Atorvastatin Protects from Aβ-Induced Cell Damage and Depressive-Like Behavior via ProBDNF Cleavage.

Intracerebroventricular (icv) amyloid-beta (Aβ) infusion to mice has been demonstrated to cause neurotoxicty and depressive-like behavior and it can be used to evaluate antidepressant and neuroprotective effect of drugs. Atorvastatin is a widely used statin that has demonstrated antidepressant-like effect in predictable animal behavioral models and neuroprotective effect against Aβ infusion. The purpose of this study was to determine the effect of in vivo atorvastatin treatment against Aβ-induced changes in mood-related behaviors and biochemical parameters in ex vivo hippocampal slices from mice. Atorvastatin treatment (10 mg/kg, p.o., once a day for seven consecutive days) abolished depressive-like and anhedonic-like behaviors induced by Aβ (400 pmol/site, icv) infusion. Aβ-induced hippocampal cell damage was reversed by atorvastatin treatment. Aβ infusion decreased glutamate uptake in hippocampal slices, and atorvastatin did not altered it. Glutamine synthetase activity was not altered by any treatment. Atorvastatin also increased hippocampal mature brain-derived neurotrophic factor (mBDNF)/precursor BDNF (proBDNF) ratio, suggesting an increase of proBDNF to mBDNF cleavage. Accordingly, increased tissue-type plasminogen activator (tPA) and p11 genic expression were observed in hippocampus of atorvastatin-treated mice. Atorvastatin displays antidepressant-like and neuroprotective effects against Aβ-induced toxicity, and these effects may involve tPA- and p11-mediated cleavage of proBDNF to mBDNF.