Oxidative Medicine and Cellular Longevity

Review Article

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

Table 2

Alzheimer’s disease and mitochondria-targeted protective compounds.


Compound	Class of compound	AD model	Mechanism/effect	References

17-β-Estradiol	Estrogen	In vitro isolated mitochondria from postmortem human AD and SFAD brains	Activation of mitochondrial aconitase	[179]

Acetyl-L-carnitine	Amino acid	In vivo F344 rat model	Restoration of intact mitochondrial morphology and prevention from age-related mitochondrial decay	[180]

Acteoside	Glycoside	In vitro A-induced SH-SY5Y human neuroblastoma cells model	Maintenance 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]

ASS234	Amine with complex structure	In vitro A-induced SH-SY5Y human neuroblastoma cells model	Inhibition of the mitochondrial apoptotic pathway: ↓ levels of cleaved caspases 3 and 9 ↓ levels of proteolysed PARP	[182]

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

Colostrinin	Polypeptide	In vitro Aβ-induced human SH-SY5Y and rat PC12 cells model	Maintenance of mitochondrial integrity and function: ↓ mitochondrial H₂O₂ production	[183]

Crude caffeine	Alkaloid	In 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 A	—	In vitro isolated cortical mitochondria from mAPP-Ppif^−/−transgenic mice	Maintenance of mitochondrial integrity and function: inhibition of mPTP opening ↑ Ca²⁺ buffering capacity	[185]

D609	Tricyclodecan-9-yl-xanthogenate	In 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]

DAPT	Complex structure of butyl ester	In vitro N2a/APP695 and N2a/APPswe cells models	Maintenance of mitochondrial integrity and function: stabilization of normal MMP and ATP levels	[187]

Dimebon	Tetrahydrocarboline	In vitro A-exposed isolated rat brain mitochondria	Maintenance of mitochondrial integrity and function: inhibition of mPTP opening	[188]

Edaravone	Pyrazolinone	In vitro N2a/Swe.Δ9 cells model	Maintenance 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 trimethylbetaine	In vitro A-induced PC12 rat pheochromocytoma cells model	Maintenance of mitochondrial integrity and function: ↓ MMP loss Inhibition of the mitochondrial apoptotic pathway, ↓ ratio Bax/Bcl-X_L ↓ caspase-3 activation	[189]

Gelsolin	Peptide	In vitro A-induced rat epithelial cells model	Maintenance of mitochondrial integrity and function: increase in mitochondrial complex IV activity	[190]

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

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

Glutathione	Tripeptide	In vitro Aβ-induced human HCN-1A cells model	Maintenance of mitochondrial integrity and function: ↓ mitochondrial membrane depolarization	[193]
Glutathione	Tripeptide	In vitro isolated mitochondria from postmortem human AD and SFAD brains	Activation of mitochondrial aconitase	[179]

Gypenoside XVII	Phytoestrogen	In vitro A-induced PC12 cells model	Maintenance 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-4	—	In vitro Aβ-induced human SH-SY5Y cells model	Prevention from MnCl₂-induced loss of mitochondrial activity	[195]

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

		In vitro Aβ_25–35-induced mouse microglial BV2 cells model	Inhibition of the mitochondrial apoptotic pathway: activation of Bcl-2 antiapoptotic pathways ↓ Bax mRNA level ↑ Bcl-2 expression ↓ caspase-3 activity	[197]
		In vitro Aβ_25–35-induced rat hippocampal neurons model	Maintenance of mitochondrial integrity and function: restoration of MMP loss attenuation of respiratory chain complexes ↑ ATP levels	[198]
Melatonin	Hormone	In vivo APP/PS1 transgenic mice	Maintenance of mitochondrial integrity and function: restoration of mitochondrial respiratory rates ↑ MMP ↑ ATP levels	[170]
Melatonin	Hormone	In vivo APPsw mice model	Maintenance 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 brains	Activation of mitochondrial aconitase	[179]
		In vivo APP transgenic mice model	Maintenance of mitochondrial integrity and function, ↑ SOD activity Inhibition of the mitochondrial apoptotic pathway, ↓ Bax, caspase-3, and Par-4 expressions	[168]

Methylene blue	Phenothiazine	In vivo C57BL/6 mice	Maintenance of mitochondrial integrity and function, ↑ mitochondrial complex IV (CytC oxidase) activity ↓ MAO activity	[199]

		In vitro Aβ-induced mouse neuroblastoma N2a cells model	Maintenance of mitochondrial integrity and function, ↓ abnormal expression of peroxiredoxins and mitochondrial structural genes normalization in mitochondria number	[200]
Mito Q	Methanesulfonate	In vivo AβPP transgenic mice	Maintenance of mitochondrial integrity and function: ↓ CypD expression	[200]
Mito Q	Methanesulfonate	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 peptides	Maintenance 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)	Quinazolinone	In vitro Aβ-induced mouse BV-2 cells and primary microglial cells model	Maintenance of mitochondrial integrity and function: ↓ abnormal mitochondrial fission ↓ MMP loss ↓ CytC release Inhibition of the mitochondrial apoptotic pathway: ↓ caspase-3 activation	[182]
Mitochondrial division inhibitor 1 (Mdivi-1)	Quinazolinone	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 derivative	In vitroβ-amyloid-induced human HCN-1A cells model	Maintenance of mitochondrial integrity and function: ↓ mitochondrial membrane depolarization	[193]
		In vivo APP/PS-1 mice	Amelioration of energy levels and mitochondrial-related proteins	[202]
		In vitro fibroblasts from AD patients	Maintenance of mitochondrial integrity and function: ↓ NMP-induced mitochondrial oxidative stress Inhibition of the mitochondrial apoptotic pathway: ↓ Bax and caspase-9 levels	[196]

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

Nicotinamide	Amide	In vivo A-induced rat model	Upregulation of mitochondrial function Inhibition of the mitochondrial apoptotic pathway: ↑ Bcl-2 levels ↓ Bax levels	[204]

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

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

Probucol	—	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]

Puerarin	Phytoestrogen	In vivo A-induced rat model	Inhibition of the mitochondrial apoptotic pathway: ↓ caspase-9 activity and mRNA levels	[207]
Puerarin	Phytoestrogen	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 model	Maintenance of mitochondrial integrity and function: inhibition of mPTP opening Inhibition of the mitochondrial apoptotic pathway: ↓ caspases 3 and 9 activations	[209]

Resistin	Adipokine protein	In 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	Polyphenol	In vitro Aβ-induced mouse neuroblastoma N2a cells model	Maintenance of mitochondrial integrity and function: ↓ abnormal expression of peroxiredoxins and mitochondrial structural genes Normalization in mitochondria number	[200]
Resveratrol	Polyphenol	In vivo AβPP transgenic mice	Maintenance of mitochondrial integrity and function: ↓ CypD expression	[200]

Salicylate Sulindac sulfide Indomethacin Ibuprofen R-flurbiprofen	NSAIDs	In 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]

SS31	Peptide	In vitro A-induced C57BL/6 mice hippocampal neurons model	Maintenance 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 model	Maintenance of mitochondrial integrity and function: ↓ abnormal expression of peroxiredoxins and mitochondrial structural genes Normalization in mitochondria number	[200]
		In vivo AβPP transgenic mice	Maintenance of mitochondrial integrity and function: ↓ CypD expression	[200]
		In vitro Tg2576 mice primary neurons	Maintenance of mitochondrial integrity and function: restoration of mitochondrial transport ↓ percentage of defective mitochondria	[211]

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

Tournefolic acid B	Polyphenol	In 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 E	In 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	Peptides	Mitochondrial fraction of postmortem human AD brains	↑ Mitochondrial Mn-SOD activity	[191]

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

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

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

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.