Graphs demonstrating the ability of CJC-1295 to reverse M3-receptor knockout- (Br-M3-KO) induced effects on pituitary function in mice. From: Gautam D, Jeon J, Starost MF, et al. Neuronal M(3) muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(15):6398-6403, available through PNAS Open Access.

Graphs demonstrating the ability of CJC-1295 to reverse M3-receptor knockout- (Br-M3-KO) induced effects on pituitary function in mice. From: Gautam D, Jeon J, Starost MF, et al. Neuronal M(3) muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(15):6398-6403, available through PNAS Open Access.

Introduction 

CJC-1295 is an analog of the human growth-hormone releasing factor (also known as GHRH)1,2. This synthetic peptide has selectivity for albumin (through a covalent bond with its 34th amino acid residue), thus increasing its half-life once administered2. Such a property confers advantages for CJC-1295 as a research compound and possible future therapeutic agent over human GHRH. CJC-1295 has demonstrated the ability to increase the AUC for human growth hormone (hGH) that was four-fold compared to that elicited by hGHRH. Its activity can be detected in laboratory animals for a number of days after administration2. The administration of CJC-1295 may also result in the increased release of insulin-like growth factor 1 (IGF-1)1. It may also have a positive effect on the proliferation of somatotroph cells1. CJC-1295 possesses the distinguishing feature of a modified lysine residue at the C-terminus2. 

CJC-1295 and Growth Promotion 

Treatment with CJC-1295 may restore growth rates to nearly normal in animal models of growth hormone deficiency. A study compared the effects of 2μg subcutaneous CJC1295 given once every 24, 48 or 72 hours for five weeks in week-old GH-knockout mice1. Similar groups of knockout and normal mice injected once daily with saline were used as controls. Knockout mice who received 2μg CJC-1295 every 24 hours exhibited significant increases in bodyweight and length compared to those injected every 48 or 72 hours, or to knockout controls1. The weights and lengths of the '24 hour' group were not significantly different from those of the normal control mice1. These growth-related values observed in the '48-' and '72-' hour groups were also significantly different to those in the control knockout group1. The '24 hour' group exhibited a 13-fold increase in pituitary development (as measured by total RNA detection) compared to knockout control mice1. This group also had an eleven-fold increase in pituitary GH expression (as indicated by mRNA detection) compared to knockout controls1. In addition, the '24-hour' group had significantly greater concentrations of IGF-1 compared to normal controls1. This indicates the potential of CJC-1295 to affect growth and somatotroph proliferation, provided the dose used is administered in line with the half-life of albumin (approximately 24 hours in mice)2. 

CJC-1295 and the Neuronal Regulation of the Pituitary 

This compound may also have a role in the determination of the nerve-cell activity (e.g. which receptors are involved, etc.) underpinning the normal function of the pituitary gland, which is not as yet fully understood. For example, it is not clear how the cells of the anterior pituitary are regulated, although muscarinic acetylcholine receptors appear to be involved in this3. Animals that do not express the M3 subtype of this receptor in brain cells exhibit a dwarfed phenotype with significantly reduced GH release and thus impaired anterior pituitary development and function4. 'Knockout' mice were treated with 2μg subcutaneous CJC-1295 daily for eight weeks, with similarly-treated normal mice as controls4. Body length and anterior pituitary size were not significantly different between these two groups4. GH and IGF-1 concentrations in the CJC-1295-treated knockout mice were increased at least two-fold compared to identical untreated knockout controls4. This supports the theory that neurons associated with the release of GHRH in the brain express M3 muscarinic receptors.

References:

1. Alba M, Fintini D, Sagazio A, et al. Once-daily administration of CJC-1295, a long-acting growth hormone-releasing hormone (GHRH) analog, normalizes growth in the GHRH knockout mouse. American Journal of Physiology - Endocrinology and Metabolism. 2006;291(6):E1290-E1294.

2. Jette L, Leger R, Thibaudeau K, et al. Human growth hormone-releasing factor (hGRF)1-29-albumin bioconjugates activate the GRF receptor on the anterior pituitary in rats: identification of CJC-1295 as a long-lasting GRF analog. Endocrinology. 2005;146(7):3052-3058.

3. Giustina A, Veldhuis JD. Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocrine reviews. 1998;19(6):717-797.

4. Gautam D, Jeon J, Starost MF, et al. Neuronal M(3) muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(15):6398-6403.