Looking for a Treatment for the Early Stage of Alzheimer's Disease: Preclinical Evidence with Co-Ultramicronized Palmitoylethanolamide and Luteolin.
Alzheimer Disease
/ drug therapy
Animals
Brain-Derived Neurotrophic Factor
/ genetics
Cytokines
/ genetics
Drug Combinations
Ethanolamines
/ administration & dosage
Glial Cell Line-Derived Neurotrophic Factor
/ genetics
Gliosis
/ drug therapy
Hippocampus
/ drug effects
Luteolin
/ administration & dosage
Male
Neuroglia
/ drug effects
Neuroprotective Agents
/ administration & dosage
Prodromal Symptoms
Rats
Rats, Sprague-Dawley
astrocytes
beta amyloid
luteolin
microglia
neuroinflammation
neuroprotection
palmitoylethanolamide
preclinical Alzheimer’s disease
prodromal Alzheimer’s disease
reactive gliosis
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
27 May 2020
27 May 2020
Historique:
received:
04
05
2020
revised:
25
05
2020
accepted:
26
05
2020
entrez:
31
5
2020
pubmed:
31
5
2020
medline:
17
2
2021
Statut:
epublish
Résumé
At the earliest stage of Alzheimer's disease (AD), although patients are still asymptomatic, cerebral alterations have already been triggered. In addition to beta amyloid (Aβ) accumulation, both glial alterations and neuroinflammation have been documented at this stage. Starting treatment at this prodromal AD stage could be a valuable therapeutic strategy. AD requires long-term care; therefore, only compounds with a high safety profile can be used, such as the new formulation containing palmitoylethanolamide and luteolin (co-ultra PEALut) already approved for human use. Therefore, we investigated it in an in vivo pharmacological study that focused on the prodromal stage of AD. We tested the anti-inflammatory and neuroprotective effects of co-ultra PEALut (5 mg/Kg) administered for 14 days in rats that received once, 5 µg Aβ Glial activation and elevated levels of proinflammatory mediators were observed in Aβ-infused rats. Early administration of co-ultra PEALut prevented the Aβ-induced astrogliosis and microgliosis, the upregulation in gene expression of pro-inflammatory cytokines and enzymes, as well as the reduction of mRNA levels BDNF and GDNF. Our findings also highlight an important neuroprotective effect of co-ultra PEALut treatment, which promoted neuronal survival. Our results reveal the presence of cellular and molecular modifications in the prodromal stage of AD. Moreover, the data presented here demonstrate the ability of co-ultra PEALut to normalize such Aβ-induced alterations, suggesting it as a valuable therapeutic strategy.
Sections du résumé
BACKGROUND
BACKGROUND
At the earliest stage of Alzheimer's disease (AD), although patients are still asymptomatic, cerebral alterations have already been triggered. In addition to beta amyloid (Aβ) accumulation, both glial alterations and neuroinflammation have been documented at this stage. Starting treatment at this prodromal AD stage could be a valuable therapeutic strategy. AD requires long-term care; therefore, only compounds with a high safety profile can be used, such as the new formulation containing palmitoylethanolamide and luteolin (co-ultra PEALut) already approved for human use. Therefore, we investigated it in an in vivo pharmacological study that focused on the prodromal stage of AD.
METHODS
METHODS
We tested the anti-inflammatory and neuroprotective effects of co-ultra PEALut (5 mg/Kg) administered for 14 days in rats that received once, 5 µg Aβ
RESULTS
RESULTS
Glial activation and elevated levels of proinflammatory mediators were observed in Aβ-infused rats. Early administration of co-ultra PEALut prevented the Aβ-induced astrogliosis and microgliosis, the upregulation in gene expression of pro-inflammatory cytokines and enzymes, as well as the reduction of mRNA levels BDNF and GDNF. Our findings also highlight an important neuroprotective effect of co-ultra PEALut treatment, which promoted neuronal survival.
CONCLUSIONS
CONCLUSIONS
Our results reveal the presence of cellular and molecular modifications in the prodromal stage of AD. Moreover, the data presented here demonstrate the ability of co-ultra PEALut to normalize such Aβ-induced alterations, suggesting it as a valuable therapeutic strategy.
Identifiants
pubmed: 32471239
pii: ijms21113802
doi: 10.3390/ijms21113802
pmc: PMC7312730
pii:
doi:
Substances chimiques
Brain-Derived Neurotrophic Factor
0
Cytokines
0
Drug Combinations
0
Ethanolamines
0
Glial Cell Line-Derived Neurotrophic Factor
0
Neuroprotective Agents
0
co-ultraPEALut
0
Luteolin
KUX1ZNC9J2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : SAPIENZA University of Rome
ID : MA116154CD981DAE
Déclaration de conflit d'intérêts
Funding: The present study was funded by SAPIENZA, University of Rome grant n.MA116154CD981DAE (CS).
Références
Front Neurol. 2017 Jun 06;8:233
pubmed: 28634464
Lancet. 2001 Aug 11;358(9280):461-7
pubmed: 11513911
Arthritis Res Ther. 2013;15(6):R192
pubmed: 24246048
Mol Neurobiol. 2015 Oct;52(2):1034-42
pubmed: 26055231
CNS Neurol Disord Drug Targets. 2015;14(7):828-37
pubmed: 25801844
Neurotox Res. 2011 Feb;19(2):330-40
pubmed: 20221904
J Clin Med. 2020 Feb 05;9(2):
pubmed: 32033363
Alzheimers Dement. 2018 Apr;14(4):535-562
pubmed: 29653606
Oxid Med Cell Longev. 2018 Jan 16;2018:4720532
pubmed: 29576849
J Neurochem. 2005 Jun;93(6):1412-21
pubmed: 15935057
Mol Neurobiol. 2018 Jan;55(1):103-114
pubmed: 28822061
Arch Gen Psychiatry. 2012 Jan;69(1):98-106
pubmed: 22213792
J Neuroendocrinol. 2011 Jul;23(7):591-600
pubmed: 21554431
Psychiatry Res. 2010 Oct 30;184(1):57-62
pubmed: 20832251
Front Pharmacol. 2018 Mar 20;9:249
pubmed: 29615912
J Inflamm Res. 2016 Nov 03;9:199-208
pubmed: 27843334
Neurobiol Aging. 2009 Jul;30(7):1026-36
pubmed: 19376612
Int J Dev Neurosci. 2006 Apr-May;24(2-3):157-65
pubmed: 16384684
Ann N Y Acad Sci. 2007 Dec;1122:23-34
pubmed: 18077562
Clin Ther. 2013 May;35(5):592-602
pubmed: 23688534
Psychopharmacology (Berl). 2018 Oct;235(10):2929-2945
pubmed: 30058012
J Ethnopharmacol. 2018 Oct 28;225:342-358
pubmed: 29801717
Cell Death Dis. 2014 Sep 11;5:e1419
pubmed: 25210802
Alzheimers Res Ther. 2017 Sep 12;9(1):71
pubmed: 28899416
Indian J Psychiatry. 2018 Jan-Mar;60(1):32-37
pubmed: 29736060
Neurology. 2018 Aug 28;91(9):e867-e877
pubmed: 30054439
Transl Stroke Res. 2016 Feb;7(1):54-69
pubmed: 26706245
Br J Pharmacol. 2017 Jun;174(11):1349-1365
pubmed: 27539936
J Nucl Med. 2012 Jan;53(1):37-46
pubmed: 22213821
J Neurol Neurosurg Psychiatry. 2018 Apr;89(4):339-345
pubmed: 29248892
Nat Rev Neurol. 2010 Feb;6(2):67-77
pubmed: 20139996
Cell Death Differ. 2009 Mar;16(3):378-85
pubmed: 19057621
Front Pharmacol. 2019 Jun 06;10:644
pubmed: 31244658
Psychopharmacology (Berl). 2017 Aug;234(15):2219-2231
pubmed: 28550455
Philos Trans R Soc Lond B Biol Sci. 2001 Sep 29;356(1413):1453-65
pubmed: 11571036
Obesity (Silver Spring). 2009 Mar;17(3):431-8
pubmed: 19131941
Neurobiol Aging. 1995 May-Jun;16(3):271-8; discussion 278-84
pubmed: 7566337
Antioxidants (Basel). 2020 Mar 05;9(3):
pubmed: 32150935
Br J Pharmacol. 2007 Aug;151(8):1272-9
pubmed: 17592514
Alzheimers Res Ther. 2013 Sep 06;5(5):40
pubmed: 24007939
J Neurosci. 2006 Jan 11;26(2):662-70
pubmed: 16407564
J Pharmacol Exp Ther. 2007 Sep;322(3):1137-43
pubmed: 17565008
J Neuroinflammation. 2005 Oct 07;2:22
pubmed: 16212664
Brain. 2017 Jul 1;140(7):2002-2011
pubmed: 28575151
J Neuroinflammation. 2013 Jul 23;10:91
pubmed: 23880066
Front Aging Neurosci. 2018 Sep 19;10:275
pubmed: 30283329
Neuropsychopharmacology. 2012 Jun;37(7):1784-92
pubmed: 22414817
Alzheimers Dement. 2016 Mar;12(3):292-323
pubmed: 27012484
J Cell Mol Med. 2011 Dec;15(12):2664-74
pubmed: 21255263
Aging Dis. 2015 Oct 01;6(5):331-41
pubmed: 26425388
J Neuroinflammation. 2014 Aug 28;11:136
pubmed: 25164769
Front Pharmacol. 2014 May 13;5:89
pubmed: 24860504
Eur J Neurol. 2008 Oct;15(10):1080-4
pubmed: 18717723
J Neuroinflammation. 2011 Dec 07;8:171
pubmed: 22152162
Lancet Neurol. 2015 Apr;14(4):388-405
pubmed: 25792098
Science. 1980 Aug 15;209(4458):809-10
pubmed: 7403847
Front Cell Neurosci. 2017 Jul 24;11:216
pubmed: 28790893
J Neuroinflammation. 2012 Jul 23;9:179
pubmed: 22824372
JAMA. 2003 Jun 4;289(21):2819-26
pubmed: 12783912
Alzheimers Dement (N Y). 2019 Jul 09;5:272-293
pubmed: 31334330
Food Sci Nutr. 2016 Jun 15;5(2):292-309
pubmed: 28265364
CNS Neurol Disord Drug Targets. 2014;13(9):1530-41
pubmed: 25106636
Adv Protein Chem Struct Biol. 2017;108:33-57
pubmed: 28427563
Mol Pharmacol. 2005 Jan;67(1):15-9
pubmed: 15465922
Nutrients. 2019 Sep 11;11(9):
pubmed: 31514292
Physiol Rev. 2011 Apr;91(2):461-553
pubmed: 21527731
Prog Neurobiol. 2016 Sep;144:121-41
pubmed: 26797041
Brain Res. 2016 Oct 1;1648(Pt A):409-417
pubmed: 27423516
Brain Res Bull. 2015 Oct;119(Pt A):1-11
pubmed: 26361743
Neurobiol Aging. 2001 Nov-Dec;22(6):903-8
pubmed: 11754997
CNS Neurol Disord Drug Targets. 2013 Feb 1;12(1):62-9
pubmed: 23394526
J Alzheimers Dis. 2013;34(3):769-80
pubmed: 23271318
J Neuroinflammation. 2012 Mar 09;9:49
pubmed: 22405189
Exp Ther Med. 2017 Sep;14(3):1905-1908
pubmed: 28962102
J Neurotrauma. 2016 Jan 1;33(1):132-46
pubmed: 25046306
Planta Med. 2008 Nov;74(14):1667-77
pubmed: 18937165
Aging Clin Exp Res. 2016 Dec;28(6):1279-1282
pubmed: 26820462
Evid Rep Technol Assess (Full Rep). 2010 Apr;(193):1-727
pubmed: 21500874
Curr Alzheimer Res. 2011 Feb;8(1):67-80
pubmed: 21143158
Glia. 2006 Apr 1;53(5):484-90
pubmed: 16369931
J Pharmacol Exp Ther. 2008 Jul;326(1):12-23
pubmed: 18367664
Front Neurol. 2018 Sep 26;9:797
pubmed: 30319529
Front Mol Neurosci. 2018 Oct 31;11:407
pubmed: 30429774
Prog Neuropsychopharmacol Biol Psychiatry. 2018 Jan 3;80(Pt B):123-131
pubmed: 28533150
Curr Pharm Des. 2017;23(33):4979-4989
pubmed: 28699521
Cold Spring Harb Perspect Biol. 2014 Nov 07;7(2):a020420
pubmed: 25380660
Brain Res Mol Brain Res. 1998 Jun 1;57(1):1-9
pubmed: 9630473
Neurobiol Dis. 2005 Apr;18(3):602-17
pubmed: 15755686
Lancet. 2016 Jul 30;388(10043):505-17
pubmed: 26921134
Mediators Inflamm. 2013;2013:328797
pubmed: 23533304
Brain Pathol. 2017 Sep;27(5):629-644
pubmed: 28805002
Neuropharmacology. 2016 Jun;105:639-650
pubmed: 26777278
Neurobiol Dis. 2000 Dec;7(6 Pt B):574-85
pubmed: 11114257
Mini Rev Med Chem. 2009 Jan;9(1):31-59
pubmed: 19149659
Transl Psychiatry. 2018 Jan 31;8(1):32
pubmed: 29382825
J Alzheimers Dis. 2015;46(2):407-21
pubmed: 25765918
Alzheimers Dement. 2012 Jan;8(1):1-13
pubmed: 22265587
Alzheimers Res Ther. 2019 Aug 31;11(1):76
pubmed: 31470905
Neurology. 2013 May 7;80(19):1784-91
pubmed: 23576620
Neurobiol Aging. 2003 Nov;24(7):909-14
pubmed: 12928049
CNS Neurol Disord Drug Targets. 2015;14(10):1350-65
pubmed: 26295827
Front Pharmacol. 2020 Jan 29;10:1656
pubmed: 32063858
J Neurosci. 2012 Sep 12;32(37):12735-43
pubmed: 22972997
Alzheimers Res Ther. 2017 Aug 9;9(1):60
pubmed: 28793924
Mol Neurobiol. 2014 Feb;49(1):234-50
pubmed: 23934644
Methods Mol Biol. 2018;1727:343-352
pubmed: 29222793
Neurology. 1999 Apr 12;52(6):1158-65
pubmed: 10214737
J Pharmacol Exp Ther. 2019 Apr;369(1):163-172
pubmed: 30635472
PLoS One. 2012;7(8):e41880
pubmed: 22912680
N Engl J Med. 2013 Mar 28;368(13):1169-71
pubmed: 23484795
Mol Autism. 2018 Dec 27;9:66
pubmed: 30603062
Clin Transl Sci. 2020 Feb 10;:
pubmed: 32043310
PLoS One. 2011;6(12):e28668
pubmed: 22163051
J Alzheimers Dis. 2015;46(2):423-9
pubmed: 25737042