PMID- 30243986
OWN - NLM
STAT- MEDLINE
DCOM- 20190410
LR  - 20190410
IS  - 1090-2430 (Electronic)
IS  - 0014-4886 (Linking)
VI  - 311
DP  - 2019 Jan
TI  - Early intrathecal infusion of everolimus restores cognitive function and mood in 
      a murine model of Alzheimer's disease.
PG  - 88-105
LID - S0014-4886(18)30489-8 [pii]
LID - 10.1016/j.expneurol.2018.09.011 [doi]
AB  - The discovery that mammalian target of rapamycin (mTOR) inhibition increases 
      lifespan in mice and restores/delays many aging phenotypes has led to the 
      identification of a novel potential therapeutic target for the treatment of 
      Alzheimer's disease (AD). Among mTOR inhibitors, everolimus, which has been 
      developed to improve the pharmacokinetic characteristics of rapamycin, has been 
      extensively profiled in preclinical and clinical studies as anticancer and 
      immunosuppressive agent, but no information is available about its potential 
      effects on neurodegenerative disorders. Using a reliable mouse model of AD 
      (3 x Tg-AD mice), we explored whether short-term treatment with everolimus 
      injected directly into the brain by osmotic pumps was able to modify AD-like 
      pathology with low impact on peripheral organs. We first established in 
      non-transgenic mice the stability of everolimus at 37  degrees C in comparison with 
      rapamycin and, then, evaluated its pharmacokinetics and pharmacodynamics profiles 
      through either a single peripheral (i.p.) or central (i.c.v.) route of 
      administration. Finally, 6-month-old (symptomatic phase) 3 x Tg-AD mice were 
      treated with continuous infusion of either vehicle or everolimus 
      (0.167 mug/mul/day, i.c.v.) using the osmotic pumps. Four weeks after the beginning 
      of infusion, we tested our hypothesis following an integrated approach, including 
      behavioral (tests for cognitive and depressive-like alterations), biochemical and 
      immunohistochemical analyses. Everolimus (i) showed higher stability than 
      rapamycin at 37  degrees C, (ii) poorly crossed the blood-brain barrier after i.p. 
      injection, (iii) was slowly metabolized in the brain due to a longer t(1/2) in 
      the brain compared to blood, and (iv) was more effective in the CNS when 
      administered centrally compared to a peripheral route. Moreover, the 
      everolimus-induced mTOR inhibition reduced human APP/Abeta and human tau levels and 
      improved cognitive function and depressive-like phenotype in the 3 x Tg-AD mice. 
      The intrathecal infusion of everolimus may be effective to treat early stages of 
      AD-pathology through a short and cyclic administration regimen, with short-term 
      outcomes and a low impact on peripheral organs.
CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
FAU - Cassano, Tommaso
AU  - Cassano T
AD  - Department of Clinical and Experimental Medicine, Medical School, University of 
      Foggia, 71100 Foggia, Italy. Electronic address: tommaso.cassano@unifg.it.
FAU - Magini, Alessandro
AU  - Magini A
AD  - Department of Chemistry, Biology and Biotechnology, University of Perugia, 06126 
      Perugia, Italy.
FAU - Giovagnoli, Stefano
AU  - Giovagnoli S
AD  - Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, 
      Italy.
FAU - Polchi, Alice
AU  - Polchi A
AD  - Department of Chemistry, Biology and Biotechnology, University of Perugia, 06126 
      Perugia, Italy.
FAU - Calcagnini, Silvio
AU  - Calcagnini S
AD  - Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of 
      Rome, 00185 Rome, Italy.
FAU - Pace, Lorenzo
AU  - Pace L
AD  - Department of Clinical and Experimental Medicine, Medical School, University of 
      Foggia, 71100 Foggia, Italy.
FAU - Lavecchia, Michele Angelo
AU  - Lavecchia MA
AD  - Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of 
      Rome, 00185 Rome, Italy.
FAU - Scuderi, Caterina
AU  - Scuderi C
AD  - Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of 
      Rome, 00185 Rome, Italy.
FAU - Bronzuoli, Maria Rosanna
AU  - Bronzuoli MR
AD  - Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of 
      Rome, 00185 Rome, Italy.
FAU - Ruggeri, Loredana
AU  - Ruggeri L
AD  - Division of Hematology and Clinical Immunology and Bone Marrow Transplant 
      Program, Department of Medicine, University of Perugia, 06132 Perugia, Italy.
FAU - Gentileschi, Maria Pia
AU  - Gentileschi MP
AD  - UOSD SAFU, RiDAIT Dept, The Regina Elena National Cancer Institute, 00144 Rome, 
      Italy.
FAU - Romano, Adele
AU  - Romano A
AD  - Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of 
      Rome, 00185 Rome, Italy.
FAU - Gaetani, Silvana
AU  - Gaetani S
AD  - Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of 
      Rome, 00185 Rome, Italy.
FAU - De Marco, Federico
AU  - De Marco F
AD  - UOSD SAFU, RiDAIT Dept, The Regina Elena National Cancer Institute, 00144 Rome, 
      Italy.
FAU - Emiliani, Carla
AU  - Emiliani C
AD  - Department of Chemistry, Biology and Biotechnology, University of Perugia, 06126 
      Perugia, Italy.
FAU - Dolcetta, Diego
AU  - Dolcetta D
AD  - UOSD SAFU, RiDAIT Dept, The Regina Elena National Cancer Institute, 00144 Rome, 
      Italy. Electronic address: diego.dolcetta@gmail.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180920
PL  - United States
TA  - Exp Neurol
JT  - Experimental neurology
JID - 0370712
RN  - 0 (Immunosuppressive Agents)
RN  - 9HW64Q8G6G (Everolimus)
SB  - IM
MH  - Affect/*drug effects/physiology
MH  - Alzheimer Disease/*drug therapy/genetics/metabolism
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cognition/*drug effects/physiology
MH  - Cognition Disorders/*drug therapy/genetics/metabolism
MH  - Drug Administration Schedule
MH  - Everolimus/*administration & dosage
MH  - Humans
MH  - Immunosuppressive Agents/*administration & dosage
MH  - Infusion Pumps, Implantable
MH  - Injections, Spinal
MH  - Male
MH  - Maze Learning/drug effects/physiology
MH  - Mice
MH  - Mice, 129 Strain
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
OTO - NOTNLM
OT  - 3 x Tg-AD mice
OT  - Alzheimer's disease
OT  - Depression
OT  - Everolimus
OT  - Intrathecal administration
OT  - Learning and memory
OT  - Mammalian target of rapamycin
EDAT- 2018/09/24 06:00
MHDA- 2019/04/11 06:00
CRDT- 2018/09/24 06:00
PHST- 2018/03/23 00:00 [received]
PHST- 2018/08/13 00:00 [revised]
PHST- 2018/09/17 00:00 [accepted]
PHST- 2018/09/24 06:00 [pubmed]
PHST- 2019/04/11 06:00 [medline]
PHST- 2018/09/24 06:00 [entrez]
AID - S0014-4886(18)30489-8 [pii]
AID - 10.1016/j.expneurol.2018.09.011 [doi]
PST - ppublish
SO  - Exp Neurol. 2019 Jan;311:88-105. doi: 10.1016/j.expneurol.2018.09.011. Epub 2018 
      Sep 20.