Oxidative Medicine and Cellular Longevity / 2015 / Article / Tab 2

Review Article

Mitochondria-Targeted Protective Compounds in Parkinson’s and Alzheimer’s Diseases

Table 2

Alzheimer’s disease and mitochondria-targeted protective compounds.

CompoundClass of compoundAD modelMechanism/effectReferences

17-β-Estradiol EstrogenIn vitro isolated mitochondria from postmortem human AD and SFAD brainsActivation of mitochondrial aconitase[179]

Acetyl-L-carnitineAmino acidIn vivo F344 rat modelRestoration of intact mitochondrial morphology and prevention from age-related mitochondrial decay[180]

ActeosideGlycosideIn vitro A-induced SH-SY5Y human neuroblastoma cells modelMaintenance of mitochondrial integrity and function:
↓ ROS production
↓ MMP loss
↓ CytC release
Inhibition of the mitochondrial apoptotic pathway:
↓ Bax/Bcl-2 ratio
↓ caspase-3 cleavage
[181]

ASS234Amine with complex structureIn vitro A-induced SH-SY5Y human neuroblastoma cells modelInhibition of the mitochondrial apoptotic pathway:
↓ levels of cleaved caspases 3 and 9
↓ levels of proteolysed PARP
[182]

Caffeine AlkaloidIn vivo APPsw mice modelMaintenance of mitochondrial integrity and function:
restoration of mitochondrial respiratory rate,
maintenance of MMP
↓ ROS production
↑ ATP levels
[169]

ColostrininPolypeptideIn vitro Aβ-induced human SH-SY5Y and rat PC12 cells modelMaintenance of mitochondrial integrity and function:
↓ mitochondrial H2O2 production
[183]

Crude caffeineAlkaloidIn vitro primary neurons from J20 mouse line Maintenance of mitochondrial integrity and function:
↑ ATP levels
↓ ROS production
Inhibition of the mitochondrial apoptotic pathway:
↓ caspase-3 activity
[184]

Cyclosporin AIn vitro isolated cortical mitochondria from mAPP-Ppif−/−transgenic miceMaintenance of mitochondrial integrity and function:
inhibition of mPTP opening
↑ Ca2+ buffering capacity
[185]

D609Tricyclodecan-9-yl-xanthogenateIn vitro A-induced isolated brain mitochondria model (from gerbils)Maintenance of mitochondrial integrity and function:
↓ levels of protein carbonyls
↓ levels of protein-bound HNE
↓ levels of 3-NT
↓ CytC release
Maintenance of GSH/GSSG ratio
↑ GST, GPx, and GR activities
[186]

DAPTComplex structure of butyl esterIn vitro N2a/APP695 and N2a/APPswe cells modelsMaintenance of mitochondrial integrity and function:
stabilization of normal MMP and ATP levels
[187]

DimebonTetrahydrocarbolineIn vitro A-exposed isolated rat brain mitochondriaMaintenance of mitochondrial integrity and function:
inhibition of mPTP opening
[188]

Edaravone PyrazolinoneIn vitro N2a/Swe.Δ9 cells modelMaintenance of mitochondrial integrity and function,
↑ MMP
↓ ROS production
↓ CytC release
Inhibition of the mitochondrial apoptotic pathway:
↓ Bax/Bcl2 ratio
↓ Caspase-3 activation
[173]

Ergothioneine 2-Mercaptohistidine trimethylbetaineIn vitro A-induced PC12 rat pheochromocytoma cells modelMaintenance of mitochondrial integrity and function:
↓ MMP loss
Inhibition of the mitochondrial apoptotic pathway,
↓ ratio Bax/Bcl-XL
↓ caspase-3 activation
[189]

GelsolinPeptideIn vitro A-induced rat epithelial cells modelMaintenance of mitochondrial integrity and function:
increase in mitochondrial complex IV activity
[190]

GenisteinPhytoestrogenMitochondrial fraction of postmortem human AD brains↑ mitochondrial Na/K-ATPase activity[191]

GLP-1 (9-36)amidePeptideIn vitro slices of hippocampus from APP/PS1 mice Maintenance of mitochondrial integrity and function:
↓ abnormal mitochondrial SO levels
[192]

Glutathione TripeptideIn vitro Aβ-induced human HCN-1A cells modelMaintenance of mitochondrial integrity and function:
↓ mitochondrial membrane depolarization
[193]
In vitro isolated mitochondria from postmortem human AD and SFAD brainsActivation of mitochondrial aconitase[179]

Gypenoside XVIIPhytoestrogenIn vitro A-induced PC12 cells modelMaintenance of mitochondrial integrity and function:
restoration of normal MMP
↓ CytC release
Inhibition of the mitochondrial apoptotic pathway:
↓ caspase-3 activation and cleavage
↓ PARP cleavage
[194]

JHX-4, HK-2, and HK-4In vitro Aβ-induced human SH-SY5Y cells modelPrevention from MnCl2-induced loss of mitochondrial activity[195]

Lipoic acid Organosulfur compound derived from octanoic acidIn vivo F344 rat modelRestoration of intact mitochondrial morphology and prevention from age-related mitochondrial decay[180]
In vitro fibroblasts from AD patientsMaintenance of mitochondrial integrity and function:
↓ NMP-induced mitochondrial oxidative stress
Inhibition of the mitochondrial apoptotic pathway:
↓ Bax and caspase-9 levels
[196]

In vitro Aβ25–35-induced mouse microglial BV2 cells modelInhibition of the mitochondrial apoptotic pathway:
activation of Bcl-2 antiapoptotic pathways
↓ Bax mRNA level
↑ Bcl-2 expression
↓ caspase-3 activity
[197]
In vitro Aβ25–35-induced rat hippocampal neurons modelMaintenance of mitochondrial integrity and function:
restoration of MMP loss
attenuation of respiratory chain complexes
↑ ATP levels
[198]
Melatonin HormoneIn vivo APP/PS1 transgenic miceMaintenance of mitochondrial integrity and function:
restoration of mitochondrial respiratory rates
↑ MMP
↑ ATP levels
[170]
In vivo APPsw mice modelMaintenance of mitochondrial integrity and function,
restoration of mitochondrial respiratory rate
maintenance of MMP
↓ ROS production
↑ ATP levels
[169]
In vitro isolated mitochondria from postmortem human AD and SFAD brainsActivation of mitochondrial aconitase[179]
In vivo APP transgenic mice modelMaintenance of mitochondrial integrity and function,
↑ SOD activity
Inhibition of the mitochondrial apoptotic pathway,
↓ Bax, caspase-3, and Par-4 expressions
[168]

Methylene bluePhenothiazineIn vivo C57BL/6 miceMaintenance of mitochondrial integrity and function,
↑ mitochondrial complex IV (CytC oxidase)
activity
↓ MAO activity
[199]

In vitro Aβ-induced mouse neuroblastoma N2a cells modelMaintenance of mitochondrial integrity and function,
↓ abnormal expression of peroxiredoxins and
mitochondrial structural genes
normalization in mitochondria number
[200]
Mito Q MethanesulfonateIn vivo AβPP transgenic miceMaintenance of mitochondrial integrity and function:
↓ CypD expression
In vivo 3xTg-AD mice Maintenance of mitochondrial integrity and function:
prevention of MMP loss
Inhibition of the mitochondrial apoptotic pathway:
blockage of caspases-3/7 activation
[171]
In vivo Caenorhabditis elegans model overexpressing human Aβ peptidesMaintenance of mitochondrial integrity and function,
↓ depletion of mitochondrial lipid cardiolipin
Protection of complexes IV and I of the ETC
[201]

Mitochondrial division inhibitor 1 (Mdivi-1) QuinazolinoneIn vitro Aβ-induced mouse BV-2 cells and primary microglial cells modelMaintenance of mitochondrial integrity and function:
↓ abnormal mitochondrial fission
↓ MMP loss
↓ CytC release
Inhibition of the mitochondrial apoptotic pathway:
↓ caspase-3 activation
[182]
In vitro cybrid cells model (mtDNA-depleted neuronal SH5Y5Y cells transfected with platelet mitochondria from AD patient)Maintenance of mitochondrial integrity and function:
↓ mitochondrial ROS production
↑ MMP
↑ mitochondrial length and density
↑ CytC oxidase activity
↑ SOD activity
↑ ATP levels
↓ impaired mitochondrial fission and fusion dynamics
[174]

N-Acetyl cysteine Amino acid derivativeIn vitroβ-amyloid-induced human HCN-1A cells modelMaintenance of mitochondrial integrity and function:
↓ mitochondrial membrane depolarization
[193]
In vivo APP/PS-1 miceAmelioration of energy levels and mitochondrial-related proteins[202]
In vitro fibroblasts from AD patientsMaintenance of mitochondrial integrity and function:
↓ NMP-induced mitochondrial oxidative stress
Inhibition of the mitochondrial apoptotic pathway:
↓ Bax and caspase-9 levels
[196]

Neuregulin-1PeptideIn vitro model of SH-SY5Y human neuroblastoma cells transfected with C-terminal fragments of APPMaintenance of mitochondrial integrity and function:
↓ MMP loss
Inhibition of the mitochondrial apoptotic pathway:
↑ Bcl-2 expression
[203]

NicotinamideAmideIn vivo A-induced rat modelUpregulation of mitochondrial function
Inhibition of the mitochondrial apoptotic pathway:
↑ Bcl-2 levels
↓ Bax levels
[204]

Peroxiredoxin 3EnzymeIn vivo APP transgenic mice (Tg2576) and APP/Prdx3 transgenic mice modelsMaintenance of mitochondrial integrity and function:
↓ mitochondrial DNA oxidation
↑ activity of mitochondrial complexes I and IV
[205]

Peroxiredoxin 6EnzymeIn vitro A-induced PC12 cells modelInhibition of the mitochondrial apoptotic pathway:
↓ caspases 3 and 9 activation
↓ PARP activation
↓ Bcl-2 and Bax dysregulations
[206]

ProbucolIn vitro cybrid cells model (mtDNA-depleted neuronal SH5Y5Y cells transfected with platelet mitochondria from AD patient)Maintenance of mitochondrial integrity and function:
↓ mitochondrial ROS production
↑ MMP
↑ mitochondrial length and density
↑ CytC oxidase activity
↑ SOD activity
↑ ATP levels
↓ impaired mitochondrial fission and fusion dynamics
[174]

Puerarin PhytoestrogenIn vivo A-induced rat modelInhibition of the mitochondrial apoptotic pathway:
↓ caspase-9 activity and mRNA levels
[207]
In vitro cybrid cells model (mtDNA-depleted neuronal SH-5Y5Y cells transfected with platelet mitochondria from AD patient)Inhibition of the mitochondrial apoptotic pathway:
↑ Bcl-2 levels
↓ Bax expression
↓ caspase-3 activity
[208]

R(+) and S(−) pramipexoles In vitro A-induced SH-SY5Y human neuroblastoma cells modelMaintenance of mitochondrial integrity and function:
inhibition of mPTP opening
Inhibition of the mitochondrial apoptotic pathway:
↓ caspases 3 and 9 activations
[209]

ResistinAdipokine proteinIn vitro mouse N2a/Swe.Δ9 cells (N2a cells transfected with Sw-APP mutant and presenilin exon 9 deletion mutant)Maintenance of mitochondrial integrity and function:
↑ ATP levels
↑ MMP
Inhibition of the mitochondrial apoptotic pathway:
↓ Bax/Bcl2 ratio
↓ CytC release
↓ caspase-3 activation
[210]

Resveratrol PolyphenolIn vitro Aβ-induced mouse neuroblastoma N2a cells modelMaintenance of mitochondrial integrity and function:
↓ abnormal expression of peroxiredoxins and
mitochondrial structural genes
Normalization in mitochondria number
[200]
In vivo AβPP transgenic miceMaintenance of mitochondrial integrity and function:
↓ CypD expression

Salicylate
Sulindac sulfide
Indomethacin Ibuprofen
R-flurbiprofen
NSAIDsIn vitro A- and A-induced rat cerebellar granule cells and cortical neurons model Maintenance of mitochondrial integrity and function:
↑ MMP
↓ mitochondrial Ca2+ overload
↓ CytC release
[172]

SS31PeptideIn vitro A-induced C57BL/6 mice hippocampal neurons modelMaintenance of mitochondrial integrity and function:
↓ levels of mitochondrial fission proteins (Drp1,
Fis1), matrix protein, and CypD
↑ number of healthy and intact mitochondria
Restoration of mitochondrial transport
[162]
In vitro Aβ-induced mouse neuroblastoma N2a cells modelMaintenance of mitochondrial integrity and function:
↓ abnormal expression of peroxiredoxins and
mitochondrial structural genes
Normalization in mitochondria number
[200]
In vivo AβPP transgenic miceMaintenance of mitochondrial integrity and function:
↓ CypD expression
In vitro Tg2576 mice primary neurons Maintenance of mitochondrial integrity and function:
restoration of mitochondrial transport
↓ percentage of defective mitochondria
[211]

Thymoquinone BenzoquinoneIn vitro A-induced PC12 cells modelMaintenance of mitochondrial integrity and function:
↑ MMP
[212]
In vitro A-induced primary rat neurons modelMaintenance of mitochondrial integrity and function:
↑ MMP
[213]

Tournefolic acid BPolyphenolIn vitro -induced rat cortical neurons model Maintenance of mitochondrial integrity and function:
↓ mitochondrial Ca2+ levels
delay in CytC release
Inhibition of the mitochondrial apoptotic pathway:
↓ tBid levels
[214]

Trolox Analog of vitamin EIn vitro dentate granule cells from transgenic mouse AD model (Tg2576) Maintenance of mitochondrial integrity and function:
scavenging of mitochondrial SO
restoration of Ca2+ clearance
↑ MMP
[215]

UPF1 and UPF17 PeptidesMitochondrial fraction of postmortem human AD brains↑ Mitochondrial Mn-SOD activity[191]

Vitamin CVitaminIn vitro Aβ-induced human HCN-1A cells model Maintenance of mitochondrial integrity and function:
↓ mitochondrial membrane depolarization
[193]
In vivo 5XFAD Knockout-transgenic mice modelMaintenance of mitochondrial integrity and function:
prevention of abnormal mitochondrial morphology
[216]

Wy-14.463 (peroxisome proliferator)In vitro A-induced primary rat hippocampal neurons modelMaintenance of mitochondrial integrity and function:
↑ MMP
[217]

ZeoliteIn vitro H2O2-induced SH-SY5Y cells model Maintenance of mitochondrial integrity and function:
↓ mitochondrial ROS production
[218]
In vivo APPswePS1dE9 transgenic mice modelSignificant increase in SOD activity

ETC: electron transport chain; MMP: mitochondrial membrane potential; CytC: cytochrome C; SO: superoxide; SOD: superoxide dismutase; SwAPP: Swedish amyloid precursor protein; ROS: reactive oxygen species; 4HNE: 4-hydroxy-2-nonenal; AChE: acetylcholine esterase; GSH: glutathione; GR: glutathione reductase; GPx: glutathione peroxidase; SFAD: Swedish Familial Alzheimer’s disease; MAO: monoamine oxidase; tBid: BH3 interacting domain death agonist; Bak: Bcl-2 agonist killer 1; mPTP: mitochondrial permeability transition pore; CypD: cyclosporine D; NMP: N-methyl protoporphyrin; SP-04: dimethyl-carbamic acid 2,3-bis-dimethylcarbamoyloxy-6-(4-ethyl-piperazine-1-carbonyl)-phenyl ester; SP-04m: 4-(4-ethyl-piperazin-1-yl)-1-(2,3,4-trihydroxy-phenyl)-butan-1-one; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; FCCP: carbonyl cyanide p-trifluoromethoxy-phenylhydrazone; PAO: phenylarsine oxide; PARP: poly-ADP-ribosyl polymerase; mtDNA: mitochondrial DNA; Par-4: prostate apoptosis response-4; 3-NT: 3-nitrotyrosine; GSH: reduced glutathione; GSSG: oxidized glutathione; GST: glutathione-S-transferase; GPx: glutathione peroxidase; GR: glutathione reductase; ASS234: N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine; APP: amyloid precursor protein; Aβ: β amyloid; NSAIDs: nonsteroidal anti-inflammatory drugs.