Neuroprotective effects of dehydroepiandrosterone (DHEA) in rat model of Alzheimer's disease
The current study was undertaken to elucidate a possible neuroprotective role of dehydroepiandrosterone (DHEA) against the development of Alzheimer's disease in experimental rat model. Alzheimer's disease was produced in young female ovariectomized rats by intraperitoneal administration of AlCl3 (4.2 mg/kg body weight) daily for 12 weeks. Half of these animals also received orally DHEA (250 mg/kg body weight, three times weekly) for 18 weeks. Control groups of animals received either DHAE alone, or no DHEA, or were not ovariectomized. After such treatment the animals were analyzed for oxidative stress biomarkers such as hydrogen peroxide, nitric oxide and malondialdehyde, total antioxidant capacity, reduced glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase activities, antiapoptotic marker Bcl-2 and brain derived neurotrophic factor. Also brain cholinergic markers (acetylcholinesterase and acetylcholine) were determined. The results revealed significant increase in oxidative stress parameters associated with significant decrease in the antioxidant enzyme activities in Al-intoxicated ovariectomized rats. Significant depletion in brain Bcl-2 and brain-derived neurotrophic factor levels were also detected. Moreover, significant elevations in brain acetylcholinesterase activity accompanied with significant reduction in acetylcholine level were recorded. Significant amelioration in all investigated parameters was detected as a result of treatment of Al-intoxicated ovariectomized rats with DHEA. These results were confirmed by histological examination of brain sections. These results clearly indicate a neuroprotective effect of DHEA against Alzheimer's disease.
- Abd El-Rahman SS (2003) Neuropathology of aluminum toxicity in rats (glutamate and GABA impairment). Pharmacol Res 47: 189-194.
- Aebi H (1984) Catalase in vitro. Methods Enzymol 105: 121-126.
- Alleva K, Rankin J, Santucci D (1998) Neurobehavioral alteration in rodents following developmental exposure to aluminum. Toxicol Ind Health 14: 209-221.
- Aragno M, Tamagno E, Gatto V, Brignardello E, Parola S, Danni O, Boccuzzi G (1999) Dehydroepiandrosterone protects tissues of streptozotocin-treated rats against oxidative stress. Free Radic Biol Med 26: 1467-1474.
- Armitage P, Berry G (1987) Comparison of several groups. In: Statistical methods in medical research, 2nd edn, pp 186-213. Blockwell Significant Publication, Oxford.
- Barakat-Walter I (1996) Brain-derived neurotrophic factor-like immunoreactivity is localized mainly in small sensory neurons of rat dorsal root ganglia. J Neurosci Methods 68: 281-288.
- Barbareschi M, Caffo O, Veronese S, Leek RD, Fina P, Fox S, Bonzanini M, Girlando S, Morelli L, Eccher C, Pezzella F, Doglioni C, Palma PD, Harris A (1996) Bcl-2 and P53 expression in node-negative breast carcinoma: a study with long-term follow-up. Hum Pathol 27: 1149-1155.
- Behl C, Moosmann B (2002) Oxidative nerve cell death in Alzheimer's disease and stroke: antioxidants as neuroprotective compounds. Biol Chem 383: 521-536.
- Berkels R, Purol-Schnabel S, Roesen R (2004) Measurement of nitric oxide by reconversion of nitrate/nitrite to nitric oxide. Methods Mol Biol 279: 1-8.
- Bharathi P, Vasudevaraju P, Govindaraju M, Palanisamy AP, Sambamurti K, Rao KS (2008) Molecular toxicity of aluminium in relation to neurodegeneration. Indian J Med Res 128: 545-556.
- Cardounel A, Regelson W, Kalimi M (1999) Dehydroepiandrosterone protects hippocampal neurons against neurotoxin-induced cell death: mechanism of action. Proc Soc Exp Biol Med 222: 145-149.
- Charalampopoulos I, Alexaki VI, Lazaridis I, Dermitzaki E, Avlonitis N, Tsatsanis C, Calogeropoulou T, Margioris AN, Castanas E, Gravanis A, (2006) G protein-associated, specific membrane binding sites mediate the neuroprotective effect of dehydroepiandrosterone. FASEB J 20: 577-579.
- Den Blaauwen DH, Poppe WA, Tritschler W (1983) Acetylcholinesterase with acetylthiocholine iodide as substrate: references depending on age and sex with special reference to hormonal effects and pregnancy. J Clin Chem Clin Biochem 21: 381-386.
- Devchand PR, Keller H, Peters JM, Vazquez M, Gonzalez FJ, Wahli W (1996) The PPARα-leukotriene B4 pathway to inflammation control. Nature 384: 39-43.
- Di J, Yao K, Han W, Bi S (2006a) Study on the interaction of copper-zinc superoxide dismutase with aluminum ions by electrochemical and fluorescent method. Spectrochim Acta A Mol Biomol Spectrosc 65: 896-900.
- Di J, Zhang M, Yao K, Bi S (2006b) Direct voltammetry of catalase immobilized on silica sol-gel and cysteine modified gold electrode and its application. Biosens Bioelectron 22: 247-252.
- Drury RAB, Wallington EA (1980) Carleton's histological technique, 5th edn, pp 188-189, 237-240, 290-291. Oxford University Press, Oxford, New York, Toronto.
- El-Rigal NS, Aly SA, Rizk MZ, Said, AA (2006) Effect of Ailanthus altissima and Ziziphus spina Christi extracts on some hepatic marker enzymes and antioxidants in Shistosoma mansoni infected mice. Pol J Food Nutr Sci 15/56: 199-206.
- Erden M, Bor NM (1984) Changes of reduced glutathion, glutathion reductase and glutathione peroxidase after radiation in guinea pigs, Biochem Med 31: 217-227.
- Gao J, Sun HY, Zhu ZR, Ding Z, Zhu L (2005) Antioxidant effects of dehydroepiandrosterone are related to upregulation of thioredoxin in SH-SY5Y cells. Acta Biochim Biophys Sin 37: 119-125.
- Garrel C, Lafond JL, Guiraud P, Faure P, Favier A (1994) Induction of production of nitric oxide in microglial cells by insoluble form of aluminum. Ann New York Acad Sci 738: 455-461.
- Goel RM, Cappola AR (2011) Dehydroepiandrosterone sulfate and postmenopausal women. Curr Opin Endocrinol Diabetes Obes (in press).
- Grosgen S, Grimm MO, Friess P, Hartmann T (2010) Role of amyloid beta in lipid homeostasis. Biochim Biophys Acta 1801: 966-974.
- Guix FX, Uribesalgo I, Coma M, Munoz FJ (2005) The physiology and pathophysiology of nitric oxide in the brain. Prog Neurobiol 76: 126-152.
- Huh JW, Choi M M, Lee JH, Yang SJ, Kim MJ, Choi J, Lee KH, Lee JE, Cho SW (2005) Activation of monoamine oxidase isotypes by prolonged intake of aluminum in rat brain. J Inorg Biochem 99: 2088-2091.
- Johnson VJ, Kim S, Sharma RP (2005) Aluminum-maltolate induces apoptosis and necrosis in neuro-2a cells: potential role for p53 signaling. Toxicol Sci 83: 329-339.
- Julka D, Gill KD (1996) Effect of aluminum on regional brain antioxidant defense status in wistar rats. Res Exp Med (Berl) 196: 187-194.
- Kaizer RR, Correa MC, Gris LR, da Rosa CS, Bohrer D, Morsch VM, Schetinger MR (2008) Effect of long-term exposure to aluminum on the acetylcholinesterase activity in the central nervous system and erythrocytes. Neurochem Res 33: 2294-2301.
- Koracevic D, Koracevic G, Djordjevic V, Andrejevic S, Cosic V (2001) Method for the measurement of antioxidant activity in human fluids. J Clin Pathol 54: 356-361.
- Krysiak R, Frysz-Naglak D, Okopie B (2008) Current views on the role of dehydroepiandrosterone in physiology, pathology and therapy. Pol Merkur Lekarski 24: 66-71.
- Kumar P, Taha A, Sharma D, Kale RK, Baquer NZ (2008) Effect of dehydroepiandrosterone (DHEA) on monoamine oxidase activity, lipid peroxidation and lipofuscin accumulation in aging rat brain regions. Biogerontology 9: 235-246.
- Kumar V, Bal A, Gill KD (2009a) Susceptibility of mitochondrial superoxide dismutase to aluminum-induced oxidative damage. Toxicology 255: 117-123.
- Kumar V, Bal A, Gill KD (2009b) Aluminium-induced oxidative DNA damage recognition and cell cycle disruption in different regions of rat brain. Toxicology 264: 137-144.
- Kurata K, Takebayashi M, Morinobu S, Yamawaki S (2004) Beta-estradiol, dehydroepiandrosterone, and dehydroepiandrosterone sulfate protect against N-methyl-D-aspartate-induced neurotoxicity in rat hippocampal neurons by different mechanisms. J Pharmacol Exp Ther 311: 237-245.
- Lardy H, Henwood SM, Weeks CE (1999) An acute oral gavage study of β-acetoxyandrost-5-ene-7, 17-dione (7-oxo-DHEA-acetate) in rats. Biochem Biophys Res Commun 254: 120-123.
- Lazaridis I, Charalampopoulos I, Alexaki VI, Avlonitis N, Pediaditakis I, Efstathopoulos P, Calogeropoulou T, Castanas E, Gravanis A (2011) Neurosteroid dehydroepiandrosterone interacts with nerve growth factor (NGF) receptors, preventing neuronal apoptosis. PLoS Biol 9: e1001051.
- Li W, Ota K, Nakamura J, Naruse K, Nakashima E, Oiso Y, Hamada Y (2008) Antiglycation effect of gliclazide on in vitro AGE formation from glucose and methylglyoxal. Exp Biol Med (Maywood) 233: 176-179.
- Lowry OH, Rosebrough NJ, Farr A L, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193: 265-275.
- Luppi C, Fioravanti M, Bertolini B, Inguscio M, Grugnetti A, Guerriero F, Rovelli C, Cantoni F, Guagnano P, Marazzi E, Rolfo E, Ghianda D, Levante D, Guerrini C, Bonacasa R, Solerte SB (2009) Growth factors decrease in subjects with mild to moderate Alzheimer's disease (AD): potential correction with dehydroepiandrosterone sulphate (DHEAS). Arch Gerontol Geriatr 49: 173-184.
- Mahieu S, Contini MD, Gonzez M, Millen N (2009) Melatonin reduces oxidative damage induced by aluminum in rat kidney. Toxicol Lett 190: 9-15.
- Marklund SL, Westman NG, Lundgren E, Roos G (1982) Copper- and zinc-containing superoxide dismutase, manganese-containing superoxide dismutase, catalase, and glutathione peroxidase in normal and neoplastic human cell lines and normal human tissues. Cancer Res 42: 1955-1961.
- Mohan PF, Jacobson MS (1993) Inhibition of macrophage superoxide generation by dehydroepiandrosterone. Am J Med Sci 306: 10-15.
- Moron MS, Depierre JW, Mannervik B (1979) Levels of glutathione, glutathione reductase and glutathion-S-transferase activities in rat lung and liver. Biochem Biophys Acta 582: 67-68.
- Munoz-Castaneda JR, Muntane J, Munoz MC, Bujalance I, Montilla P, Tunez I (2006) Estradiol and catecholestrogens protect against adriamycin-induced oxidative stress in erythrocytes of ovariectomized rats. Toxicol Lett 160: 196-203.
- Nagatsu T, Mogi M, Ichinose H, Togari A (2000) Changes in cytokines and neurotrophins in Parkinson's disease. J Neural Transm Suppl 60: 277-290.
- Nishikimi M, Appaji N, Yagi K (1972) The occurrence of superoxide anion in the reaction of reduced phenazine methosulfate and molecular oxygen. Biochem Biophys Res Commun 46: 849-854.
- Oswald C, Smits SH, Hoing M, Sohn-Bosser L, Dupont L, Le Rudulier D, Schmitt L, Bremer E (2008) Crystal structures of the choline/acetylcholine substrate-binding protein chox from sinorhizobium meliloti in the liganded and unliganded-closed states. J Biol Chem 283: 32848-32859.
- Ozdemir G, Ozden M, Maral H, Kuskay S, Cetinalp P (2005) Malondialdehyde, glutathione, glutathione peroxidase and homocysteine levels in type 2 diabetic patients with and without microalbuminuria. Ann Clin Biochem 42: 99-104.
- Peters JM, Zhou YC, Ram PA, Lee SS, Gonzalez FJ, Waxman DJ (1996) Peroxisome proliferator-activated receptor α required for gene induction by dehydroepiandrosterone-3-β-sulfate. Mol Pharmacol 50: 67-74.
- Rhodes ME, Li PK, Flood JF, Johnson DA (1996) Enhancement of hippocampal acetylcholine release by the neurosteroid dehydroepiandrosterone sulfate: an in vivo microdialysis study. Brain Res 733: 284-286.
- Satoh K (1978) Serum lipid peroxide in cerebrovascular disorders determined by a new colorimetric method. Clin Chim Acta 90: 37-43.
- Schwartz AG, Whitcomb JM, Nyce JW, Lewbart ML, Pashko LL (1988) Dehydroepiandrosterone and structural analogs: a new class of cancer chemopreventive agents. Adv Cancer Res 51: 391-425.
- Sharma K, Mehra RD (2008) Long-term administration of estrogen or tamoxifen to ovariectomized rats affords neuroprote-ction to hippocampal neurons by modulating the expression of Bcl-2 and Bax. Brain Res 1204: 1-15.
- Tabuchi A, Sakaya H, Kisukeda T, Fushiki H, Tsuda M (2002) Involvement of an upstream stimulatory factor as well as cAMP responsive element binding protein in the activation of brain derived neurotrophic factor gene promoter. J. Biol Chem 277: 35920-35931.
- Takuma K, Matsuo A, Himeno Y, Hoshina Y, Ohno Y, Funatsu Y, Arai S, Kamei H, Mizoguchi H, Nagai T, Koike K, Inoue M, Yamada K (2007) 17-β estradiol attenuates hippocampal neuronal loss and cognitive dysfunction induced by chronic restraint stress in ovariectomized rats. Neuroscience 146: 60-68.
- Tsakiris S, Schulpis KH, Marinou K, Behrakis P (2004) Protective effect of L-cysteine and glutathione on the modulated suckling rat brain Na+, K+-ATPase and Mg2+-ATPase activities induced by the in vitro galactosaemia. Pharmacol Res 49: 475-479.
- Tuneva J, Chittur S, Boldyrev AA, Birman I, Carpenter DO (2006) Cerebellar granule cell death induced by aluminum. Neurotox Res 9: 297-304.
- Van Groen T, Kadish I (2005) Transgenic AD model mice, effects of potential anti-AD treatments on inflammation and pathology. Brain Res Rev 48: 370-378.
- Vina J, Sastre J, Pallardo FV, Gambini J, Borras C (2008) Modulation of longevity-associated genes by estrogens or phytooestrogens. Biol Chem 389: 273-277.
- Yildirim A, Gumus M, Dalga S, Sahin YN, Akcay F (2003) Dehydroepiandrosterone improves hepatic antioxidant systems after renal ischemia-reperfusion injury in rabbits. Ann Clin Lab Sci 33: 459-464.
- Walton JR, Wang MX (2009) APP expression, distribution and accumulation are altered by aluminum in a rodent model for Alzheimer's disease. J Inorg Biochem 103: 1548-1554.
- Yousif MF, El-Rigal NS (2004) C-glycolsyl flavones O-glycosides of clerodendrum splendens G.Don. and antioxidants activity in schistosome-infected mice. Egypt J Biomed Sci 14: 128-137.
- Yu BC, Chang CK, Ou HY, Cheng KC, Cheng JT (2008) Decrease of peroxisome proliferator-activated receptor delta expression in cardiomyopathy of streptozotocin-induced diabetic rats. Cardiovasc Res 80: 78-87.
- Zheng J, Yang JQ, He BC, Zhou QX, Yu HR, Tang Y, Liu BZ (2009) Berberine and total base from rhizoma coptis chinensis attenuate brain injury in an aluminum-induced rat model of neurodegenerative disease. Saud Med J 30: 760-766.
- Zheng P (2009) Neuroactive steroid regulation of neurotransmitter release in the CNS: action, mechanism and possible significance. Prog Neurobiol 89: 134-152