Atorvastatin prevents hippocampal cell death, neuroinflammation and oxidative stress following amyloid-β(1-40) administration in mice: evidence for dissociation between cognitive deficits and neuronal damage.
The accumulation of amyloid-beta (Aβ) peptides in the brain of human and rodents has been associated with the activation of glial cells, neuroinflammatory and oxidative responses, and cognitive deficits. These oxidative changes leave glutamate transporters more vulnerable and may result in reduction of their functions, resulting in excitotoxic damage. Herein, we evaluated the effects of atorvastatin, a HMG-CoA reductase inhibitor, in molecular and behavioral alterations induced by a single intracerebroventricular injection of aggregated Aβ(1-40) (400 pmol) in mice. An increased glial fibrillar acidic protein (GFAP) expression and cyclooxygenase-2 (COX-2) levels, as well as increased lipid peroxidation and impairment in the glutathione antioxidant system and cell degeneration was found in the hippocampus of Aβ(1-40)-treated mice. Aβ(1-40) also induced a marked decrease in glutamatergic transporters (GLAST and GLT-1) expression and in l-[³H] glutamate uptake in mice hippocampus, in addition to spatial learning and memory deficits. Atorvastatin (10 mg/kg/day v.o.) was administered after Aβ(1-40) injection and through seven consecutive days. Atorvastatin treatment was neuroprotective against cell degeneration induced by Aβ(1-40), reducing inflammatory and oxidative responses and increasing the expression of glutamatergic transporters. On the other hand, atorvastatin did not reverse the cognitive impairments and failed to alter the hippocampal glutamate uptake in Aβ(1-40)-treated mice. These results reinforce and extend the notion of the potential neuroprotective action of atorvastatin against the neuronal toxicity induced by Aβ(1-40). In addition, the present findings suggest that the spatial learning and memory deficits induced by Aβ peptides in rodents may not be entirely related to neuronal damage.
Piermartiri
Tetsadê C B
TC
Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, 88040-900 Florianópolis, SC, Brazil.
Figueiredo
Cláudia P
CP
Rial
Daniel
D
Duarte
Filipe S
FS
Bezerra
Sarah C
SC
Mancini
Gianni
G
de Bem
Andreza F
AF
Prediger
Rui D S
RD
Tasca
Carla I
CI
D027322:Amino Acid Transport System X-AG / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects; D000069059:Atorvastatin; D016923:Cell Death / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004660:Encephalitis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D005452:Fluoresceins; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology*; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007859:Learning Disabilities / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D009930:Organic Chemicals; D018384:Oxidative Stress / Q000187:drug effects*; D010446:Peptide Fragments / Q000633:toxicity*; D011419:Propidium; D011758:Pyrroles / Q000494:pharmacology*; D014316:Tritium / Q000378:metabolism
D027322:Amino Acid Transport System X-AG; D016229:Amyloid beta-Peptides; D005452:Fluoresceins; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009419:Nerve Tissue Proteins; D009930:Organic Chemicals; D010446:Peptide Fragments; D011758:Pyrroles; C078592:amyloid beta-protein (1-40); C435731:fluoro jade; D014316:Tritium; D011419:Propidium; D018698:Glutamic Acid; D000069059:Atorvastatin; D005979:Glutathione Peroxidase; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D005980:Glutathione Reductase; D005978:Glutathione