TY - JOUR
T1 - The antineoplastic drug flavopiridol reverses memory impairment induced by Amyloid-ß1-42 oligomers in mice
AU - Leggio, Gian Marco
AU - Catania, Maria Vincenza
AU - Puzzo, Daniela
AU - Spatuzza, Michela
AU - Pellitteri, Rosalia
AU - Gulisano, Walter
AU - Torrisi, Sebastiano Alfio
AU - Giurdanella, Giovanni
AU - Piazza, Cateno
AU - Impellizzeri, Agata Rita
AU - Gozzo, Lucia
AU - Navarria, Andrea
AU - Bucolo, Claudio
AU - Palmeri, Agostino
AU - Salomone, Salvatore
AU - Copani, Agata
AU - Caraci, Filippo
AU - Drago, Filippo
PY - 2016/4/1
Y1 - 2016/4/1
N2 - The ectopic re-activation of cell cycle in neurons is an early event in the pathogenesis of Alzheimer's disease (AD), which could lead to synaptic failure and ensuing cognitive deficits before frank neuronal death. Cytostatic drugs that act as cyclin-dependent kinase (CDK) inhibitors have been poorly investigated in animal models of AD. In the present study, we examined the effects of flavopiridol, an inhibitor of CDKs currently used as antineoplastic drug, against cell cycle reactivation and memory loss induced by intracerebroventricular injection of Aß1-42 oligomers in CD1 mice. Cycling neurons, scored as NeuN-positive cells expressing cyclin A, were found both in the frontal cortex and in the hippocampus of Aβ-injected mice, paralleling memory deficits. Starting from three days after Aβ injection, flavopiridol (0.5, 1 and 3 mg/kg) was intraperitoneally injected daily, for eleven days. Here we show that a treatment with flavopiridol (0.5 and 1 mg/kg) was able to rescue the loss of memory induced by Aβ1-42, and to prevent the occurrence of ectopic cell-cycle events in the mouse frontal cortex and hippocampus. This is the first evidence that a cytostatic drug can prevent cognitive deficits in a non-transgenic animal model of AD.
AB - The ectopic re-activation of cell cycle in neurons is an early event in the pathogenesis of Alzheimer's disease (AD), which could lead to synaptic failure and ensuing cognitive deficits before frank neuronal death. Cytostatic drugs that act as cyclin-dependent kinase (CDK) inhibitors have been poorly investigated in animal models of AD. In the present study, we examined the effects of flavopiridol, an inhibitor of CDKs currently used as antineoplastic drug, against cell cycle reactivation and memory loss induced by intracerebroventricular injection of Aß1-42 oligomers in CD1 mice. Cycling neurons, scored as NeuN-positive cells expressing cyclin A, were found both in the frontal cortex and in the hippocampus of Aβ-injected mice, paralleling memory deficits. Starting from three days after Aβ injection, flavopiridol (0.5, 1 and 3 mg/kg) was intraperitoneally injected daily, for eleven days. Here we show that a treatment with flavopiridol (0.5 and 1 mg/kg) was able to rescue the loss of memory induced by Aβ1-42, and to prevent the occurrence of ectopic cell-cycle events in the mouse frontal cortex and hippocampus. This is the first evidence that a cytostatic drug can prevent cognitive deficits in a non-transgenic animal model of AD.
KW - Alzheimer's disease
KW - Cell cycle
KW - Flavopiridol
KW - Memory deficit
KW - Oligomers
KW - β-amyloid
UR - http://www.scopus.com/inward/record.url?scp=84958280806&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84958280806&partnerID=8YFLogxK
U2 - 10.1016/j.phrs.2016.02.007
DO - 10.1016/j.phrs.2016.02.007
M3 - Article
AN - SCOPUS:84958280806
VL - 106
SP - 10
EP - 20
JO - Pharmacological Research
JF - Pharmacological Research
SN - 1043-6618
ER -