Table 1.

Anti-oxidative, anti-inflammatory and anti-apoptotic effects of flavonols in various experimental conditions related to neurodegenerative diseases.

Model System	Treatment	Anti-Oxidative Effects	Anti-Inflammatory Effects	Anti-Apoptotic Effects	Reference
Quercetin
PC12 cells	H2O2	↓ ROS production, ↓ MDA levels, ↑ GSH content, ↑ catalase, SOD and GSH-Px expression		↓ Bax and ↑ Bcl-2 expression, ↓ cleaved caspase-3 and -9, ↓ p53 expression, ↑ activation of PI3K/Akt	[203,204,206]
PC12 cells	Aβ25-35	↓ levels of MDA, and HO-1 protein, ↑ levels of SOD, GSH-Px, catalase, Sirt1 and Nrf2 protein			[212]
P19 neurons	H2O2	↓ ROS production		↓ caspase-3/7 activation, ↓ nuclear condensation, ↓ p53 and ↑ Bcl-2 expression, ↑ activation of PI3K/Akt and ERK1/2	[186,188]
Cerebellar granule neurons	H2O2	↑ GSH levels, Nrf2 translocation, ↑ expression of GCLC mRNA			[205]
P19 neurons	CuSO4	↓ ROS production in moderate OS, pro-oxidative activity in severe OS		↓ caspase-3/7 activation, ↓ chromatin condensation, ↓ PUMA expression, ↑ activation of PI3K/Akt and ERK1/2	[123]
HT22 cells	Okadaic acid	↓ levels of ROS and MDA, ↑ levels of SOD and GSH-Px, ↑ mitochondrial membrane potential	↓ expression of NF-κB p-p65	↓ Bax levels, ↓ cleaved caspase-3, activation of PI3K/Akt pathway, inhibition of p38 and JNK, reduced intracellular Ca2+ levels	[213,215]
Drosophila AD model				Restored expression of genes involved in p53 signaling	[219]
Wild-type C57BL/6N mice	LPS		↓ gliosis, ↓ expression of p-NF-κB, ↓ levels of TNF-α, IL-1β, COX-2 and iNOS	↓ cytochrome c release and Bax/Bcl-2 ratio, ↓ caspase-3 activity, ↓ synaptic loss	[200]
Wistar albino rats (hippocampus)	Al-lactate	↓ ROS production, ↑ MnSOD activity, preserved mitochondrial morphology		↓ Bax and ↑ Bcl-2 expression, ↓ cytochrome c expression, ↓ caspase-3 activation, ↓ DNA fragmentation, ↓ p53 expression	[207]
APPswe/ PS1dE9 mice (C57/BL) (cortex, hippocampus)		Restoration of mitochondrial membrane potential, ROS levels and ATP production			[209]
3xTg-AD mice (hippocampus)			↓ activation of microglia, ↓ iNOS and COX-2 immunoreactivity, ↓ IL-1β		[210]
Sprague Dawley rats (brain homogenate)	Aβ	↑ SOD, catalase and GSH, ↓ MDA, activation of Nrf2/HO-1 pathway			[220]
MN9D dopaminergic cells		↑ mitochondrial biogenesis and mtDNA content		↑ pAkt expression, ↑ BDNF levels	[225]
SK-N-MC neuroblastoma cells	Mn	↑ SOD and catalase activity, ↑ GSH levels, ↓ MDA, ↑ levels of Nrf2 and HO-1	↓ level of P-IκBα and NF-κB p65	↓ staining with Hoechst 33342, ↓ number of apoptotic cells	[226]
Albino rats	rotenone	↓ MDA levels, ↑ thioredoxin reductase reactivity		↓ DNA fragmentation	[222]
Sprague Dawley rats (brain homogenate)	Mn	↓ ROS and protein carbonyl levels, ↑ Cu/Zn-SOD activity, ↑ Nrf2 and HO-1 mRNAs	↓ TNF-α, IL-1β, IL-6, COX-2 and iNOS protein expression, ↓ NF-κB and iNOS mRNAs	↓ Bax expression, ↓ cytochrome c expression, ↓ cleaved caspase-3 expression, ↓ PARP-1 levels	[226]
3-NP-induced model of HD in Wistar rats (striatum)		Restored ATP levels, ↑ mitochondrial SOD and catalase activity, ↓ MDA levels and ↑ thiol content		↓ number of pyknotic and condensed nuclei	[227]
Rutin
Sprague Dawley rats (hippocampus)	TMT		↓ mRNA markers of reactive microglia and pro-inflammatory cytokines		[234]
Wistar rats (hippocampus)	STZ	↓ TBARS content and nitrite levels, ↑ GSH, ↑ GPx, GR and catalase activity	↓ GFAP, COX-2, iNOS, IL-8 and p65 NF-κB expression	Restored PARP-1 activity, prevented histological abnormalities	[235]
PP/PS1 (APPswe/ PSEN1dE9) mice (brain homogenate)			↓ microglial activation, ↓ TNF-α, IL-1β, IL-6, ↑ IL-4 and IL-10	Reversed synaptic dysfunction, enhanced microglial Aβ phagocytosis	[236]
Sprague Dawley rats (brain homogenate)	Colistin	↑ SOD, GSH-Px and catalase content, ↑ GSH levels, ↓ MDA, ↑ levels of Nrf2	↓ GFAP expression, ↓ expression of NF-κB, TNF-α, ↓ nNOS activity	↑ Bcl-2 and ↓ Bax expression, ↓ caspase-3 activity, ↓ p53 level, modulation of ERK1/2 pathway	[238]
Myricetin
Primary neuronal cultures	Glutamate	↓ ROS production		↓ calcium overload, ↓ activation of caspase-3, ↓ nuclear fragmentation	[241]
Primary neuronal cultures	Aβ			↓ nuclear fragmentation, ↓ caspase-3 activation	[242]
MES23.5 cells	MPP+	↓ ROS production, restored mitochondrial membrane potential		↓ nuclear condensation, ↓ Bax/Bcl-2 ratio, ↓ caspase-3 activation, ↓ pJNK expression	[245]
Myricitrin
C57BL/6 mice (substantia nigra)	6-OHDA		↓ number of Iba1-positive cells, ↓ expression TNF-α		[261]
Sprague Dawley rats (brain homogenate)	TBI of the spinal cord	↑ SOD, GSH-Px and catalase content, ↓ MDA levels	↓ TNF-α, IL-1β, IL-6 and NF-κB p65 subunit content, ↓ COX-2 and TGF-β1 mRNA expression	↓ Bax/Bcl-2 ratio, ↓ p53 levels	[262]
Fisetin
HT22 cells	Glutamate	↓ ROS production, ↑ GSH levels			[265]
APPswe/ PS1dE9 mice (hippocampus)		↓ protein carbonylation	↓ cPLA2 levels, ↓ COX-2, ↓ astrocytic reactivity	↑ pERK, preserved expression of synaptic markers	[268]
C57BL/6N mice (hippocampus)	Aβ		↓ expression of p-IKKβ, p-NF-ҡB, TNFα and IL-1β, ↓ number of activated Iba-1- and GFAP-positive cells	↓ Bax expression, ↑ Bcl-2 expression, ↓ cytochrome c activation, ↓ cleaved caspase-3 and -9, ↓ expression of p53 and PARP-1, ↑ activation of PI3K/Akt, restored synaptic function	[271]
C57BL/6N mice (hippocampus)	LPS	↓ ROS production and lipid peroxidation, ↑ GSH levels	↓ reactivity of TLR4 and pNF-ҡB, ↓ TNFα, IL-1β and COX-2, ↓ activation of Iba-1- and GFAP-positive cells	↓ expression of cytochrome c, Apaf-1, caspase-3 and -9 and PARP-1, ↓ activation of JNK pathway, prevented morphological changes	[272]
Swiss albino mice (cortex and hippocampus)	AlCl3			↓ Bax and ↑ Bcl-2 mRNA expression, ↓ expression of cytochrome c, caspase-3 and -9, ↓ expression of p53, ↓ number of TUNEL-positive neurons, ↓ JNK activation	[273]
C57BL/6N mice (striatum)	MPTP			↓ number of TUNEL-positive neurons	[274]
Wistar rats (brain homogenate)	D-galactose	↓ production of ROS and NO, ↓ protein carbonylation and lipid hydroperoxidation, ↑ SOD and catalase levels, ↑ total thiol content	↓ expression of TNF-α and IL-1β		[277]
C57BL/6N mice	D-galactose	↓ ROS and MDA levels, ↑ levels of Sirt1, Nrf2 and HO-1	↓ pNF-ҡB, NF-ҡB, Iba-1, GFAP, IL-1β, TNF-α and iNOS	↓ Bax and ↑ Bcl-2 expression, ↓ expression of caspase-3 and PARP-1	[278]
Kaempferol
PC12	HNE			↑ Bcl-2 levels, ↓ caspase-3 activation, ↓ nuclear condensation and PARP-1 cleavage, inhibited activation of NADPH oxidase and JNK phosphorylation	[283]
SH-SY5Y cells	Rotenone	↓ production of ROS, ↓ mitochondrial carbonyls, restored mitochondrial function		Prevented round-shape phenotype, preserved nuclear morphology, ↓ reduced caspase-9/3 cleavage, ↓ activation of JNK and p38	[168]
SH-SY5Y cells	Rotenone	↓ production of ROS, ↓ MDA content, ↑ GSH, SOD, GSH-Px and catalase levels		↑ expression of TH	[282]
Albino rats	Rotenone	↓ production of ROS, ↓ MDA levels, ↑ GSH, SOD, GSH-Px and catalase levels	↓ levels of TNF-α and IL-6		[282]
Drosophila model of PD		↑ free radical scavenging, ↓ TBARS and protein carbonyl content, ↑ SOD, GSH-S-transferase and catalase activity		↓ reduced caspase-3 and -9 activity, ↑ TH staining and L-DOPA levels	[283]
Drosophila model of AD		↑ GSH content, ↓ TBARS and protein carbonyl content		↓ caspase-3 and -9 activity	[286]
C57BL/6 mice (substantia nigra)	MPTP	↑ SOD and GSH-Px activity, ↓ MDA content		↑ TH staining	[285]
Kunming mice (hippocampus)	D-galactose	↓ TBARS, ↑ SOD		↑ activation of ERK/CREB pathway	[287]
Morin
SH-SY5Y cells	Aβ	↓ production of ROS		↓ staining with Hoechst 33342 and PI	[293]
Differentiated PC12 cells	MPP+	↓ production of ROS		↓ caspase-3 activity	[290]
Primary cultured neurons	MPP+	↓ ROS production, prevented mitochondrial membrane disruption		↓ staining with Hoechst 33342 and PI	[294]
Primary cultured astrocytes	MPP+		↓ astrocyte activation, ↓ nuclear translocation of p65 NF-ҡB		[294]
Cultured cortical neurons	Aβ	↓ ROS production and protein oxidation, ↑ SOD and catalase activity, ↓ calcium uptake and mitochondrial membrane depolarization, restored respiratory capacity		↓ PI staining, ↓ cytochrome c release	[291]
Sprague Dawley rats (brain homogenate)	Ifosfamide	↓ MDA levels, ↑ GSH, SOD, GSH-Px and catalase activities, ↑ Nrf2 levels	↓ GFAP levels, ↓ NF-ҡB and TNF-α, ↓ nNOS activity	↓ caspase-3 and p53 levels, ↓ JNK activation	[295]
APPswe/ PS1dE9 mice (cortex, hippocampus)			↓ activation of glial cells	↓ cerebral Aβ production, ↑ expression of synaptic markers	[291]
C57BL/6 mice (striatum and substantia nigra)	MPTP		↓ astrocyte activation, ↓ levels of TNF-α	↓ loss of dopaminergic cells	[294]
B57/BL mice (substantia nigra)	MPTP			↑ number of TH-positive cells	[290]
Isorhamnetin
PC12 cells	H2O2	↓ formation of ROS, ↑ catalase activity		↓ calcium levels, ↓ caspase-3 activation, ↑ Akt signaling and ↓ activation of JNK pathway	[301]
N2a cells	TG	↓ formation of ROS		↓ calcium overload, ↓ PI fluorescence, ↑ phosphorylation of PKCε	[302]
HT22 neurons	OGD/R	↑ Akt/Sirt1/Nrf2/HO-1 pathway			[303]
Albino rats (hippocampus)	Aβ25-35	↓ formation of H2O2, ↓ MAO activity	↓ expression of iNOS and IL-1β mRNA		[308]
Albino mice (prefrontal cortex and hippocampus)	SCP	↓ MDA and nitrite production, ↑ GSH levels, ↑ SOD and catalase activities			[309]

Aβ—amyloid β; cPLA2—cytosolic phospholipase A2; GSH—glutathione; GCLC—glutamate–cysteine ligase catalytic subunit; GFAP—glial fibrillary acidic protein; GSH-Px—glutathione peroxidase; MAO—monoamino oxidase; MDA—malondialdehyde; MPP⁺—1-methyl-4-phenylpyridinium; MPTP—1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 3-NP—3-nitropropionic acid; OGD/R– oxygen–glucose deprivation and reoxygenation; 6-OHDA—6-hydroxydopamine; PI—propidium iodide; PUMA—p53-upregulated mediator of apoptosis; ROS—reactive oxygen species; SCP—scopolamine (muscarinic antagonist); SOD—superoxide dismutase; STZ—streptozotocin; TG—thapsigargin (inductor of endoplasmic reticulum stress); TBARS—thiobarbituric acid reactive substances; TH—tyrosine hydroxylase; TLR4—Toll-like receptor 4; TMT—trimethyltin.