Abstract
Sitagliptin (SIT) is a dipeptidyl peptidase-4 (DPP-4) inhibitor that enhances the effects of incretin hormones, such as Glucose-dependent Insulinotropic Peptide (also known as Gastric Inhibitory Polypeptide, GIP) and Glucagon-Like Peptide 1 (GLP-1). We have now evaluated the effect of SIT on proliferation of neural progenitors in diabetic mice. A condition resembling the non-obese type 2 diabetes mellitus (D2) was achieved by a combination of streptozotocin and nicotinamide (NA-STZ), whereas a type 1-like disease (D1) was provoked by STZ without NA. Non-diabetic mice received vehicle injections. Cell proliferation was estimated by bromodeoxyuridine (BrdU) incorporation in two different regions of the subventricular zone (SVZ), the largest reserve of neural stem cells in the adult brain. SIT treatment did not modify the high fasting blood glucose (BG) levels and intraperitoneal glucose tolerance test (IPGTT) of D1 mice. By contrast, in D2 mice, SIT treatment significantly reduced BG and IPGTT. Both D1 and D2 mice showed a substantial reduction of BrdU labeling in the SVZ. Remarkably, SIT treatment improved BrdU labeling in both conditions. Our findings suggest that SIT would protect proliferation of neural progenitor cells even in the presence of non-controlled diabetic alterations.
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References
American Diabetes Association (2010) Diagnosis and classification of diabetes mellitus. Diabetes Care 33(Suppl 1):S62–S69. doi:10.2337/dc10-S062
Andrikopoulos S, Blair AR, Deluca N, Fam BC, Proietto J (2008) Evaluating the glucose tolerance test in mice. Am J Physiol Endocrinol Metab 295:E1323–E1332. doi:10.1152/ajpendo.90617.2008
Bachor TP, Suburo AM (2012) Neural stem cells in the diabetic brain. Stem Cells Int 2012:820790. doi:10.1155/2012/820790
Beauquis J, Roig P, Homo-Delarche F, De Nicola A, Saravia F (2006) Reduced hippocampal neurogenesis and number of hilar neurones in streptozotocin-induced diabetic mice: reversion by antidepressant treatment. Eur J Neurosci 23:1539–1546. doi:10.1111/j.1460-9568.2006.04691.x
Beauquis J, Saravia F, Coulaud J, Roig P, Dardenne M, Homo-Delarche F, De Nicola A (2008) Prominently decreased hippocampal neurogenesis in a spontaneous model of type 1 diabetes, the nonobese diabetic mouse. Exp Neurol 210:359–367. doi:10.1016/j.expneurol.2007.11.009
Beauquis J et al. (2010) Hippocampal neurovascular and hypothalamic-pituitary-adrenal axis alterations in spontaneously type 2 diabetic GK rats. Exp Neurol 222:125–134. doi:10.1016/j.expneurol.2009.12.022
Castañeda MM, Cubilla MA, López-Vicchi MM, Suburo AM (2010) Endothelinergic cells in the subependymal region of mice. Brain Res 1321:20–30. doi:10.1179/016164111X12881719352219
Castañeda MM, Cubilla MA, Bachor T, Suburo AM (2011) Endothelinergic signaling during recovery of brain cortical lesions. Neurol Res 33:137–144. doi:10.1179/016164111X12881719352219
Chen S, Liu AR, An FM, Yao WB, Gao XD (2011) Amelioration of neurodegenerative changes in cellular and rat models of diabetes-related Alzheimer’s disease by exendin-4. Age (Dordr) 34:1121–1124. doi:10.1007/s11357-011-9303-8
Cheng G, Huang C, Deng H, Wang H (2012) Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies. Intern Med J 42:484–491. doi:10.1111/j.1445-5994.2012.02758.x
Codega P, Silva-Vargas V, Paul A, Maldonado-Soto AR, Deleo AM, Pastrana E, Doetsch F (2014) Prospective identification and purification of quiescent adult neural stem cells from their in vivo niche. Neuron 82:545–559. doi:10.1016/j.neuron.2014.02.039
Creutzfeldt W, Ebert R (1985) New developments in the incretin concept. Diabetologia 28:565–573
D’Amico M, Di Filippo C, Marfella R, Abbatecola AM, Ferraraccio F, Rossi F, Paolisso G (2010) Long-term inhibition of dipeptidyl peptidase-4 in Alzheimer’s prone mice. Exp Gerontol 45:202–207. doi:10.1016/j.exger.2009.12.004
Darsalia V et al. (2012) Glucagon-like peptide-1 receptor activation reduces ischaemic brain damage following stroke in Type 2 diabetic rats. Clin Sci (Lond) 122:473–483. doi:10.1042/CS20110374
Darsalia V et al. (2013) The DPP-4 inhibitor linagliptin counteracts stroke in the normal and diabetic mouse brain: a comparison with glimepiride. Diabetes 62:1289–1296. doi:10.2337/db12-0988
Darsalia V et al. (2014) Linagliptin enhances neural stem cell proliferation after stroke in type 2 diabetic mice. Regul Pept 190-191:25–31. doi:10.1016/j.regpep.2014.05.001
Desrocher M, Rovet J (2004) Neurocognitive correlates of type 1 diabetes mellitus in childhood. Child Neuropsychol 10:36–52. doi:10.1076/chin.10.1.36.26241
Drucker DJ, Nauck MA (2006) The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368:1696–1705. doi:10.1016/S0140-6736(06)69705-5
Ellis SL, Moser EG, Snell-Bergeon JK, Rodionova AS, Hazenfield RM, Garg SK (2011) Effect of sitagliptin on glucose control in adult patients with Type 1 diabetes: a pilot, double-blind, randomized, crossover trial. Diabet Med 28:1176–1181. doi:10.1111/j.1464-5491.2011.03331.x
Faivre E, Hamilton A, Holscher C (2012) Effects of acute and chronic administration of GIP analogues on cognition, synaptic plasticity and neurogenesis in mice. Eur J Pharmacol 674:294–306. doi:10.1016/j.ejphar.2011.11.007
Gil-Perotin S, Duran-Moreno M, Cebrian-Silla A, Ramirez M, Garcia-Belda P, Garcia-Verdugo JM (2013) Adult neural stem cells from the subventricular zone: a review of the neurosphere assay. Anat Rec 296:1435–1452. doi:10.1002/ar.22746
Greenwood CE, Winocur G (2005) High-fat diets, insulin resistance and declining cognitive function. Neurobiol Aging 26:S42–S45. doi:10.1016/j.neurobiolaging.2005.08.017
Guo J et al. (2010) Impaired neural stem/progenitor cell proliferation in streptozotocin-induced and spontaneous diabetic mice. Neurosci Res 68:329–336. doi:10.1016/j.neures.2010.08.012
Hamilton A, Patterson S, Porter D, Gault VA, Holscher C (2011) Novel GLP-1 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain. J Neurosci Res 89:481–489. doi:10.1002/jnr.22565
Hirose M et al. (2006) Inhibition of self-renewal and induction of neural differentiation by PACAP in neural progenitor cells. Ann N Y Acad Sci 1070:342–347. doi:10.1196/annals.1317.042
Ho N, Brookshire BR, Clark JE, Lucki I (2014) Indomethacin reverses decreased hippocampal cell proliferation in streptozotocin-induced diabetic mice. Metab Brain Dis. doi:10.1007/s11011-014-9611-7
Hunter K, Holscher C (2012) Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci 13:33. doi:10.1186/1471-2202-13-33
Hwang IK, Yi SS, Song W, Won MH, Yoon YS, Seong JK (2010) Effects of age and treadmill exercise in chronic diabetic stages on neuroblast differentiation in a rat model of type 2 diabetes. Brain Res 1341:63–71. doi:10.1016/j.brainres.2009.12.009
Jackson-Guilford J, Leander JD, Nisenbaum LK (2000) The effect of streptozotocin-induced diabetes on cell proliferation in the rat dentate gyrus. Neurosci Lett 293:91–94
Jackson EK, Mi Z (2008) Sitagliptin augments sympathetic enhancement of the renovascular effects of angiotensin II in genetic hypertension. Hypertension 51:1637–1642. doi:10.1161/HYPERTENSIONAHA.108.112532
Jungraithmayr W et al. (2010) Inhibition of CD26/DPP IV attenuates ischemia/reperfusion injury in orthotopic mouse lung transplants: the pivotal role of vasoactive intestinal peptide. Peptides 31:585–591. doi:10.1016/j.peptides.2009.12.012
Kokovay E et al. (2010) Adult SVZ lineage cells home to and leave the vascular niche via differential responses to SDF1/CXCR4 signaling. Cell Stem Cell 7:163–173. doi:10.1016/j.stem.2010.05.019
Kosaraju J, Murthy V, Khatwal RB, Dubala A, Chinni S, Muthureddy Nataraj SK, Basavan D (2013) Vildagliptin: an anti-diabetes agent ameliorates cognitive deficits and pathology observed in streptozotocin-induced Alzheimer’s disease. J Pharm Pharmacol 65:1773–1784. doi:10.1111/jphp.12148
Landgren H, Curtis MA (2011) Locating and labeling neural stem cells in the brain. J Cell Physiol 226:1–7. doi:10.1002/jcp.22319
Lang BT, Yan Y, Dempsey RJ, Vemuganti R (2009) Impaired neurogenesis in adult type-2 diabetic rats. Brain Res 1258:25–33. doi:10.1016/j.brainres.2008.12.026
Lee J, Duan W, Mattson MP (2002) Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem 82:1367–1375
Li Y et al. (2010) GLP-1 receptor stimulation reduces amyloid-beta peptide accumulation and cytotoxicity in cellular and animal models of Alzheimer’s disease. J Alzheimers Dis 19:1205–1219. doi:10.3233/JAD-2010-1314
Mansouri S, Ortsater H, Pintor Gallego O, Darsalia V, Sjoholm A, Patrone C (2012) Pituitary adenylate cyclase-activating polypeptide counteracts the impaired adult neural stem cell viability induced by palmitate. J Neurosci Res 90:759–768. doi:10.1002/jnr.22803
Martin B et al. (2009) Exendin-4 improves glycemic control, ameliorates brain and pancreatic pathologies, and extends survival in a mouse model of Huntington’s disease. Diabetes 58:318–328. doi:10.2337/db08-0799
Mercer A et al. (2004) PACAP promotes neural stem cell proliferation in adult mouse brain. J Neurosci Res 76:205–215. doi:10.1002/jnr.20038
Messier C (2005) Impact of impaired glucose tolerance and type 2 diabetes on cognitive aging. Neurobiol Aging 26(Suppl 1):26–30. doi:10.1016/j.neurobiolaging.2005.09.014
Mu J et al. (2009) Inhibition of DPP-4 with sitagliptin improves glycemic control and restores islet cell mass and function in a rodent model of type 2 diabetes. Eur J Pharmacol 623:148–154. doi:10.1016/j.ejphar.2009.09.027
Nakamura T, Terajima T, Ogata T, Ueno K, Hashimoto N, Ono K, Yano S (2006) Establishment and pathophysiological characterization of type 2 diabetic mouse model produced by streptozotocin and nicotinamide. Biol Pharm Bull 29:1167–1174
Nauck MA, Baller B, Meier JJ (2004) Gastric inhibitory polypeptide and glucagon-like peptide-1 in the pathogenesis of type 2 diabetes. Diabetes 53(Suppl 3):S190–S196
Nowakowski RS, Lewin SB, Miller MW (1989) Bromodeoxyuridine immunohistochemical determination of the lengths of the cell cycle and the DNA-synthetic phase for an anatomically defined population. J Neurocytol 18:311–318
Nyberg J et al. (2005) Glucose-dependent insulinotropic polypeptide is expressed in adult hippocampus and induces progenitor cell proliferation. J Neurosci 25:1816–1825. doi:10.1523/JNEUROSCI.4920-04.2005
Omar B, Ahren B (2014) Pleiotropic mechanisms for the glucose-lowering action of DPP-4 inhibitors. Diabetes 63:2196–2202. doi:10.2337/db14-0052
Park HR, Park M, Choi J, Park KY, Chung HY, Lee J (2010) A high-fat diet impairs neurogenesis: involvement of lipid peroxidation and brain-derived neurotrophic factor. Neurosci Lett 482:235–239. doi:10.1016/j.neulet.2010.07.046
Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates. Academic, San Diego
Perry T, Greig NH (2005) Enhancing central nervous system endogenous GLP-1 receptor pathways for intervention in Alzheimer’s disease. Curr Alzheimer Res 2:377–385
Pintana H, Apaijai N, Chattipakorn N, Chattipakorn SC (2013) DPP-4 inhibitors improve cognition and brain mitochondrial function of insulin-resistant rats. J Endocrinol 218:1–11. doi:10.1530/JOE-12-0521
Ponti G, Obernier K, Guinto C, Jose L, Bonfanti L, Alvarez-Buylla A (2013) Cell cycle and lineage progression of neural progenitors in the ventricular-subventricular zones of adult mice. Proc Natl Acad Sci U S A 110:E1045–E1054. doi:10.1073/pnas.1219563110
Poucher SM, Cheetham S, Francis J, Zinker B, Kirby M, Vickers SP (2012) Effects of saxagliptin and sitagliptin on glycaemic control and pancreatic beta-cell mass in a streptozotocin-induced mouse model of type 2 diabetes. Diabetes Obes Metab 14:918–926. doi:10.1111/j.1463-1326.2012.01619.x
Ramos-Rodriguez JJ et al. (2014) Central proliferation and neurogenesis is impaired in type 2 diabetes and prediabetes animal models. PLoS One 9:e89229. doi:10.1371/journal.pone.0089229
Sakr HF (2013) Effect of sitagliptin on the working memory and reference memory in type 2 diabetic Sprague–Dawley rats: possible role of adiponectin receptors 1. J Physiol Pharmacol 64:613–623
Saravia F, Revsin Y, Lux-Lantos V, Beauquis J, Homo-Delarche F, De Nicola AF (2004) Oestradiol restores cell proliferation in dentate gyrus and subventricular zone of streptozotocin-diabetic mice. J Neuroendocrinol 16:704–710. doi:10.1111/j.1365-2826.2004.01223.x
Saravia FE et al. (2002) Increased astrocyte reactivity in the hippocampus of murine models of type 1 diabetes: the nonobese diabetic (NOD) and streptozotocin-treated mice. Brain Res 957:345–353
Sato N, Morishita R (2014) Brain alterations and clinical symptoms of dementia in diabetes: abeta/tau-dependent and independent mechanisms. Front Endocrinol 5:143. doi:10.3389/fendo.2014.00143
Scharf E, May V, Braas KM, Shutz KC, Mao-Draayer Y (2008) Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) regulate murine neural progenitor cell survival, proliferation, and differentiation. J Mol Neurosci 36:79–88. doi:10.1007/s12031-008-9097-z
Shimizu R, Sakazaki F, Okuno T, Nakamuro K, Ueno H (2012) Difference in glucose intolerance between C57BL/6 J and ICR strain mice with streptozotocin/nicotinamide-induced diabetes. Biomed Res 33:63–66
Strachan MW (2011) R D Lawrence Lecture 2010. The brain as a target organ in Type 2 diabetes: exploring the links with cognitive impairment and dementia. Diabet Med 28:141–147. doi:10.1111/j.1464-5491.2010.03199.x
Stranahan AM, Khalil D, Gould E (2006) Social isolation delays the positive effects of running on adult neurogenesis. Nat Neurosci 9:526–533. doi:10.1038/Nn1668
Suh SW et al. (2005) Hypoglycemia induces transient neurogenesis and subsequent progenitor cell loss in the rat hippocampus. Diabetes 54:500–509
Tahara A, Matsuyama-Yokono A, Nakano R, Someya Y, Shibasaki M (2008) Effects of antidiabetic drugs on glucose tolerance in streptozotocin-nicotinamide-induced mildly diabetic and streptozotocin-induced severely diabetic mice. Horm Metab Res 40:880–886. doi:10.1055/s-0028-1087167
Takeda Y et al. (2012) Reduction of both beta cell death and alpha cell proliferation by dipeptidyl peptidase-4 inhibition in a streptozotocin-induced model of diabetes in mice. Diabetologia 55:404–412. doi:10.1007/s00125-011-2365-4
van Praag H, Christie BR, Sejnowski TJ, Gage FH (1999) Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci USA 96:13427–13431. doi:10.1073/pnas.96.23.13427
Ventura RE, Goldman JE (2007) Dorsal radial glia generate olfactory bulb interneurons in the postnatal murine brain. J Neurosci 27:4297–4302. doi:10.1523/JNEUROSCI.0399-07.2007
Yang D, Nakajo Y, Iihara K, Kataoka H, Yanamoto H (2013) Alogliptin, a dipeptidylpeptidase-4 inhibitor, for patients with diabetes mellitus type 2, induces tolerance to focal cerebral ischemia in non-diabetic, normal mice. Brain Res 1517:104–113. doi:10.1016/j.brainres.2013.04.015
Yi SS et al. (2009) Effects of treadmill exercise on cell proliferation and differentiation in the subgranular zone of the dentate gyrus in a rat model of type II diabetes. Neurochem Res 34:1039–1046. doi:10.1007/s11064-008-9870-y
Zerilli T, Pyon EY (2007) Sitagliptin phosphate: a DPP-4 inhibitor for the treatment of type 2 diabetes mellitus. Clin Ther 29:2614–2634. doi:10.1016/j.clinthera.2007.12.034
Zhang WJ, Tan YF, Yue JT, Vranic M, Wojtowicz JM (2008) Impairment of hippocampal neurogenesis in streptozotocin-treated diabetic rats. Acta Neurol Scand 117:205–210. doi:10.1111/j.1600-0404.2007.00928.x
Zhao Y et al. (2014) Dipeptidyl peptidase 4 inhibitor sitagliptin maintains beta-cell function in patients with recent-onset latent autoimmune diabetes in adults: one year prospective study. J Clin Endocrinol Metab 99:E876–E880. doi:10.1210/jc.2013-3633
Zhu L et al. (2003) The role of dipeptidyl peptidase IV in the cleavage of glucagon family peptides: in vivo metabolism of pituitary adenylate cyclase activating polypeptide-(1-38). J Biol Chem 278:22418–22423. doi:10.1074/jbc.M212355200
Acknowledgments
TPB and MDM are research fellows funded by Universidad Austral and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). AMS is principal researcher at CONICET. Research funds were granted by Universidad Austral. We are very grateful to Guillermo Gastón and Santiago Cabrera for their skilful assistance in the care of mice.
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Bachor, T.P., Marquioni-Ramella, M.D. & Suburo, A.M. Sitagliptin protects proliferation of neural progenitor cells in diabetic mice. Metab Brain Dis 30, 885–893 (2015). https://doi.org/10.1007/s11011-015-9656-2
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DOI: https://doi.org/10.1007/s11011-015-9656-2