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April 2015

  1. What is LGD-4033?

    LGD-4033. By Yikrazuul (Own work) [Public domain], via Wikimedia Commons LGD-4033. By Yikrazuul (Own work) [Public domain], via Wikimedia Commons   LGD-4033 is a selective androgen receptor modulator (SARMs). It has a high affinity (approximately 1nM) for the receptor, and has attracted much interest in some areas of medical research1. SARMs are associated with potential in the treatment of age-related decreases in muscle mass and function and in bone density1. These effects may be due to decreases in circulating levels of androgen-receptor agonists (e.g. testosterone and its analogs found in the body) and/or degradations in the receptor protein or its regulators (which are proteins that are required to form a complex with the androgen receptor and ensure that it carries out its functions, which are mainly binding to certain locations on DNA following activation) over time2. Age-related bone and muscle loss (or osteopenia and sarcopenia respectively) are associated with reductions in mobility, function and life quality1. They may also be associated with conditions such as some types of cancer, kidney failure and chronic obstructive pulmonary disease1. SARMs may also have potential in the treatment of muscle loss related to causes other than aging. These may include hypogonadism, recovering from burns, osteoporosis or cancer3. Some researchers assert that these compounds have additional therapeutic applications related to conditions and applications such as depression, anemia, wound healing and benign prostate growths4. However, many SARMs are testosterone analogs (i.e. steroids). These are linked to prostate disease and other adverse effects. LGD-4033, on the other hand, binds to the androgen receptor, but is not a steroid1. Therefore, it may have positive effects on muscle and bone mass retention, without adverse effects on other organs and systems. It has demonstrated these effects in animal studies, without reports of damage or diseases of the prostate in males1. Another advantage of LGD-4033 and other similar SARMs is that they may be administered orally1. LGD-4033 and other SARMs interact with the ligand-binding domain (LBD) of the androgen receptor, but in a different manner to natural androgens2. LGD-4033 is associated with improvements in the bending strength, density and growth of bone in preclinical studies1. Other similar nonsteroidal SARMs have demonstrated similar effects on bone and muscle, and also on sexual function, in rats, compared to control animals5. Administration with these has also been associated with the prevention of prostate tumor growth in rats, and a significant reduction in the rate of tumor growth in mice transfected with human prostate cancer cells6. Some models of age-related bone loss (or osteopenia) are achieved through orchidectomy (or castration) of older male rats6. The administration of non-steroidal SARMs resulted in significantly reduced rates of bone volume and mineral density loss compared to these values in control orchidectomized rats6. This intervention was also associated with improvements in the conservation of lean body mass in orchidectomized rats6. The administration of another non-steroidal SARM significantly increased muscle strength in a mouse model of Duchenne's muscular dystrophy7. The SARM also had beneficial effects on the running ability of these mice, whereas similar animals in control groups or groups receiving a steroid instead (nandrolone or alpha-methylprednisolone), exhibited significant increases in fatigue7.  References:  1. Basaria S, Collins L, Dillon EL, et al. The Safety, Pharmacokinetics, and Effects of LGD-4033, a Novel Nonsteroidal Oral, Selective Androgen Receptor Modulator, in Healthy Young Men. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 2013;68(1):87-95. 2. Narayanan R, Mohler ML, Bohl CE, Miller DD, Dalton JT. Selective androgen receptor modulators in preclinical and clinical development. Nuclear Receptor Signaling. 2008;6:e010. 3. Segal S, Narayanan R, Dalton JT. Therapeutic potential of the SARMs: revisiting the androgen receptor for drug discovery. Expert opinion on investigational drugs. 2006;15(4):377-387. 4. Omwancha J, Brown TR. Selective androgen receptor modulators: in pursuit of tissue-selective androgens. Current opinion in investigational drugs (London, England : 2000). 2006;7(10):873-881. 5. Miner JN, Chang W, Chapman MS, et al. An orally active selective androgen receptor modulator is efficacious on bone, muscle, and sex function with reduced impact on prostate. Endocrinology. 2007;148(1):363-373. 6. Allan G, Lai MT, Sbriscia T, et al. A selective androgen receptor modulator that reduces prostate tumor size and prevents orchidectomy-induced bone loss in rats. The Journal of steroid biochemistry and molecular biology. 2007;103(1):76-83. 7. Cozzoli A, Capogrosso RF, Sblendorio VT, et al. GLPG0492, a novel selective androgen receptor modulator, improves muscle performance in the exercised-mdx mouse model of muscular dystrophy. Pharmacological research : the official journal of the Italian Pharmacological Society. 2013;72:9-24.
  2. What is Liothyronine?

    Liothyronine. By Boghog (Own work) [CC BY-SA 4.0 (http://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons

    Liothyronine. By Boghog (Own work) [CC BY-SA 4.0 (http://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons

      Liothyronine is a synthetic form of triidothyronine (or T3). T3 is a thyroid hormone with many physiological functions. It is present in the hypothalamus, adipose tissue and skeletal muscle tissue1. T3 is associated with the regulation of glucose metabolism by modulating the response to insulin in the liver1. It is also associated with the metabolism of cholesterol1. It plays a role in the adaptation to cold in humans and animals, through the T3 receptors-alpha and -beta2. T3 also regulates uncoupling protein-3, which is involved in the production of heat in brown adipose tissue and skeletal muscle3. Thyroid hormones may also have important roles in the immune system. T3 levels in the immune cells of female (but not male) rats have been shown to decrease significantly in response to the administration of insulin4. Infusions of T3 have been shown to reverse the effects of thyroidectomy (i.e. reduced thyroxine turnover) in rats5. T3 is inhibited by type 3 iodothyronine deiodinase (D3), which inactivates this hormone by converting it to inactive T26. A recent murine-cell in vitro study found that D3 is regulated by glucagon-like peptide-1 (GLP-1)6. Reduced free T3 levels are also associated with cardiac ischemia7. Supplemental T3 improved mitochrondrial function and cell viability in rat models of post-cardiac event ischemia8. Deficiencies in the levels of thyroid hormones, including T3, are known as hypothyroidism. This condition may be associated with many adverse effects on health, including fatigue, weight gain and constipation. It may be associated with additional physiological effects such as mitochrondrial dysfunction or damage and hepatic cell death9. The administration of T3 reduced apoptosis in the liver cells, and oxidative damage in the mitochrondria, of rats with experimentally-induced hypothyroidism9. T3 may also promote the proliferation of liver cells10. Hepatocytes from rats fed T3 for two to seven days showed that this is mediated through beta-catenin phosphorylated by protein kinase A (PKA)10. Decreased thyroid hormone levels may also affect pain sensitivity and other CNS functions11. Treatment with T3 (compared to a control treatment) significantly restored normal thermal (but not mechanical) pain thresholds in a mouse model of hypothyroidism11. T3 also restored the normal levels of pain-regulating neurotransmitters in the anterior cingulate cortex of mice with hypothyroidism11. T3 is also associated with bone development12. This is due to the fact that T3 receptors alpha and beta are present in bone cells12. Some studies have demonstrated that younger animals with hypothyroidism exhibit bone malformations and dysfunctions12. A study used a mutation to generate mice with inactive T3 alpha-receptors. This resulted in dysfunctional chrondrocyte proliferation and differentiation12. However, mature chondrocytes were not affected by mutated T3 alpha-receptors12. Thyroid hormones may also have cardioprotective functions, especially in response to adverse events13. Rats that underwent an experimental myocardial infarction treated with T3 and T4 for 26 days demonstrated a quicker return to normal cardiac function compared to similar untreated rats14. Treatment with T3 is also associated with the maturation of cardiac muscle cells derived from stem cells13. References: 1. Mullur R, Liu YY, Brent GA. Thyroid hormone regulation of metabolism. Physiological reviews. 2014;94(2):355-382. 2. Maslov LN, Vychuzhanova EA, Gorbunov AS, Tsybul'nikov S, Khaliulin IG, Chauski E. [Role of thyroid system in adaptation to cold]. Rossiiskii fiziologicheskii zhurnal imeni I.M. Sechenova / Rossiiskaia akademiia nauk. 2014;100(6):670-683. 3. Branco M, Ribeiro M, Negrao N, Bianco AC. 3,5,3'-Triiodothyronine actively stimulates UCP in brown fat under minimal sympathetic activity. The American journal of physiology. 1999;276(1 Pt 1):E179-187. 4. Pallinger E, Csaba G. In vivo effect of insulin on the hormone production of immune cells in mice - gender differences. Acta microbiologica et immunologica Hungarica. 2014;61(4):417-423. 5. Nagao H, Sasaki M, Imazu T, Takahashi K, Aoki H, Minato K. Effects of triiodothyronine on turnover rate and metabolizing enzymes for thyroxine in thyroidectomized rats. Life sciences. 2014;116(2):74-82. 6. Akiyama S, Ogiwara T, Aoki T, Tsunekawa K, Araki O, Murakami M. Glucagon-like peptide-1 stimulates type 3 iodothyronine deiodinase expression in a mouse insulinoma cell line. Life sciences. 2014;115(1-2):22-28. 7. Novitzky D, Cooper DK. Thyroid hormone and the stunned myocardium. The Journal of endocrinology. 2014;223(1):R1-8. 8. Forini F, Kusmic C, Nicolini G, et al. Triiodothyronine prevents cardiac ischemia/reperfusion mitochondrial impairment and cell loss by regulating miR30a/p53 axis. Endocrinology. 2014;155(11):4581-4590. 9. Mukherjee S, Samanta L, Roy A, Bhanja S, Chainy GB. Supplementation of T3 recovers hypothyroid rat liver cells from oxidatively damaged inner mitochondrial membrane leading to apoptosis. BioMed research international. 2014;2014:590897. 10. Fanti M, Singh S, Ledda-Columbano GM, Columbano A, Monga SP. Tri-iodothyronine induces hepatocyte proliferation by protein kinase A-dependent beta-catenin activation in rodents. Hepatology (Baltimore, Md.). 2014;59(6):2309-2320. 11. Yi J, Zheng JY, Zhang W, Wang S, Yang ZF, Dou KF. Decreased pain threshold and enhanced synaptic transmission in the anterior cingulate cortex of experimental hypothyroidism mice. Molecular pain. 2014;10:38. 12. Desjardin C, Charles C, Benoist-Lasselin C, et al. Chondrocytes play a major role in the stimulation of bone growth by thyroid hormone. Endocrinology. 2014;155(8):3123-3135. 13. Yang X, Rodriguez M, Pabon L, et al. Tri-iodo-l-thyronine promotes the maturation of human cardiomyocytes-derived from induced pluripotent stem cells. Journal of molecular and cellular cardiology. 2014;72:296-304. 14. de Castro AL, Tavares AV, Campos C, et al. Cardioprotective effects of thyroid hormones in a rat model of myocardial infarction are associated with oxidative stress reduction. Molecular and cellular endocrinology. 2014;391(1-2):22-29.
  3. Novel and Current Uses of GHRP-6

    GHRP-6. By Edgar181 (Own work) [Public domain], via Wikimedia Commons

    GHRP-6. By Edgar181 (Own work) [Public domain], via Wikimedia Commons

      GHRP-6 is a synthetic hexapeptide associated with the secretion of growth hormone in the pituitary glands of humans and animals1. It is thought to achieve this through increases in intracellular calcium (Ca2+), activated PKC and the DAG/IP3 pathway2,3. There are two main forms of this molecule: GHRP-6 and [D-Lys (3)]GHRP-6. The latter is a ghrelin receptor (GHS-R) antagonist4. In other words, it countermands the actions of GHRP-6. This is useful in many studies, as its use can validate a putative effect of GHRP-6; i.e. if GHRP-6 stimulates a particular pathway, this can be confirmed by its inhibition by [D-Lys (3)]GHRP-6. This version of the peptide can also confirm the role of ghrelin in novel applications4. [D-Lys (3)]GHRP-6 may also have its own potential in research and medicine. It has been associated with improvements in the biomarkers of obesity (or the metabolic syndrome), including ghrelin levels, leptin levels, blood cholesterol and blood glucose5. In addition, the administration of [D-Lys (3)]GHRP-6 may be associated with reductions in body mass5. New applications for GHRP-6 Some researchers have reported novel properties and/or functions of GHRP-6 or[D-Lys (3)]GHRP-6 that may affect how they are used in science and medicine in the near future. Alternatively, these peptides may be used to quantify the putative effects of ghrelin. Ghrelin is thought to have beneficial effects in situations such as adverse cardiac effects, cardiomyopathy, cerebrovascular complications (e.g. stroke), and vascular protection following retinopathy (in which new blood vessels may be abnormal and non-functional)1,6. Most of these are based on in vitro or in vivo (animal) trials and studies. Intraperitoneal administration of combined EGF and GHRP-6 reduced clinical signs, and conserved nerve cell density, in an animal model of stroke7. GHRP-6 demonstrated the ability to significantly reduce infarct sizes, necrosis and oxidative stress (caused by reactive oxygen species) compared to a control treatment (saline) in an animal model of myocardial infarction. The control treatment was also associated with significant increases in IGF-1 expression compared to GHRP-61. This indicates that GHRP-6 initiates cardioprotective mechanisms that are distinct from those associated with IGF-1. Treatment with GHRP-6 significantly conserved vascular density, increased IGF-1 levels and increased VEGF levels in a rat model of retinopathy6. The addition of [D-Lys (3)]GHRP-6 negated these effects6. A study using a rat model of Alzheimer's disease found that the relevant markers (acetylcholinesterase and amyloid-beta) were reduced in animals treated with [D-Lys (3)]GHRP-6 compared to controls5. Rats treated with this peptide also showed improved performance in a spatial orientation task5. Other research indicates that ghrelin anatagonists may reduce alcohol intake behaviours, e.g. preference for this rather than water in animal studies8. However, a study randomizing C57BL/6J mice to [D-Lys (3)]GHRP-6 or another ghrelin antagonist (JMV2959) found that [D-Lys (3)]GHRP-6 reduced ethanol intake and preference on the first day of treatment only8. JMV2959 reduced this intake at all time-points, but also reduced food and water intake8. [D-Lys (3)]GHRP-6 was also used to confirm the role of ghrelin in relaxing the dilator and sphincter muscles of the rabbit iris9. References: 1. Berlanga J, Cibrian D, Guevara L, et al. Growth-hormone-releasing peptide 6 (GHRP6) prevents oxidant cytotoxicity and reduces myocardial necrosis in a model of acute myocardial infarction. Clinical science (London, England : 1979). 2007;112(4):241-250. 2. Bresson-Bepoldin L, Dufy-Barbe L. GHRP6-stimulated hormone secretion in somatotrophs: involvement of intracellular and extracellular calcium sources. Journal of neuroendocrinology. 1996;8(4):309-314. 3. Mau SE, Witt MR, Bjerrum OJ, Saermark T, Vilhardt H. Growth hormone releasing hexapeptide (GHRP-6) activates the inositol (1,4,5)-trisphosphate/diacylglycerol pathway in rat anterior pituitary cells. Journal of receptor and signal transduction research. 1995;15(1-4):311-323. 4. Luque EM, Torres PJ, de Loredo N, et al. Role of ghrelin in fertilization, early embryo development, and implantation periods. Reproduction (Cambridge, England). 2014;148(2):159-167. 5. Madhavadas S, Kutty BM, Subramanian S. Amyloid beta lowering and cognition enhancing effects of ghrelin receptor analog [D-Lys (3)] GHRP-6 in rat model of obesity. Indian journal of biochemistry & biophysics. 2014;51(4):257-262. 6. Zaniolo K, Sapieha P, Shao Z, et al. Ghrelin modulates physiologic and pathologic retinal angiogenesis through GHSR-1a. Investigative ophthalmology & visual science. 2011;52(8):5376-5386. 7. Garcia Del Barco-Herrera D, Martinez NS, Coro-Antich RM, et al. Epidermal growth factor and growth hormone-releasing peptide-6: combined therapeutic approach in experimental stroke. Restorative neurology and neuroscience. 2013;31(2):213-223. 8. Gomez JL, Ryabinin AE. The effects of ghrelin antagonists [D-Lys(3) ]-GHRP-6 or JMV2959 on ethanol, water, and food intake in C57BL/6J mice. Alcoholism, clinical and experimental research. 2014;38(9):2436-2444. 9. Rocha-Sousa A, Saraiva J, Henriques-Coelho T, Falcao-Reis F, Correia-Pinto J, Leite-Moreira AF. Ghrelin as a novel locally produced relaxing peptide of the iris sphincter and dilator muscles. Experimental eye research. 2006;83(5):1179-1187.

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