Abstract
Complications arising from diabetes mellitus include cognitive deficits, neurophysiological and structural changes in the brain. The current study investigated the expression of cholinergic, insulin, Vitamin D receptor and GLUT 3 in the brainstem of streptozotocin-induced diabetic rats. Radioreceptor binding assays and gene expression were done in the brainstem of male Wistar rats. Our results showed that Bmax of total muscarinic, muscarinic M3 receptors was increased and muscarinic M1 receptor was decreased in diabetic rats compared to control. A significant increase in gene expression of muscarinic M3, α7 nicotinic acetylcholine, insulin, Vitamin D3 receptors, acetylcholine esterase, choline acetyl transferase and GLUT 3 were observed in the brainstem of diabetic rats. Immunohistochemistry studies of muscarinic M1, M3 and α7 nicotinic acetylcholine receptors confirmed the gene expression at protein level. Vitamin D3 and insulin treatment reversed diabetes-induced alterations to near control. This study provides an evidence that diabetes can alter the expression of cholinergic, insulin, Vitamin D receptors and GLUT 3 in brainstem. We found that Vitamin D3 treatment could modulate the Vitamin D receptors and plays a pivotal role in maintaining the glucose transport and expressional level of cholinergic receptors in the brainstem of diabetic rats. Thus, our results suggest a therapeutic role of Vitamin D3 in managing neurological disorders associated with diabetes.
Similar content being viewed by others
References
Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820
Gold SM, Dziobek I, Sweat V, Tirsi A, Rogers K, Bruehl H, Tsui W, Richardson S, Javier E, Convit A (2007) Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes. Diabetologia 50:711–719
Qiu WQ, Price LL, Hibberd P, Buell J, Collins L, Leins D, Mwamburi DM, Rosenberg I, Smaldone L, Scott TM, Siegel RD, Summergrad P, Sun X, Wagner C, Wang L, Yee J, Tucker KL, Folstein M (2006) Executive dysfunction in 723 homebound older people with diabetes mellitus. J Am Geriatr Soc 54:496–501
Pare D, Steriade M (1990) Control of the mammillothalamic axis by brainstem cholinergic laterodorsal tegmental afferents: possible involvement in mnemonic processes. In: Steriade M, Bieso D (eds) Brain cholinergic systems. Oxford University Press, Oxford, pp 337–354
Steriade M (1996) Arousal: revisiting the reticular activating system. Science 272:225–226
Mathieu C, Gysemans C, Giulietti A, Bouillon R (2005) Vitamin D and diabetes. Diabetologia 48:1247–1257
Chiu KC, Chu A, Go VL, Saad MF (2004) Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr 79:820–825
McGrath J, Feron F, Eyles D, Mackay-Sim A (2001) Vitamin D: the neglected neurosteroid? Trends Neurosci 24:570–572
Brands AM, Henselmans JM, de Haan EH, Biessels GJ (2003) Diabetic encephalopathy: an underexposed complication of diabetes mellitus. Ned Tijdschr Geneeskd 147:11–14
Mijnhout GS, Scheltens P, Diamant M, Biessels GJ, Wessels AM, Simsek S, Snoek FJ, Heine RJ (2006) Diabetic encephalopathy: a concept in need of a definition. Diabetologia 49:1447–1448
Hohenegger M, Rudas B (1971) Kidney function in experimental diabetic ketosis. Diabetologia 7:334–338
Arison RN, Ciaccio EI, Glitzer MS, Cassaro JA, Pruss MP (1967) Light and electron microscopy of lesions in rats rendered diabetic with streptozotocin. Diabetes 16:51–56
De Souza Santos R, Marques Vianna Lucia T (2005) Effect of Cholecalciferol supplementation on blood glucose in an experimental model of type 2 diabetes mellitus in spontaneously hypertensive rats and Wistar rats. Clin Chim Acta 358:146–150
Glowinski J, Iversen LL (1966) Regional studies of catecholamines in the rat brain, the disposition of [3H]norepinephrine, [3H]dopa in various regions of brain. J Neurochem 13:655–669
Yamamura HI, Synder G (1981) Binding of [3H] QNB in rat brain. Proc Natl Acad Sci USA 71:1725–1729
Lowry OH, Roserbrough NJ, Farr AL, Randall RJ (1951) Protein measurement with Folin Phenol reagent. J Biol Chem 193:265–275
Scatchard G (1949) The attraction of proteins for small molecules and ions. Ann NY Acad Sci 51:660–672
Joseph A, Peeyush KT, Nandhu MS, Paulose CS (2010) Enhanced NMDAR1, NMDA2B and mGlu5 receptors gene expression in the cerebellum of insulin induced hypoglycaemic and streptozotocin induced diabetic rats. Eur J Pharmacol 630:61–68
Zeitz U, Weber K, Soegiarto DW, Wolf E, Balling R, Erben RG (2003) Impaired insulin secretory capacity in mice lacking a functional vitamin D receptor. FASEB J 17:509–511
Walters MR (1992) Newly identified actions of the vitamin D endocrine system. Endocr Rev 13:719–764
Borissova AM, Tankova T, Kirilov G, Dakovska L, Kovacheva R (2003) The effect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients. Int J Clin Pract 57:258–261
Rudnicki PM, Molsted-Pedersen L (1997) Effect of 1,25-dihydroxycholecalciferol on glucose metabolism in gestational diabetes mellitus. Diabetologia 40:40–44
Low PA, Nickander KK, Tritschler HJ (1997) The role of oxidative stress and antioxidant treatment in experimental diabetic neuropathy. Diabetes 46:38
Donnini D, Zambito AM, Perella G (1996) Glucose may induce cell death through a free radical-mediated mechanism. Biochem Biophys Res Commun 219:412–417
Ayoub RS (2009) Effect of exercise on spatial learning and memory in male diabetic rats. Int J Diabetes Metab 17:93–98
Gireesh G, Reas SK, Jobin M, Paulose CS (2008) Decreased muscarinic M1 receptor gene expression in the cerebral cortex of streptozotocin–induced diabetic rats and Aegle marmelose leaf extract’s therapeutic function. J Ethnopharmacol 116:296–304
Peeyush KT, Gireesh G, Jobin M, Paulose CS (2009) Neuroprotective role of curcumin in the cerebellum of streptozotocin-induced diabetic rats. Life Sci 85:704–710
Vogt BA (1993) Structural organization of cingulate cortex: areas, neurons, and somatodendritic transmitter receptors. In: Vogt BA, Gabriel M (eds) Neurobiology of cingulate cortex, limbic thalamus. Birkhauser, Boston, pp 19–70
Gabriel M (1993) Discriminative avoidance learning: a model system. In: Vogt BA, Gabriel M (eds) Neurobiology of cingulate cortex, limbic thalamus. Birkhauser, Boston, pp 478–576
Bereiter DA, Rohner-Jeanrenaud F, Berthoud H, Jeanrenaud R (1981) CNS modulation of pancreatic endocrine function: multiple mode of expression. Diabetologia 20:417–425
Azmitia EC, Gannon P (1986) Anatomy of the serotonergic system in the primate and sub-primate brain. J Adv Neurol 43:407–468
Steriade M, McCormick DT, Sejnowski TJ (1993) Thalamocortical oscillations in the sleeping and aroused brain. Science 262:679–685
Hosey MM (1992) Diversity of structure, signaling and regulation within the family of muscarinic cholinergic receptors. FASEB J 6:845–852
Levin ED, Bradley A, Addy N, Sigurani N (2002) Hippocampal alpha 7 and alpha 4 beta 2 nicotinic receptors and working memory. Neuroscience 109:757–765
Olincy A, Harris JG, Johnson LL, Pender V, Kongs S, Allensworth D, Ellis J, Zerbe GO, Leonard S, Stevens KE, Stevens JO, Martin L, Adler LE, Soti F, Kem WR, Freedman R (2006) Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry 63:630–638
Freedman R, Olincy A, Buchanan RW, Harris JG, Gold JM, Johnson L, Allensworth D, Guzman-Bonilla A, Clement B, Ball MP, Kutnick J, Pender V, Martin LF, Stevens KE, Wagner BD, Zerbe GO, Soti F, Kem WR (2008) Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am J Psychiatry 165:1040–1047
Bitner RS, Bunnelle WH, Anderson DJ, Briggs CA, Buccafusco J, Curzon P, Decker MW, Frost JM, Gronlien JH, Gubbins E, Li J, Malysz J, Markosyan S, Marsh K, Meyer MD, Nikkel AL, Radek RJ, Robb HM, Timmermann D, Sullivan JP, Gopalakrishnan M (2007) Broad-spectrum efficacy across cognitive domains by alpha7 nicotinic acetylcholine receptor agonism correlates with activation of ERK1/2 and CREB phosphorylation pathways. J Neurosci 27:10578–10587
Boess FG, De Vry J, Erb C, Flessner T, Hendrix M, Luithle J, Methfessel C (2007) Brain insulin receptors and spatial memory. J Biol Chem 274:34893–34902
Frazier CJ, Buhler AV, Weiner JL, Dunwiddie TV (1998) Synaptic potentials mediated via alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors in rat hippocampal interneurons, J. Neurosci 16:8228–8235
Freedman R, Hall M, Adler LE, Leonard S (1995) Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia. Biol Psychiatry 38:22–23
Vijayaraghavan S, Pugh P, Zhang ZW, Rathouz M, Berg D (1992) Nicotinic receptors that bind alpha-bungarotoxin on neurons raise intracellular free Ca. Neuron 8:353–362
Komuro H, Rakic P (1996) Intracellular Ca fluctuations modulate the rate of neuronal migration. Neuron 17:275–285
Sastry PS, Rao KS (2000) Apoptosis and the nervous system. J Neurochem 74:1–20
Wonnacott S (1997) Presynaptic nicotinic ACh receptors. Trends Neurosci 20:92–98
Girod R, Role LW (2001) Long-lasting enhancement of glutamatergic synaptic transmission by acetylcholine contrasts with response adaptation after exposure to low-level nicotine. J Neurosci 21:5182–5190
Tõugu V, Kesvatera T (1996) Role of ionic interactions in cholinesterase catalysis. Biochim Biophys Acta 1298:12–30
Soreq H, Seidman S (2001) Acetylcholinesterase—new roles for and old actor. Nat Rev Neurosci 2:294–302
Schmatz R, Mazzanti CM, Spanevello R, Stefanello N, Gutierres J, Corrêa M, da Rosa MM, Rubin MA, Chitolina Schetinger MR, Morsch VM (2009) Resveratrol prevents memory deficits and the increase in acetylcholinesterase activity in streptozotocin-induced diabetic rats. Eur J Pharmacol 21:42–48
Gascon-Barre M, Huet PM (1983) Apparent [3H]1,25-dihydroxyvitamin D3 uptake by canine and rodent brain. Am J Physiol 244:E266–E271
Musiol IM, Stumpf WE, Bidmon HJ, Heiss C, Mayerhofer A, Bartke A (1992) Vitamin D nuclear binding to neurons of the septal, substriatal and amygdaloid area in the Siberian hamster (Phodopus sungorus) brain. Neuroscience 48:841–848
Brewer LD, Thibault V, Chen KC, Langub MC, Landfield PW, Porter NM (2001) Vitamin D hormone confers neuroprotection in parallel with downregulation of Ltype alcium channel expression in hippocampal neurons. J Neurosci 21:8–108
Zhao W, Chen H, Xu H, Moore E, Meiri N, Quon MJ, Alkon DL (1999) Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J Biol Chem 274:34893–34902
Frolich L, Blum-degen D, Bernstein HG, Engelsberger S, Humrich J, Laufer S, Muschner D, Thalheimer A, Turk A, Hoyer S, Zochling R, Boissl KW, Jellinger K, Piederer P (1998) Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease. J Neural Transm 105:423–438
Blanchard JG, Duncan PM (1997) Effect of combinations of insulin, glucose and scopolamine on radial arm maze performance. Pharmacol Biochem Behav 58:209–214
Messier C, Destrade C (1994) Insulin attenuates scopolamine-induced memory deficits. Psychobiology 22:16–21
Schwartz MW, Figlewicz DP, Baskin DG, Woods SC, Porte DJ (1992) Insulin in the brain: a hormonal regulator of energy balance. Endocr Rev 13:387–414
Banks WA, Jaspan JB, Kastin AJ (1997) Selective, physiological transport of insulin across the blood-brain barrier: novel demonstration by species-specific radioimmunoassays. Peptides 18:1257–1262
Banks WA, Jaspan JB, Huang W, Kastin AJ (1997) Transport of insulin across the blood-brain barrier: saturability at euglycemic doses of insulin. Peptides. 18:1423–1429
Lund-Anderen H (1979) Transport of glucose from blood to brain. Physiol Rev 59:305–310
Pardridge WM (1983) Brain metabolism: a perspective from the blood-brain barrier. Physiol Rev 63:1481–1535
Gruefter R, Novotny EJ, Boulware SD, Rothman DL, Mason GG, Shulman Hashimoto K, Ishima T, Fujita Y, Matsuo M, Kobashi T, Takahagi M, Tsukada H, Iyo M (2008) Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the novel selective alpha7 nicotinic receptor agonist SSR180711. Biol Psychiatry 63:92–97
Pramming S, Thorsteinsson B, Theilgaard A, Pinner BM, Binder C (1986) Cognitive function during hypoglycaemia in type I diabetes mellitus. Br Med J 292:647–650
Devivo DC, Trifiletti RR, Jacobson RI, Rosen GM, Behmand RA, Harik SI (1991) Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med 325:703–709
McNay EC, Fries TM, Gold PE (2000) Decreases in rat extracellular hippocampal glucose concentration associated with cognitive demand during a spatial task. Proc Natl Acad Sci USA 97:2881–2885
Friedman HR, Goldman-Rakic PS (1994) Coactivation of prefrontal cortex and inferior parietal cortex in working memory tasks revealed by 2DG functional mapping in the rhesus monkey. J Neurosci 14:2775–2788
Balabanova S, Richter HP, Antoniadis G, Homoki J, Kremmer N, Hanle J, Teller WM (1984) 25-Hydroxyvitamin D, 24,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D in human cerebrospinal fluid. Klin Wochenschr 62:1086–1090
Acknowledgments
This work was supported by grants from DST, DBT, ICMR, Govt. of India, and KSCSTE, Govt. of Kerala, to Dr. C. S. Paulose. Peeyush Kumar. T thanks the Department of Science and Technology, India for SRF and Dr. Ranjit Parhar, Cell Biology-Cardio Vascular unit, King Faisal Specialist Hospital and Research Centre for his valuable advice in the preparation of manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Peeyush Kumar, T., Paul, J., Antony, S. et al. Expression of Cholinergic, Insulin, Vitamin D Receptors and GLUT 3 in the Brainstem of Streptozotocin Induced Diabetic Rats: Effect of Treatment with Vitamin D3 . Neurochem Res 36, 2116–2126 (2011). https://doi.org/10.1007/s11064-011-0536-9
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-011-0536-9