTG TGG AA-3'; CRH-BP (229 bp) 5'-TAC GAC CCT TTC METHODS CTG CTT TTC AGC-3' and 5'-GAA ATC CCC ACC CTG GCA GTC GAT-3'; ␤-actin (340 bp) 5'-CAA GAG ATG GCC All animal studies in this report have been approved by the ACG GCT GCT-3' and 5'-TCC TTC TGC ATC CTG TCG Queen’s University Institutional Review Board in accordance GCA-3'. The oligonucleotide primers were synthesized in the with the Guidelines of the Canadian Council on Animal Care. Department of Biochemistry at Queen’s University. Systemic ACTH administration. ACTH was dissolved in RIA for CRH and CRH-BP. CRH RIA was performed 0.9% saline, and ~100 ␮L was injected into rats (i.p.) at a using protocols and reagents from IgG Corp. (Nashville, TN, dosage of 0.5 mg · kgϪ1 · dϪ1 · (17). The injections were U.S.A.) as described previously (18, 20). Briefly, tissue lysates performed at 1100 h for 7 consecutive days (postnatal days (100 ␮L) were incubated with 100 ␮L of primary antibodies 3–9). Rats were killed under ketamine anesthesia on postnatal (1:100, IgG-hCRH; IgG Corp.) for3dat4°C. Then 125I-Tyr- 10, and blood was subsequently withdrawn from the left hCRH (DuPont NEN, Boston, MA, U.S.A.) in 100 ␮LofRIA ventricle of the heart. Rat blood was immediately centrifuged buffer was added and incubated for another 2 d at 4°C. A total to isolate serum.
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