{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T20:16:56Z","timestamp":1784751416496,"version":"3.55.0"},"reference-count":111,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T00:00:00Z","timestamp":1674086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Business, Innovation, and Employment (MBIE)"},{"name":"Health Research Council (HRC)"},{"name":"Tertiary Education Commission"},{"name":"Auckland Medical Research Foundation (AMRF)"},{"name":"cGPlab Limited New Zealand (previous known as the Vitality New Zealand)"},{"name":"Swedish Research Council and the Swedish Brain Foundation"},{"name":"Chinese Scholarship Council"},{"name":"the Higher-level University Construction Project"},{"name":"Guang-zhou University of Chinese Medicine"},{"name":"New Zealand Brain Research Institute (NZBRI)"},{"name":"Biomarkers and Recovery in Stroke (BARISTa)"},{"name":"University of Auckland"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Insulin-like growth factor-1 (IGF-1) function declines with age and is associated with brain ageing and the progression of age-related neurological conditions. The reversible binding of IGF-1 to IGF binding protein (IGFBP)-3 regulates the amount of bioavailable, functional IGF-1 in circulation. Cyclic glycine-proline (cGP), a metabolite from the binding site of IGF-1, retains its affinity for IGFBP-3 and competes against IGF-1 for IGFBP-3 binding. Thus, cGP and IGFBP-3 collectively regulate the bioavailability of IGF-1. The molar ratio of cGP\/IGF-1 represents the amount of bioavailable and functional IGF-1 in circulation. The cGP\/IGF-1 molar ratio is low in patients with age-related conditions, including hypertension, stroke, and neurological disorders with cognitive impairment. Stroke patients with a higher cGP\/IGF-1 molar ratio have more favourable clinical outcomes. The elderly with more cGP have better memory retention. An increase in the cGP\/IGF-1 molar ratio with age is associated with normal cognition, whereas a decrease in this ratio with age is associated with dementia in Parkinson disease. In addition, cGP administration reduces systolic blood pressure, improves memory, and aids in stroke recovery. These clinical and experimental observations demonstrate the role of cGP in regulating IGF-1 function and its potential clinical applications in age-related brain diseases as a plasma biomarker for\u2014and an intervention to improve\u2014IGF-1 function.<\/jats:p>","DOI":"10.3390\/molecules28031021","type":"journal-article","created":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T06:22:10Z","timestamp":1674109330000},"page":"1021","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Cyclic Glycine-Proline (cGP) Normalises Insulin-Like Growth Factor-1 (IGF-1) Function: Clinical Significance in the Ageing Brain and in Age-Related Neurological Conditions"],"prefix":"10.3390","volume":"28","author":[{"given":"Jian","family":"Guan","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Clinical Pharmacology, Faculty of Medicine and Health Sciences, School of Biomedical Sciences, The University of Auckland, Auckland 1142, New Zealand"},{"name":"Centre for Brain Research, Faculty of Medicine and Health Sciences, School of Biomedical Sciences, The University of Auckland, Auckland 1142, New Zealand"},{"name":"Brain Research New Zealand, The Centre for Research Excellent, Dunedin 9016, New Zealand"},{"name":"The cGP Lab Limited New Zealand, Auckland 1021, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1034-3683","authenticated-orcid":false,"given":"Fengxia","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Clinical Pharmacology, Faculty of Medicine and Health Sciences, School of Biomedical Sciences, The University of Auckland, Auckland 1142, New Zealand"},{"name":"Centre for Brain Research, Faculty of Medicine and Health Sciences, School of Biomedical Sciences, The University of Auckland, Auckland 1142, New Zealand"},{"name":"Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou 510075, China"},{"name":"The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dali","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Clinical Pharmacology, Faculty of Medicine and Health Sciences, School of Biomedical Sciences, The University of Auckland, Auckland 1142, New Zealand"},{"name":"Centre for Brain Research, Faculty of Medicine and Health Sciences, School of Biomedical Sciences, The University of Auckland, Auckland 1142, New Zealand"},{"name":"Brain Research New Zealand, The Centre for Research Excellent, Dunedin 9016, New Zealand"},{"name":"Shenyang Medical College, Shenyang 110034, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1116-3839","authenticated-orcid":false,"given":"Tim","family":"Anderson","sequence":"additional","affiliation":[{"name":"New Zealand Brain Research Institute, Christchurch 4710, New Zealand"},{"name":"Department of Medicine, University of Otago, Dunedin 9016, New Zealand"},{"name":"Department of Neurology, Canterbury District Health Board, Christchurch 4710, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4661-5038","authenticated-orcid":false,"given":"Toni","family":"Pitcher","sequence":"additional","affiliation":[{"name":"New Zealand Brain Research Institute, Christchurch 4710, New Zealand"},{"name":"Department of Medicine, University of Otago, Dunedin 9016, New Zealand"},{"name":"Department of Neurology, Canterbury District Health Board, Christchurch 4710, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6672-033X","authenticated-orcid":false,"given":"John","family":"Dalrymple-Alford","sequence":"additional","affiliation":[{"name":"Department of Neurology, Canterbury District Health Board, Christchurch 4710, New Zealand"},{"name":"Department of Psychology, University of Canterbury, Christchurch 4710, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Shorten","sequence":"additional","affiliation":[{"name":"AgResearch Ltd., Ruakura Research Centre, Hamilton 3214, New Zealand"},{"name":"Riddet Institute, Massey University, Palmerston North 4474, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gagandeep","family":"Singh-Mallah","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.neurobiolaging.2017.11.017","article-title":"The association between peripheral total IGF-1, IGFBP-3, and IGF-1\/IGFBP-3 and functional and cognitive outcomes in the Mayo Clinic Study of Aging","volume":"66","author":"Wennberg","year":"2018","journal-title":"Neurobiol. Aging"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.neuroscience.2016.03.056","article-title":"The role of Insulin-Like Growth Factor 1 (IGF-1) in brain development, maturation and neuroplasticity","volume":"325","author":"Dyer","year":"2016","journal-title":"Neuroscience"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.arr.2005.02.001","article-title":"Growth hormone and insulin-like growth factor-1 (IGF-1) and their influence on cognitive aging","volume":"4","author":"Sonntag","year":"2005","journal-title":"Ageing Res. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1677\/joe.0.1380421","article-title":"Effect of high-protein feed supplements on concentrations of growth hormone (GH), insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 in plasma and on the amounts of GH and messenger RNA for GH in the pituitary glands of adult rams","volume":"138","author":"Clarke","year":"1993","journal-title":"J. Endocrinol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.pneurobio.2003.08.002","article-title":"Insulin-like growth factor-1 and post-ischemic brain injury","volume":"70","author":"Guan","year":"2003","journal-title":"Prog. Neurobiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"101416","DOI":"10.1016\/j.ghir.2021.101416","article-title":"Relationship between circulating insulin-like growth factor-1 and blood pressure in adults: A systematic review and meta-analysis of observational studies","volume":"60\u201361","author":"Leng","year":"2021","journal-title":"Growth Horm. IGF Res. Off. J. Growth Horm. Res. Soc. Int. IGF Res. Soc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9833","DOI":"10.1073\/pnas.0400337101","article-title":"Insulin-like growth factor I is required for vessel remodeling in the adult brain","volume":"101","author":"LeRoith","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.ghir.2019.01.002","article-title":"IGF-1 and cardiovascular disease","volume":"45","author":"Higashi","year":"2019","journal-title":"Growth Horm IGF Res"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1038\/nrendo.2013.67","article-title":"The GH\/IGF-1 axis in ageing and longevity","volume":"9","author":"Junnila","year":"2013","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1093\/gerona\/gls118","article-title":"Aging, synaptic dysfunction, and insulin-like growth factor (IGF)-1","volume":"67","author":"Deak","year":"2012","journal-title":"J. Gerontol. Ser. A Biol. Sci. Med. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1093\/gerona\/gls072","article-title":"The emerging role of IGF-1 deficiency in cardiovascular aging: Recent advances","volume":"67","author":"Ungvari","year":"2012","journal-title":"J. Gerontol. Ser. A Biol. Sci. Med. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/0006-291X(92)91774-K","article-title":"A role for IGF-1 in the rescue of CNS neurons following hypoxic- ischemic injury","volume":"182","author":"Gluckman","year":"1992","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1007\/s11906-011-0195-x","article-title":"Vascular mechanisms in the pathogenesis of stroke","volume":"13","author":"Sierra","year":"2011","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1677\/joe.0.1620243","article-title":"Enhanced proteolytic activity directed against the N-terminal of IGF-I in diabetic rats","volume":"162","author":"Yamamoto","year":"1999","journal-title":"J. Endocrinol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1007\/s10903-017-0583-7","article-title":"Cognitive Function and Vascular Risk Factors Among Older African American Adults","volume":"20","author":"Williams","year":"2018","journal-title":"J. Immigr. Minor. Health"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"27","DOI":"10.3233\/JAD-150516","article-title":"Vascular Health Indices and Cognitive Domain Function: Singapore Longitudinal Ageing Studies","volume":"50","author":"Lim","year":"2016","journal-title":"J. Alzheimers Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.bbr.2012.08.002","article-title":"Age-related memory decline is associated with vascular and microglial degeneration in aged rats","volume":"235","author":"Zhang","year":"2012","journal-title":"Behav. Brain Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1677\/joe.0.1700063","article-title":"The acid-labile subunit (ALS) of the 150 kDa IGF-binding protein complex: An important but forgotten component of the circulating IGF system","volume":"170","author":"Boisclair","year":"2001","journal-title":"J. Endocrinol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5964","DOI":"10.2174\/1381612823666171002114545","article-title":"IGF-1 as a Drug for Preterm Infants: A Step-Wise Clinical Development","volume":"23","author":"Hellstrom","year":"2017","journal-title":"Curr. Pharm. Des."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/0006-8993(89)91678-8","article-title":"Insulin-like growth factor 1 (IGF-1) receptors in the human brain: Quantitative autoradiographic localization","volume":"503","author":"Adem","year":"1989","journal-title":"Brain Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/0167-0115(93)90409-2","article-title":"Identification of IGF-1 receptors in primitive vertebrates","volume":"43","author":"Drakenberg","year":"1993","journal-title":"Regul. Pept."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1152\/physrev.1990.70.3.591","article-title":"Insulin-like growth factors and their binding proteins","volume":"70","author":"Sara","year":"1990","journal-title":"Physiol. Rev."},{"key":"ref_23","first-page":"166","article-title":"Targeting IGF-I, IGFBPs and IGF-I receptor system in cancer: The current and future in breast cancer therapy","volume":"6","author":"Mohanraj","year":"2011","journal-title":"Recent Pat. Anti-Canc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1677\/joe.0.1500067","article-title":"IGF-I and IGF-binding protein-3 in plasma of GH-deficient rats","volume":"150","author":"Butler","year":"1996","journal-title":"J. Endocrinol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"E967","DOI":"10.1152\/ajpendo.2000.278.6.E967","article-title":"Insulin-like growth factor (IGF)-binding proteins: Interactions with IGFs and intrinsic bioactivities","volume":"278","author":"Baxter","year":"2000","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"105191","DOI":"10.1016\/j.psyneuen.2021.105191","article-title":"The autocrine regulation of insulin-like growth factor-1 in human brain of Alzheimer\u2019s disease","volume":"127","author":"Kang","year":"2021","journal-title":"Psychoneuroendocrinology"},{"key":"ref_27","first-page":"2161-0460","article-title":"Vascular Remodelling is Impaired in Parkinson Disease","volume":"7","author":"Yang","year":"2017","journal-title":"J. Alzheimers Dis. Park."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/BF02257671","article-title":"Insulin-like growth factors and insulin-like growth factor binding proteins in cerebrospinal fluid and serum of patients with dementia of the Alzheimer type","volume":"5","author":"Tham","year":"1993","journal-title":"J. Neural Transm. Park. Dis. Dement. Sect."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4388","DOI":"10.1038\/srep04388","article-title":"Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1","volume":"4","author":"Guan","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1677\/joe.0.1460141","article-title":"Enzymatic conversion of IGF-I to des(1-3)IGF-I in rat serum and tissues: A further potential site of growth hormone regulation of IGF-I action","volume":"146","author":"Yamamoto","year":"1995","journal-title":"J. Endocrinol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1111\/j.1749-6632.1993.tb26216.x","article-title":"The biological role of truncated Insulin-like Growth Factor-1 and the tripeptide GPE in the central nervous system","volume":"692","author":"Sara","year":"1993","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/S0006-8993(99)02051-X","article-title":"Role of insulin-like growth factor binding proteins in limitation of IGF-1 degradation into the N-methyl-D-aspartate receptor antagonist GPE: Evidence from gonadotrophin-releasing hormone secretion in vitro at two developmental stages","volume":"847","author":"Bourguignon","year":"1999","journal-title":"Brain Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1517\/14728222.2015.1010514","article-title":"The role for IGF-1-derived small neuropeptides as a therapeutic target for neurological disorders","volume":"19","author":"Guan","year":"2015","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1016\/j.neuropharm.2004.07.002","article-title":"Neuroprotective effects of the N-terminal tripeptide of insulin-like growth factor-1, glycine-proline-glutamate (GPE) following intravenous infusion in hypoxic-ischemic adult rats","volume":"47","author":"Guan","year":"2004","journal-title":"Neuropharmacology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.npep.2004.11.001","article-title":"Central penetration and stability of N-terminal tripeptide of insulin-like growth factor-I, glycine-proline-glutamate in adult rat","volume":"39","author":"Baker","year":"2005","journal-title":"Neuropeptides"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1002\/acn3.743","article-title":"Plasma cyclic glycine proline\/IGF-1 ratio predicts clinical outcome and recovery in stroke patients","volume":"6","author":"Fan","year":"2019","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/0014-5793(96)00722-3","article-title":"Identification of a novel endogenous memory facilitating cyclic dipeptide cyclo-prolylglycine in rat brain","volume":"391","author":"Gudasheva","year":"1996","journal-title":"FEBS Lett."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1007\/s10517-016-3241-5","article-title":"Neuropeptide Cycloprolylglycine Exhibits Neuroprotective Activity after Systemic Administration to Rats with Modeled Incomplete Global Ischemia and in In Vitro Modeled Glutamate Neurotoxicity","volume":"160","author":"Povarnina","year":"2016","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1023\/A:1013663126973","article-title":"Proline-containing dipeptide GVS-111 retains nootropic activity after oral administration","volume":"132","author":"Ostrovskaya","year":"2001","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1097\/00008877-199909000-00013","article-title":"Memory restoring and neuroprotective effects of the proline-containing dipeptide, GVS-111, in a photochemical stroke model","volume":"10","author":"Ostrovskaya","year":"1999","journal-title":"Behav. Pharm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1111\/j.1476-5381.2009.00256.x","article-title":"IGF-1 derived small neuropeptides and analogues: A novel strategy for the development of pharmaceuticals for neurological conditions","volume":"157","author":"Guan","year":"2009","journal-title":"Br. J. Pharm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/j.neuropharm.2007.08.010","article-title":"Peripheral administration of a novel diketopiperazine, NNZ 2591, prevents brain injury and improves somatosensory-motor function following hypoxia-ischemia in adult rats","volume":"53","author":"Guan","year":"2007","journal-title":"Neuropharmacology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"113561","DOI":"10.1016\/j.bbr.2021.113561","article-title":"Oral administration of cyclic glycyl-proline facilitates task learning in a rat stroke model","volume":"417","author":"Kaneko","year":"2022","journal-title":"Behav. Brain Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3130","DOI":"10.1210\/en.2016-1189","article-title":"Maternally Administered Cyclic Glycine-Proline Increases Insulin-Like Growth Factor-1 Bioavailability and Novelty Recognition in Developing Offspring","volume":"157","author":"Singh","year":"2016","journal-title":"Endocrinology"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Fan, D., Alamri, Y., Liu, K., MacAskill, M., Harris, P., Brimble, M., Dalrymple-Alford, J., Prickett, T., Menzies, O., and Laurenson, A. (2018). Supplementation of Blackcurrant Anthocyanins Increased Cyclic Glycine-Proline in the Cerebrospinal Fluid of Parkinson Patients: Potential Treatment to Improve Insulin-Like Growth Factor-1 Function. Nutrients, 10.","DOI":"10.3390\/nu10060714"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"101935","DOI":"10.1016\/j.npep.2019.05.006","article-title":"Cyclic glycine-proline administration normalizes high-fat diet-induced synaptophysin expression in obese rats","volume":"76","author":"Li","year":"2019","journal-title":"Neuropeptides"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.bbr.2010.02.039","article-title":"NNZ-2591, a novel diketopiperazine, prevented scopolamine-induced acute memory impairment in the adult rat","volume":"210","author":"Guan","year":"2010","journal-title":"Behav. Brain Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1111\/j.1476-5381.2008.00064.x","article-title":"A novel diketopiperazine improves functional recovery given after the onset of 6-OHDA induced motor deficit in rats","volume":"156","author":"Krishnamurthi","year":"2008","journal-title":"Br. J. Pharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.pediatrneurol.2020.04.019","article-title":"A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the Treatment of Fragile X Syndrome","volume":"110","author":"Horrigan","year":"2020","journal-title":"Pediatr. Neurol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1007\/s40261-022-01156-4","article-title":"A Phase 1, Open-Label Study to Evaluate the Effects of Food and Evening Dosing on the Pharmacokinetics of Oral Trofinetide in Healthy Adult Subjects","volume":"42","author":"Darwish","year":"2022","journal-title":"Clin. Drug Investig."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"106704","DOI":"10.1016\/j.cct.2022.106704","article-title":"Design and outcome measures of LAVENDER, a phase 3 study of trofinetide for Rett syndrome","volume":"114","author":"Neul","year":"2022","journal-title":"Contemp. Clin. Trials"},{"key":"ref_52","first-page":"S98","article-title":"Population pharmacokinetics of NNZ-2566 in healthy subjects","volume":"109S","author":"Oosterholt","year":"2017","journal-title":"Eur. J. Pharm. Sci. Off. J. Eur. Fed. Pharm. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.pediatrneurol.2017.07.002","article-title":"A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the Treatment of Rett Syndrome","volume":"76","author":"Glaze","year":"2017","journal-title":"Pediatr. Neurol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e1912","DOI":"10.1212\/WNL.0000000000007316","article-title":"Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome","volume":"92","author":"Glaze","year":"2019","journal-title":"Neurology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/s10517-019-04455-7","article-title":"Effect of Endogenous Neuropeptide Cycloprolylglycine on GABAA Receptors in Cerebellar Purkinje Cells","volume":"167","author":"Sharonova","year":"2019","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1134\/S160767291606003X","article-title":"Neuropeptide cycloprolylglycine is an endogenous positive modulator of AMPA receptors","volume":"471","author":"Gudasheva","year":"2016","journal-title":"Doklady. Biochem. Biophys."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1097\/00001756-199901180-00031","article-title":"Neuroprotective effects of Gly-Pro-Glu, the N-terminal tripeptide of IGF-1, in the hippocampus in vitro","volume":"10","author":"Saura","year":"1999","journal-title":"Neuroreport"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1016\/S0006-291X(89)80032-4","article-title":"Indentification of Gly-Pre-Glu(GPE), the aminoterminal tripeptide of insulin-like growth factor 1 which is truncted in brain, as a novel neuroaction peptide","volume":"165","author":"Sara","year":"1989","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1159\/000085720","article-title":"Treatment in animal models","volume":"9","author":"Guan","year":"2005","journal-title":"Endocr. Dev."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1159\/000105480","article-title":"Delayed peripheral administration of a GPE analogue induces astrogliosis and angiogenesis and reduces inflammation and brain injury following hypoxia-ischemia in the neonatal rat","volume":"29","author":"Svedin","year":"2007","journal-title":"Dev. Neurosci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.neulet.2009.03.003","article-title":"Delayed peripheral administration of the N-terminal tripeptide of IGF-1 (GPE) reduces brain damage following microsphere induced embolic damage in young adult and aged rats","volume":"454","author":"Shapira","year":"2009","journal-title":"Neurosci. Lett."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.mbs.2014.11.002","article-title":"Modeling the effect of insulin-like growth factor-1 on human cell growth","volume":"259","author":"Phillips","year":"2015","journal-title":"Math. Biosci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1002\/acn3.732","article-title":"Cardiovascular risk factors and Parkinson\u2019s disease in 500,000 Chinese adults","volume":"6","author":"Kizza","year":"2019","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/bs.irn.2019.06.003","article-title":"Exercise and Parkinson\u2019s disease","volume":"147","author":"Xu","year":"2019","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"134626","DOI":"10.1016\/j.neulet.2019.134626","article-title":"Hypertension accelerates cerebral tissue PO(2) disruption in Alzheimer\u2019s disease","volume":"715","author":"Lu","year":"2020","journal-title":"Neurosci. Lett."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"332","DOI":"10.25122\/jml-2019-0088","article-title":"Possibilities of Dementia Prevention\u2014It is Never Too Early to Start","volume":"12","author":"Morovic","year":"2019","journal-title":"J. Med. Life"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.3233\/JAD-200473","article-title":"Alzheimer\u2019s Disease: The Link Between Amyloid-\u03b2 and Neurovascular Dysfunction","volume":"76","author":"Solis","year":"2020","journal-title":"J. Alzheimer\u2019s Dis. JAD"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"25","DOI":"10.7150\/ijms.13800","article-title":"Systematic Review of Metabolic Syndrome Biomarkers: A Panel for Early Detection, Management, and Risk Stratification in the West Virginian Population","volume":"13","author":"Srikanthan","year":"2016","journal-title":"Int. J. Med. Sci."},{"key":"ref_69","first-page":"330","article-title":"The IGF system in metabolism regulation","volume":"21","author":"Binoux","year":"1995","journal-title":"Diabete Metab."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.blre.2014.09.010","article-title":"All in the family: Clueing into the link between metabolic syndrome and hematologic malignancies","volume":"29","author":"Karmali","year":"2015","journal-title":"Blood Rev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1186\/1479-5876-9-136","article-title":"Liver-spleen axis, insulin-like growth factor-(IGF)-I axis and fat mass in overweight\/obese females","volume":"16","author":"Savastano","year":"2011","journal-title":"J. Transl. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1161\/HYPERTENSIONAHA.113.03057","article-title":"Revisiting the relationship between blood pressure and insulin-like growth factor-1","volume":"63","author":"Schutte","year":"2014","journal-title":"Hypertension"},{"key":"ref_73","first-page":"465","article-title":"The role for cyclic Glycine-Proline, a biological regulator of insulin-like growth factor-1 in pregnancy-related obesity and weight changes","volume":"32","author":"Guan","year":"2018","journal-title":"J. Biol. Regul. Homeost Agents"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.numecd.2019.09.016","article-title":"Cyclic glycine-proline normalizes systolic blood pressure in high-fat diet-induced obese male rats","volume":"30","author":"Li","year":"2019","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1097\/HJH.0000000000000753","article-title":"Hypertension and lifetime risk of stroke","volume":"34","author":"Turin","year":"2016","journal-title":"J. Hypertens."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"H1598","DOI":"10.1152\/ajpheart.00490.2012","article-title":"The effects of hypertension on the cerebral circulation","volume":"304","author":"Pires","year":"2013","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/S0140-6736(13)61953-4","article-title":"Global and regional burden of stroke during 1990\u20132010: Findings from the Global Burden of Disease Study 2010","volume":"383","author":"Feigin","year":"2014","journal-title":"Lancet"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e002433","DOI":"10.1161\/JAHA.115.002433","article-title":"Stroke Severity Is a Crucial Predictor of Outcome: An International Prospective Validation Study","volume":"5","author":"Rost","year":"2016","journal-title":"J. Am. Heart Assoc."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.1161\/01.STR.28.9.1744","article-title":"Plasma insulin-like growth factor I and IGF binding protein 3 levels in patients with acute cerebral ischemic injury","volume":"28","author":"Schwab","year":"1997","journal-title":"Stroke"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"E1055","DOI":"10.1210\/jc.2010-2802","article-title":"Serum IGF-I levels correlate to improvement of functional outcome after ischemic stroke","volume":"96","author":"Aberg","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Dong, X., Chang, G., Ji, X.F., Tao, D.B., and Wang, Y.X. (2014). The relationship between serum insulin-like growth factor I levels and ischemic stroke risk. PloS ONE, 9.","DOI":"10.1371\/journal.pone.0094845"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/S0169-328X(03)00085-8","article-title":"Time- and cell type-specific induction of platelet-derived growth factor receptor-beta during cerebral ischemia","volume":"113","author":"Renner","year":"2003","journal-title":"Brain Res. Mol. Brain Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1037\/0894-4105.21.2.149","article-title":"Vascular health and longitudinal changes in brain and cognition in middle-aged and older adults","volume":"21","author":"Raz","year":"2007","journal-title":"Neuropsychology"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1080\/13825585.2018.1499866","article-title":"Framingham vascular age is associated with worse cognitive performance in the middle-aged and elderly","volume":"26","author":"Badran","year":"2019","journal-title":"Neuropsychol. Dev. Cogn. Sect. B Aging Neuropsychol. Cogn."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.pneurobio.2009.07.008","article-title":"Circulating insulin-like growth factor I and cognitive function: Neuromodulation throughout the lifespan","volume":"89","author":"Aleman","year":"2009","journal-title":"Prog. Neurobiol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.mcn.2011.07.008","article-title":"Reduced brain insulin-like growth factor I function during aging","volume":"49","author":"Muller","year":"2012","journal-title":"Mol. Cell Neurosci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.neurobiolaging.2005.10.012","article-title":"Plasma IGF-I levels and cognitive performance in older women","volume":"28","author":"Okereke","year":"2007","journal-title":"Neurobiol. Aging"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"4306","DOI":"10.1210\/jc.2006-1325","article-title":"Midlife plasma insulin-like growth factor I and cognitive function in older men","volume":"91","author":"Okereke","year":"2006","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_89","first-page":"e12025","article-title":"Changes of plasma cGP\/IGF-1 molar ratio with age is associated with cognitive status of Parkinson disease","volume":"12","author":"Fan","year":"2020","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_90","unstructured":"Wang, A. (2019). Plasma Cyclic Glycine-Proline\/Insulin-Like Growth Factor-1 Molar Ratio Is Associated with Cognitive Function in Elder People. [Ph.D. Thesis, University of Auckland]."},{"key":"ref_91","first-page":"1750","article-title":"Vascular Degeneration in Parkinson\u2019s Disease","volume":"16","author":"Guan","year":"2012","journal-title":"Brain Pathol."},{"key":"ref_92","first-page":"821","article-title":"String Vessel Formation is Increased in the Brain of Parkinson Disease","volume":"5","author":"Yang","year":"2015","journal-title":"J. Park. Dis."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1136\/jnnp.2010.232678","article-title":"Dementia in Parkinson\u2019s disease: A 20-year neuropsychological study (Sydney Multicentre Study)","volume":"82","author":"Reid","year":"2011","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"15027","DOI":"10.1038\/npjparkd.2015.27","article-title":"Different PD-MCI criteria and risk of dementia in Parkinson\u2019s disease: Four year longitudinal study","volume":"2","author":"Wood","year":"2016","journal-title":"Npj Park. Dis."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1002\/mds.27002","article-title":"Mild cognitive impairment as a risk factor for Parkinson\u2019s disease dementia","volume":"32","author":"Hoogland","year":"2017","journal-title":"Mov. Disord."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1111\/ene.12137","article-title":"Insulin-like growth factor-1 predicts cognitive functions at 2-year follow-up in early, drug-naive Parkinson\u2019s disease","volume":"21","author":"Pellecchia","year":"2014","journal-title":"Eur. J. Neurol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/S0306-4522(97)00154-1","article-title":"Distribution and levels of [125I]IGF-I, [125I]IGF-II and [125I]insulin receptor binding sites in the hippocampus of aged memory-unimpaired and -impaired rats","volume":"80","author":"Dore","year":"1997","journal-title":"Neuroscience"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1007\/s00415-013-6851-0","article-title":"Insulin-like growth factor-1 and progression of motor symptoms in early, drug-na\u00efve Parkinson\u2019s disease","volume":"260","author":"Picillo","year":"2013","journal-title":"J. Neurol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1001\/archneurol.2011.129","article-title":"Serum insulinlike growth factor 1 as possible marker for risk and early diagnosis of Parkinson disease","volume":"68","author":"Godau","year":"2011","journal-title":"Arch. Neurol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1136\/jnnp.2009.175752","article-title":"Increased serum insulin-like growth factor 1 in early idiopathic Parkinson\u2019s disease","volume":"81","author":"Godau","year":"2010","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1016\/j.jacc.2019.10.062","article-title":"Alzheimer\u2019s Disease and Vascular Aging: JACC Focus Seminar","volume":"75","author":"Iadecola","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"59","DOI":"10.2302\/kjm.55.59","article-title":"Serum insulin-like growth factor I in brain function","volume":"55","author":"Carro","year":"2006","journal-title":"Keio J. Med."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1016\/j.ajpath.2021.07.003","article-title":"Interplay between Brain Pericytes and Endothelial Cells in Dementia","volume":"191","author":"Procter","year":"2021","journal-title":"Am. J. Pathol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.nbd.2015.08.014","article-title":"Vascular dysfunction in the pathogenesis of Alzheimer\u2019s disease\u2014A review of endothelium-mediated mechanisms and ensuing vicious circles","volume":"82","author":"Venneri","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1186\/s13041-015-0174-2","article-title":"The participation of insulin-like growth factor-binding protein 3 released by astrocytes in the pathology of Alzheimer\u2019s disease","volume":"8","author":"Watanabe","year":"2015","journal-title":"Mol. Brain"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"e12801","DOI":"10.1111\/acel.12801","article-title":"The emerging roles of protein homeostasis-governing pathways in Alzheimer\u2019s disease","volume":"17","author":"Cheng","year":"2018","journal-title":"Aging Cell"},{"key":"ref_107","first-page":"10","article-title":"Administration of cyclic glycine-proline during infancy improves adult spatial memory, astrocyte plasticity, vascularization and GluR-1 expression in rats","volume":"25","author":"Ardalan","year":"2021","journal-title":"Nutr. Neurosci."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1002\/gps.4735","article-title":"The influence of vascular risk factors on cognitive function in early Parkinson\u2019s disease","volume":"33","author":"Doiron","year":"2018","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"ref_109","first-page":"105","article-title":"Cognitive impairment and stroke in elderly patients","volume":"12","author":"Lopez","year":"2016","journal-title":"Vasc. Health Risk. Manag."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Picillo, M., Pivonello, R., Santangelo, G., Pivonello, C., Savastano, R., Auriemma, R., Amboni, M., Scannapieco, S., Pierro, A., and Colao, A. (2017). Serum IGF-1 is associated with cognitive functions in early, drug-naive Parkinson\u2019s disease. PloS ONE, 12.","DOI":"10.1371\/journal.pone.0186508"},{"key":"ref_111","first-page":"137","article-title":"The use of dietary supplements and perceived quality of life in patients with Parkinson\u2019s disease","volume":"56","author":"Alamri","year":"2018","journal-title":"J. Clin. Neurosci. Off. J. Neurosurg. Soc. Australas."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/3\/1021\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:10:39Z","timestamp":1760119839000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/3\/1021"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,19]]},"references-count":111,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["molecules28031021"],"URL":"https:\/\/doi.org\/10.3390\/molecules28031021","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,19]]}}}