Table 2.

Collected studies of pure compounds suggesting neuroprotective activity of hesperidin and hesperetin.

Hesperidin
Model	Observations/proposed mechanism	Reference
Human neuroblastoma SK-N-SH cells	-Maintenance of mitochondrial membrane potential -Antioxidant—increase in glutathione, SOD, GSH-Px levels -Antiapoptotic—downregulation of Bax, caspase-3, 9; upregulation of Bcl-2	[58]
Neuro-2A cells	-Inhibition of β-amyloid-induced autophagy -Improved glucose utilization	[59]
In silico In vitro	-Inhibition of cholinoesterases—acetylcholinesterase (AChE), butyrylcholinesterase (BChE) -Inhibition of β-secretase 1 (BACE 1)	[60]
female C57 BL/6 mice	-Antidepressant-like effect -Improvement of cognitive performance and spatial memory -Antioxidant—increase in antioxidant enzymes activity and glutathione levels	[61]
Male Albino Wistar rats	-Decrease in AChE activity -Improved learning and memory -Suppression of APP, β-amyloid, β-, γ-secretases expression	[62]
Male APP/PS1 mice	-Improvement in learning and memory -Anti-inflammatory and anti-oxidant via activation of Akt/Nrf2 and inhibition of RAGE/NF-κB signaling pathways	[63]
In silico In vitro	-Anti-amyloidogenic—BACE-1 inhibition -Antioxidant	[64]
APPswe/PS1dE9 mice	-Improvement in learning and memory -Amelioration of recognition memory -Antioxidant—an increase of antioxidative defense; decrease in GKS-3β activity	[65]
Adult male C57BL/6 mice	-Amelioration of motor dysfunction -Anti-inflammatory—suppression of microglia activation; inhibition of COX-2 and attenuation of inflammatory cytokines—IL-1β, IL-4, IL-6, IL-10, TNF-α release	[66]
Male Wistar rats	-Anti-apoptotic—a decrease of Bcl-2 and increase of Bax expression -Amelioration of learning and memory -Antioxidant—increase in glutathione levels; enhancement of antioxidant enzymes activity—SOD, CAT, GPx	[67]
male transgenic APP/PS1–21 mice	-Decrease in microglial activation -Decrease in TGF-1β expression -Anti-amyloidogenic—attenuation in β-amyloid depositions accumulation and APP expression	[68]
Swiss male albino mice	-Attenuation of AChE activity -Anti-inflammatory—inhibition of NF-κB pathway and the release of COX-2 and iNOS -Inhibition of astrocytes activation -Improved memory consolidation	[69]
Hesperetin
adult male mice (C57BL/6N, wild type) HT22 cells	-Decrease in oxidative stress (via increase of Nrf2 HO-1 expression) -Anti-neuroinflammatory effect (reversion of β-amyloid-induced activation of astrocytes and microglia; decrease in TLR4, NF-κB expression) -Anti-apoptotic (downregulation of proapoptotic markers—Bax, Caspase-3, PARP-1; up-regulation of anti-apoptotic marker—Bcl-2) -Regulation of synaptic markers—increase in Syntaxin, SNAP-25, PSD-95, Syp, and SNAP-23 levels -Alleviation of short-term memory dysfunction	[70]
PC12 cells	-Antioxidant—induction of PKA, PI-3K, PGC-1α, and seladin-1 via ER- and TrkA-meditated pathways	[71]
Wistar rats	-Improvement in learning and recognition memory -Antioxidant (increase in glutathione and CAT, SOD, GRX, and GPX levels and decrease of lipid peroxidation)	[72]
PC12 cells	-Decrease in Ca2+ level -Antioxidantan increase in CAT, GSH-Px, and GRx levels -Decrease in caspase-3 activity -Maintenance of mitochondrial membrane potential -Decrease in DNA damage	[73]
Neuro-2A cells	-Inhibition of β-amyloid-induced autophagy -Improved glucose utilization	[59]
In silico In vitro	-Inhibition of cholinesterases—acetylcholinesterase (AChE), butyrylcholinesterase (BChE) -Inhibition of β-secretase 1 (BACE 1)	[60]
ICR female mice	-Antioxidant—activation of antioxidant enzymes—CAT, SOD	[74]
Male albino Wistar rats	-Decrease in AChE activity -Maintenance of mitochondrial membrane potential -Antiapoptotic—decrease in Bax, caspase-3, 9 levels and increase in Bcl2 -Antioxidant—increase in CAT, SOD, Gpx, GST activity	[75]
Male C57BL/6 N mice	-Antioxidant—decreased production of ROS and increased antioxidant proteins Nrf2, HO-1 levels -Anti-inflammatory—decreased expression of proinflammatory cytokines—TNF-α, IL-1β, p-NF-κB -Antiapoptotic—decreased expression of p-JNK, Bax, and caspase-3 increased expression of Bcl-2 -Enhanced synaptic integrity, cognition, and memory process	[76]
Male adult Wistar rats PD	-Improved motor functions -Attenuation of apoptosis by increased Bcl2 expression -Attenuation of astrogliosis by a decrease in GFAP levels -Decreased neuroinflammation by reduction of NF-κB levels	[77]
Cortical cells	-Inhibition of NMDA-induced excitotoxicity caused by the excess of glutamate -Protection against β-amyloid-induced neuronal damage	[78]
C57/BL6 male mice BV-2 microglial cells	-Inhibition of astrocyte and microglial activation -Anti-inflammatory—attenuation of production of iNOS, NO, IL-6, IL-1β	[79]
SH-SY5Y cells	-Attenuation of apoptosis—decrease in caspase-3, -9 expression -Antioxidant—increased levels of GSH, SOD, and expression of NRF2 and HO-1	[80]
Male albino mice	-Improved spatial learning and reference memory -Maintenance of cholinergic neurotransmission -Inhibition of AChE activity -Antioxidant—increase in SOD and GSH levels -Increased BDNF levels	[81]
RAW 264.7 Cells	-Anti-inflammatory effect concerning inhibition of NF-κB and activation of Nrf2/HO-1—suppression of proinflammatory cytokines (TNF-α, IL-6, IL1β) and pro-inflammatory enzymes (iNOS, COX-2) expression	[82]