1 Atorvastatin prevents hippocampal cell death, neuroinflammation and oxidative 2 stress following amyloid-β 1–40 administration in mice: Evidence for dissociation 3 between cognitive deficits and neuronal damage 4 Tetsadê C.B. Piermartiri a,c , Cláudia P. Figueiredo c , Daniel Rial b , Filipe S. Duarte b , Sarah C. Bezerra a , 5 Gianni Mancini a , Andreza F. de Bem a , Rui D.S. Prediger b,c , Carla I. Tasca a,c, ⁎ 6 a Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, 88040-900 Florianópolis, SC, Brazil 7 b Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, 88040-900 Florianópolis, SC, Brazil 8 c Programa de Pós-graduação em Neurociências, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, 88040-900 Florianópolis, SC, Brazil 9 10 abstract article info 11 Article history: 12 Received 1 February 2010 13 Revised 24 August 2010 14 Accepted 26 August 2010 15 Available online xxxx 16 17 18 19 Keywords: 20 Atorvastatin 21 Amyloid-β peptide 22 Neurotoxicity 23 Neuroinflammation 24 Oxidative stress 25 Glutamate 26 Spatial learning and memory 27 Neuroprotection 28 The accumulation of amyloid-beta (Aβ) peptides in the brain of human and rodents has been associated with 29 the activation of glial cells, neuroinflammatory and oxidative responses, and cognitive deficits. These 30 oxidative changes leave glutamate transporters more vulnerable and may result in reduction of their 31 functions, resulting in excitotoxic damage. Herein, we evaluated the effects of atorvastatin, a HMG-CoA 32 reductase inhibitor, in molecular and behavioral alterations induced by a single intracerebroventricular 33 injection of aggregated Aβ 1–40 (400 pmol) in mice. An increased glial fibrillar acidic protein (GFAP) expression 34 and cyclooxygenase-2 (COX-2) levels, as well as increased lipid peroxidation and impairment in the 35 glutathione antioxidant system and cell degeneration was found in the hippocampus of Aβ 1–40 -treated 36 mice. Aβ 1–40 also induced a marked decrease in glutamatergic transporters (GLAST and GLT-1) expression and 37 in L-[ 3 H] glutamate uptake in mice hippocampus, in addition to spatial learning and memory deficits. 38 Atorvastatin (10 mg/kg/day v.o.) was administered after Aβ 1–40 injection and through seven consecutive 39 days. Atorvastatin treatment was neuroprotective against cell degeneration induced by Aβ 1–40 , reducing 40 inflammatory and oxidative responses and increasing the expression of glutamatergic transporters. On the 41 other hand, atorvastatin did not reverse the cognitive impairments and failed to alter the hippocampal 42 glutamate uptake in Aβ 1–40 -treated mice. These results reinforce and extend the notion of the potential 43 neuroprotective action of atorvastatin against the neuronal toxicity induced by Aβ 1–40 . In addition, the 44 present findings suggest that the spatial learning and memory deficits induced by Aβ peptides in rodents may 45 not be entirely related to neuronal damage. 46 © 2010 Published by Elsevier Inc. 47 48 49 50 51 Introduction 52 Statins are the most potent agents for reduction of cholesterol 53 serum levels among all hypolipidemic drugs (Gotto, 2002). The 54 mechanism of action of statins is through inhibiting the enzyme HMG- 55 CoA (3-hydroxy-3-methyl-glutaryl-coenzyme A) reductase, thus 56 blocking the formation of mevalonate in the early stages of the 57 cholesterol biosynthesis pathway (Miida et al., 2007). However, 58 statins action can also inhibit the biosynthesis of other important 59 lipids of cholesterol pathway that can induce post-translational 60 changes in a variety of cytosolic proteins including the small G-protein 61 family (Liao and Laufs, 2005). It has been postulated that regulation of 62 these lipids gives to statins other effects independent of cholesterol 63 reduction, identified as “pleiotropic” effects. Likewise, these pleiotropic 64 effects include anti-inflammatory (Yoshida, 2003 Q1 ), vascular (Ikeda and 65 Shimada, 2001), and immunological properties (Greenwood et al., 66 2006). These pleiotropic effects have led to suggestions that statins 67 might be useful in several diseases, varying from dementia to 68 autoimmune disorders (Miida et al., 2007). 69 Atorvastatin is a member of statins family and compared to the 70 other statins it is relatively more lipophilic and display a long half-life 71 activity of HMG-CoA reductase inhibition (Schachter, 2005). Further- 72 more, the safety of high doses of atorvastatin has been demonstrated 73 (Waters, 2005). Experimental data have indicated that the treatment 74 with atorvastatin for 1 week significantly reduced neurological 75 deficits and increased the survival and synaptogenesis in the 76 hippocampus after traumatic brain injury (Lu et al., 2004). We have Experimental Neurology xxx (2010) xxx–xxx Abbreviations: Aβ, amyloid-beta; AD, Alzheimer's disease; COX-2, cyclooxygenase-2; EAATs, excitatory amino acids transporters; GFAP, glial fibrillar acidic protein; GLAST, GLT-1, glial glutamate transporters; GPx, glutathione peroxidase; GR, glutathione reductase; GSH, glutathione; HMG-CoA reductase, 3-hydroxyl-3-methyl-glutaryl- coenzyme A reductase; i.c.v., intracerebroventricular; PI, propidium iodide; TBARS, thiobarbituric acid reactive substances. ⁎ Corresponding author. Departamento de Bioquímica, CCB, UFSC, Trindade, 88040- 900 Florianópolis, SC, Brazil. Fax: + 55 48 37211 9672. E-mail address: tasca@ccb.ufsc.br (C.I. Tasca). YEXNR-10631; No. of pages: 11; 4C: 0014-4886/$ – see front matter © 2010 Published by Elsevier Inc. doi:10.1016/j.expneurol.2010.08.030 Contents lists available at ScienceDirect Experimental Neurology journal homepage: www.elsevier.com/locate/yexnr Please cite this article as: Piermartiri, T.C.B., et al., Atorvastatin prevents hippocampal cell death, neuroinflammation and oxidative stress following amyloid-β 1–40 ..., Exp. Neurol. (2010), doi:10.1016/j.expneurol.2010.08.030