Abstract
We have previously shown that chronic treatment with angiotensin-(1–7) [Ang-(1–7)] can prevent diabetes-induced cardiovascular dysfunction. However, effect of Ang-(1–7) treatment on diabetes-induced alterations in the CNS is unknown. The aim of this study was to test the hypothesis that treatment with Ang-(1–7) can produce protection against diabetes-induced CNS changes. We examined the effect of Ang-(1–7) on the number of cyclooxygenase-2 (COX-2) immunoreactive neurons and the glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes and assessed the changes in the neuronal growth-associated protein-43 (GAP-43) of the hippocampal formation in streptozotocin-induced diabetes in rats. Animals were sacrificed 30 days after induction of diabetes and/or treatment with Ang-(1–7). Ang-(1–7) treatment significantly prevented diabetes-induced decrease in the number of GFAP immunoreactive astrocytes and GAP-43 positive neurons in all hippocampal regions. Co-administration of A779, a selective Ang-(1–7) receptor antagonist, inhibited Ang-(1–7)-mediated protective effects indicating that Ang-(1–7) produces its effects through activation of receptor Mas. Further, Ang-(1–7) treatment through activation of Mas significantly prevented diabetes-induced increase in the number of the COX-2 immunolabeled neurons in all sub-regions of the hippocampus examined. These results show that Ang-(1–7) has a protective role against diabetes-induced changes in the CNS.
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References
Afsari ZH, Renno WM, Abd-El-Basset E (2008) Alteration of glial fibrillary acidic proteins immunoreactivity in astrocytes of the spinal cord diabetic rats. Anat Rec 291:390–399
Al-Maghrebi M, Benter IF, Diz DI (2009) Endogenous angiotensin-(1–7) reduces cardiac ischemia-induced dysfunction in diabetic hypertensive rats. Pharmacol Res 59:263–268
Artola A, Kamal A, Ramakers GM, Biessels GJ, Gispen WH (2005) Diabetes mellitus concomitantly facilitates the induction of long-term depression and inhibits that of long-term potentiation in hippocampus. Euro J Neurosci 22:169–178
Bagi Z, Erdei N, Papp Z, Edes I, Koller A (2006) Up-regulation of vascular cyclooxygenase-2 in diabetes mellitus. Pharmacol Rep 58:52–56
Barber AJ, Antonetti DA, Gardner TW (2000) Altered expression of retinal occludin and glial fibrillary acidic protein in experimental diabetes. Investig Ophthalmol Vis Sci 41:3561–3568
Benicky J, Sánchez-Lemus E, Honda M, Pang T, Orecna M, Wang J, Leng Y, Chuang DM, Saavedra JM (2011) Angiotensin II AT(1) receptor blockade ameliorates brain inflammation. Neuropsychopharmacology 36:857–870
Benter IF, Diz DI, Ferrario CM (1993) Cardiovascular actions of angiotensin-(1–7). Peptides 14:679–684
Benter IF, Yousif MHM, Anim JT, Cojocel C, Diz DI (2006) Angiotensin-(1–7) prevents development of severe hypertension and end-organ damage in spontaneously hypertensive rats treated with L-NAME. Am J Physiol Heart Circ Physiol 290:H684–H691
Benter IF, Yousif MHM, Cojocel C, Al-Maghrebi M, Diz DI (2007) Angiotensin-(1–7) prevents diabetes-induced cardiovascular dysfunction. Am J Physiol Heart Circ Physiol 292:H666–H672
Benter IF, Yousif MH, Dhaunsi GS, Kaur J, Chappell MC, Diz DI (2008) Angiotensin-(1–7) prevents activation of NADPH oxidase and renal vascular dysfunction in diabetic hypertensive rats. Am J Nephrol 28:25–33
Benter IF, Yousif MH, Al-Saleh FM, Raghupathy R, Chappell MC, Diz DI (2011) Angiotensin-(1–7) blockade attenuates captopril- or hydralazine-induced cardiovascular protection in spontaneously hypertensive rats treated with NG-nitro-l-arginine methyl ester. J Cardiovasc Pharmacol 57:559–567
Bohlen von, Halbach O, Albrecht D (2006) The CNS renin–angiotensin system. Cell Tissue Res 326:599–616
Chappell MC (2007) Emerging evidence for a functional angiotensin-converting enzyme 2-angiotensin-(1–7)-MAS receptor axis: more than regulation of blood pressure? Hypertension 50:596–599
Coleman ES, Dennis JC, Braden TD, Judd RL, Posner P (2010) Insulin treatment prevents diabetes-induced alterations in astrocyte glutamate uptake and GFAP content in rats at 4 and 8 weeks of diabetes duration. Brain Res 1306:131–141
de Senna PN, Ilha J, Baptista PP, do Nascimento PS, Leite MC, Paim MF, Gonçalves CA, Achaval M, Xavier LL (2011) Effects of physical exercise on spatial memory and astroglial alterations in the hippocampus of diabetic rats. Metab Brain Dis 26:269–279
El-Hashim AZ, Renno WM, Raghupathy R, Abduo HT, Akhtar S, Benter IF (2012) Angiotensin 1–7 inhibits allergic inflammation, via the Mas receptor, through suppression of ERK1/2 and NF-κB dependent pathways. Br J Pharmacol. doi:10.1111/j.1476-5381.2012.01905.x
Ellis EF, Police RJ, Rice LY, Grabeel M, Holt S (1989) Increased plasma PGE2, 6-keto-PGF1 alpha, and 12-HETE levels following experimental concussive brain injury. J Neurotrauma 6:31–37
Gallagher PE, Chappell MC, Ferrario CM, Tallant EA (2006) Distinct roles for ANG II and ANG-(1–7) in the regulation of angiotensin-converting enzyme 2 in rat astrocytes. Am J Physiol Cell Physiol 290:C420–C426
Gispen WH, Biessels GJ (2000) Cognition and synaptic plasticity in diabetes mellitus. Trends Neurosci 11:542–549
Guo F, Liu B, Tang F, Lane S, Souslova EA, Chudakov DM, Paton JF, Kasparov S (2010) Astroglia are a possible cellular substrate of angiotensin(1–7) effects in the rostral ventrolateral medulla. Cardiovasc Res 87:578–584
Ho L, Qin W, Stetka BS, Pasinetti GM (2006) Is there a future for cyclo-oxygenase inhibitors in Alzheimer’s disease? CNS Drugs 20:85–98
Huber JD (2008) Diabetes, cognitive function, and the blood–brain barrier. Curr Pharm Des 14:1594–1600
Hwang IK, Yi SS, Kim YN, Kim IY, Lee IS, Yoon YS, Seong JK (2008) Reduced hippocampal cell differentiation in the subgranular zone of the dentate gyrus in a rat model of type II diabetes. Neurochem Res 33:394–400
Kamal A, Biessels GJ, Gispen WH, Ramakers GM (2006) Synaptic transmission changes in the pyramidal cells of the hippocampus in streptozotocin-induced diabetes mellitus in rats. Brain Res 1073–1074:276–280
Kellogg AP, Cheng HT, Pop-Busui R (2008) Cyclooxygenase-2 pathway as a potential therapeutic target in diabetic peripheral neuropathy. Curr Drug Targets 9:68–76
Lang BT, Yan Y, Dempsey RJ, Vemuganti R (2009) Impaired neurogenesis in adult type-2 diabetic rats. Brain Res 1258:25–33
Lebed YV, Orlovsky MA, Lushnikova IV, Skibo GG (2008) Neurodegenerative changes in the hippocampus with the early period of experiment diabetes mellitus. Neurophysiology 40:26–31
Lechuga-Sancho AM, Arroba AI, Frago LM, García-Cáceres C, de Célix AD, Argente J, Chowen JA (2006) Reduction in the number of astrocytes and their projections in associated with increased synaptic protein density in the hypothalamus of poorly controlled diabetic rats. Endocrinology 147:5314–5324
Li ZG, Britton M, Sima AA, Dunbar JC (2004) Diabetes enhances apoptosis induced by cerebral ischemia. Life Sci 76:249–262
Li Z, Wang Y, Xie Y, Yang Z, Zhang T (2011) Protective effects of exogenous hydrogen sulfide on neurons of hippocampus in a rat model of brain ischemia. Neurochem Res 36:1840–1849
Magarinos AM, McEwen BS (2000) Experimental diabetes in rats causes hippocampal dendritic and synaptic reorganization and increase glucocorticoid reactivity to stress. Proc Natl Acad Sci USA 97:11056–11061
Nakayama M, Uchimura K, Zhu RL, Nagayama T, Rose ME, Stetler RA, Isakson PC, Chen J, Graham SH (1998) Cyclooxygenase-2 inhibition prevents delayed death of CA1 hippocampal neurons following global ischemia. Proc Natl Acad Sci USA 95:10954–10959
Paxinos, G, Watson, C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic Press, New York
Proper EA, Oestreicher AB, Jansen GH, Veelen CW, van Rijen PC, Gispen WH, de Graan PN (2000) Immunohistochemical characterization of mossy fibre sprouting in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. Brain 123:19–30
Rekart JL, Quinn B, Mesulam MM, Routtenberg A (2004) Subfield-specific increase in brain growth protein in postmortem hippocampus of Alzheimer’s patients. Neuroscience 126:579–584
Renno WM, Alkhalaf M, Afsari Z, Abd-El-Basset E, Mousa A (2008) Consumption of green tea alters glial fibriliary acidic protein immunoreactivity in the spinal cord astrocytes of STZ-diabetic rats. Nutr Neurosci 11:32–40
Revsin Y, Saravia F, Roig P et al (2005) Neuronal and astroglial alterations in the hippocampus of a mouse model for type 1 diabetes. Brain Res 1038:22–31
Saavedra JM, Sánchez-Lemus E, Benicky J (2011) Blockade of brain angiotensin II AT1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: therapeutic implications. Psychoneuroendocrinology 36:1–18
Santos RAS, Campagnole-Santos MJ, Andrade S (2000) Angiotensin-(1–7): an update. Regul Pept 91:45–62
Saravia FE, Revsin Y, Gonzalez Deniselle MC, Gonzalez SL, Roig P, Lima A, Homo-Delarche F, De Nicola AF (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
Stranahan AM, Arumugam TV, Cutler RG, Lee K, Egan JM, Mattson MP (2008) Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons. Nat Neurosci 11:309–317
Takemiya T, Maehara M, Matsumura K, Yasuda S, Sugiura H, Yamagata K (2006) Prostaglandin E2 produced by late induced COX-2 stimulates hippocampal neuron loss after seizure in the CA3 region. Neurosci Res 56:103–110
Ueda S, Masumori-Maemoto S, Wada A, Ishii M, Brosnihan KB, Umemura S (2001) Angiotensin(1–7) potentiates bradykinin-induced vasodilatation in man. J Hypertens 19:2001–2009
Xu P, Sriramula S, Lazartigues E (2011) ACE2/ANG-(1–7)/Mas pathway in the brain: the axis of good. Am J Physiol Regul Integr Comp Physiol 300:R804–R817
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
Zhou J, Wang L, Ling S, Shang X (2007) Expression changes of growth-associated protein-43 (GAP-43) and mitogen-activated protein kinase phosphatase-1 (MKP-1) and in hippocampus of Streptozotocin-inducted diabetic cognitive impairment rats. Exp Neurol 206:201–208
Zuo ZF, Wang W, Niu L, Kou ZZ, Zhu C, Wang W, Zhao XH, Luo DS, Zhang T, Zhang FX, Liu XZ, Wu SX, Li YQ (2011) RU486 (mifepristone) ameliorates cognitive dysfunction and reverses the down-regulation of astrocytic N-myc downstream-regulated gene 2 in streptozotocin-induced type-1 diabetic rats. Neuroscience 190:156–165
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This work was financially supported by Department of Anatomy, Faculty of Medicine, Kuwait University, Kuwait.
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Renno, W.M., Al-Banaw, A.G., George, P. et al. Angiotensin-(1–7) Via the Mas Receptor Alleviates the Diabetes-Induced Decrease in GFAP and GAP-43 Immunoreactivity with Concomitant Reduction in the COX-2 in Hippocampal Formation: An Immunohistochemical Study. Cell Mol Neurobiol 32, 1323–1336 (2012). https://doi.org/10.1007/s10571-012-9858-7
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DOI: https://doi.org/10.1007/s10571-012-9858-7