Honey administered orally before and after brain ischemia reduced damaged pyramidal neurons in the hippocampus, and significantly improved spatial learning and memory performance [50,160].

Quercetin and its glycosides, including isoquercetin, have a beneficial effect on pathological changes in various models of ischemic brain injury [161,162,163,164,165,166,167,168,169]. The beneficial effect of quercetin results from its anti-inflammatory, anti-apoptotic, and antioxidant effects, and from inhibiting metalloproteinase activity, which prevents blood–brain barrier failure after cerebral ischemia [161,162,163,164,165,166,167,168,169]. It is suggested that the factor Nrf2 may be involved in the antioxidant and anti-apoptotic effects [161,162,163,164,165,166,167,168,169].

Myricetin has been studied for multiple medical effects, including anti-apoptotic, anti-inflammatory, and antioxidant properties [170,171]. Studies have shown that myricetin works against brain damage after local ischemia [170,171,172]. Among the proposed molecular mechanisms of myricetin action, inhibition of p38 MAPK and enhancement of AKT and Nrf2 factors have been indicated [171,173].

A protective effect has been demonstrated with kaempferol in transient local cerebral ischemia in rats, e.g., in reducing amyloid protein precursor [174,175,176]. Studies indicate that treatment with kaempferol after ischemia prevents the development of neuroinflammation by reducing the activation of NF-kB/RelA and STAT3 [174,175,176].

Naringenin exhibits neuroprotective properties in a model of cerebral ischemia, reducing apoptosis, inflammation, oxidative stress, and neurological deficits by modulating claudin-5, MMP9, and Nrf2 [177,178,179]. In addition, naringin, a naringenin-7-O-glycoside, prevented brain microvascular thrombosis in spontaneously hypertensive rats [64].

Luteolin has been shown to have a neuroprotective effect, i.e., anti-apoptotic and blood–brain barrier stabilization, on ischemic brain damage by increasing claudin-5 and inhibiting MMP9, reducing oxidative stress, and enhancing autophagy by activating the Nrf2 pathway and reducing inflammatory changes [180,181,182,183].

Administration of caffeic acid before or after ischemia had a protective effect on the brain by improving the neurological outcome in various models of cerebral ischemia [184,185,186,187,188]. The neuroprotection provided by this substance was probably mediated by the inhibition of 5-lipoxygenase and both antioxidant and anti-inflammatory effects [64,184,185,186,187,188].

The beneficial effect of ferulic acid was confirmed in animal models of global and local brain ischemia [189,190,191,192,193,194]. There are many indications that the neuroprotective effect of ferulic acid is related to the anti-inflammatory and neurotrophic effects related to a reduction in the activity of intercellular adhesion molecule-1, an increased level of erythropoietin in the brain, and granulocyte colony-stimulating factor [64,189,190,191,192,193,194]. In addition, it has been shown that ferulic acid extends the therapeutic window after focal cerebral ischemia, which is currently very useful in the clinic [191].

On the other hand, p-coumaric acid has shown neuroprotective effects in models of local and global cerebral ischemia by inhibiting apoptosis and the production of reactive oxygen species [195,196].

However, chlorogenic acid given before or after ischemia diminished infarct size, blood–brain barrier damage, and behavioral deficits in focal cerebral ischemia by affecting the activation of MMP, increasing the levels of erythropoietin, HIF-1α, and nerve growth factor in the brain [197,198,199,200,201,202,203]. In addition, the substance supported neuroprotection in rats by affecting the Nrf2 path in a model of brain ischemia induced by ligation of both common carotid arteries [199]. It is worth noting that the other substance contained in honey, chlorogenic acid in combination with rtPA, effectively reduced behavioral deficits in focal cerebral ischemia in rabbits and extended the time window of rtPA treatment [64,204].

Another honey ingredient, ellagic acid, had a protective effect after experimental ischemic brain injury by affecting the regulation of Bcl-2/Bax activity [205].

Gallic acid protects against experimental, transient focal, and global ischemic brain injury by decreasing oxidative stress with elevated antioxidant levels and reducing markers responsible for inflammatory answer [206,207,208,209,210]. The neuroprotective effect of gallic acid is attributed to its ability to enter the brain through the blood–brain barrier, directly decreasing the concentration of reactive oxygen and nitrogen species and chelating transition metal ions [210]. Gallic acid has been documented to interrupt the vicious cycle of oxidative stress during brain injury due to ischemia [206,207,208,209,210].

In addition to the primary anti-inflammatory, antioxidant, and anti-apoptotic potential shown above, most honey ingredients, such as luteolin, myricetin, naringenin, quercetin, kaempferol, caffeic acid, ellagic acid, ferulic acid, gallic acid, and p-coumaric acid, also have a therapeutic effect on the progression of neurodegeneration associated with amyloid pathology in Alzheimer’s disease [54] and ischemia-related brain neurodegeneration of Alzheimer’s disease proteinopathy [175,176,177]. Additionally, naringenin, quercetin, naringin, ellagic acid, and caffeic acid also decrease tau protein phosphorylation in the brain in models of Alzheimer’s disease [54]. Honey components reduce the expression of genes involved in amyloidogenic neurodegeneration, such as amyloid protein precursor, β-secretase, and presenilin 1 [54,211,212,213]. In addition, myricetin and ellagic acid prevent the production of amyloid by increasing the expression and activity of α-secretase, which leads to a decrease in the cleavage of the amyloid protein precursor to soluble amyloid, and thus prevents the synaptic deposition of the latter [211,212]. These data suggest that the phenolic ingredients of honey participate in the regulation of the expression of genes involved in the reduction of oxidative stress and the development of amyloid fibrils [54]. Also, flavonoids and phenolic acids elevate the expression of the Nrf2 transcription factor, which is in charge for the induction of antioxidant genes, thus improving protection against oxidative damage [54]. Additionally, by reducing the induction of inflammatory factors, honey ingredients also weaken the immune response of microglia and astrocytes in the hippocampus, entorhinal cortex, and amygdala. Further, honey ingredients reduce tau protein hyperphosphorylation, which prevents the development of neurofibrillary tangles [214] and reduces the production and accumulation of amyloid in the form of plaques [215,216]. They also appear to exert neuroprotective effects by preventing neuronal damage and apoptosis and regulating the cholinergic system, similar to curcumin analogs in scopolamine-induced amnesia, where they increase acetylcholine and choline acetyltransferase and decrease butyrylcholinesterase [213,217,218]. Chlorogenic acid, ellagic acid, caffeic acid, gallic acid, myricetin, naringenin, quercetin, and kaempferol lower the level of acetylcholinesterase [54] like curcumin analogs in an experimental model of amnesia [217,218]. Additionally, caffeic acid and gallic acid also reduce level of butyrylcholinesterase [54]. It has also been shown that the action of chlorogenic acid leads to a reduction in memory and cognitive deficits in humans [219]. Since honey contains many flavonoids and phenolic acids, it can be expected that its consumption and proper preparation as a medicinal substance will have great potential in the prevention and/or treatment of post-ischemic brain pathology with the Alzheimer’s disease phenotype. The therapeutic potential of honey and its ingredients in preclinical models of focal and global brain ischemia (regardless of whether the administration was started before, during, or after ischemia), its effective concentration, dose, and duration of treatment, and the main effects are presented in Table 1.

Substance	Model	Treatment	Effects	References
		Honey
Malaysian Tualang honey	p2VO	Pre: 1.2 g/kg for 10 days with Post: 10 weeks	↓ Hippocampal CA1 region damage ↑ Spatial learning, memory performance	[50,161]
		Flavonoids
Quercetin	tMCAO	Post: 20 mg/kg/d for 3 days	↓ Oxidative stress, necrosis, apoptosis, brain edema, brain injury, neurological deficits	[165]
Quercetin	pMCAO	Post: 30 mg/kg single dose	↓ Brain injury	[162]
Quercetin	Photothrombotic model	Post: 25 µmol/kg every 12 h for 3 days	↓ BBB injury, brain edema, neurological deficits ↑ Functional outcomes	[164]
Quercetin	2VO	Pre: 50 mg/kg 30 min before and immediately post-ischemia, then daily for 2 days	↓ BBB injury, delayed neuronal damage in CA1, CA2, brain injury	[163]
Quercetin	tMCAO	Pre: 10 mg/kg 30 min before	↓ Neurological deficits, behavioral changes ↑ Parvalbumin expression	[169]
Quercetin	tMCAO	Pre: 10 mg/kg 1 h before	↓ Brain edema, damage in brain cortex, neurological deficits ↑ Thioredoxin, interaction of apoptosis signal-regulating kinase 1 and thioredoxin	[167]
Quercetin	tMCAO	Pre: 10 mg/kg 30 min before	↓ Infarct volume, neurological deficit ↑ Protein phosphatase 2A	[166]
Quercetin	tMCAO	Post: 10, 30, 50 mg/kg at the onset of reperfusion	↓ BBB injury, ROS, infarct volume, neurological deficit	[170]
Quercetin	pMCAO	Pre: 10 mg/kg 1 h before	↓ Intracellular calcium overload, glutamate excitotoxicity, caspase-3.	[168]
Myricetin	tMCAO	Pre: 20 mg/kg 2 h before and daily for 2 days after ischemia Pre: 25 mg/kg daily for 7 days	↓ Oxidative stress, apoptosis, neuronal loss, inflammation, infarct volume, ROS, neurological deficits ↑ Antioxidant enzymes, mitochondrial function, Nrf2 nuclear translocation, HO-1 expression	[171]
Myricetin	pMCAO	Pre: 1 mg/kg, 5 mg/kg, 25 mg/kg for 7 days	↓ IL-1β, IL-6, TNF-α, MDA, p38 MAPK, NF-κB/p65, apoptosis, infarct area, neurological deficit ↑ GSH/GSSG ratio, SOD, phosphorylated AKT	[174]
Myricetin	tMCAO	Pre: 25 mg/kg for 7 days	↓ Excitotoxicity, oxidative stress, inflammation, apoptosis	[173]
Kaempferol	tMCAO	Pre: 10,15 μmol/l 30 min before and immediately after ischemia Post: 7.5, 10 mg/kg single dose Post: 25, 50, 100 mg/kg daily for 7 days	↓ Metalloproteinase, anti-laminin staining, nitrosative-oxidative stress, caspase-9, apoptosis, poly-(ADP-ribose) polymerase, amyloid protein precursor, glial fibrillary acidic protein, phosphorylated STAT3, NF-κB p65, nuclear content of NF-κB p65, tumor necrosis factor α, interleukin 1β, intercellular adhesion molecule 1, matrix metallopeptidase 9, inducible nitric oxide synthase, myeloperoxidase, neuroinflammation, BBB injury, microglia activity, brain injury, neurological deficits	[175,176,181]
Naringenin	pMACO	Pre: 100 mg/kg daily for 4 days	↓ Neuroinflammation, edema, NOD2, RIP2, NF-κB, MMP-9, BBB injury, infarct volume, neurological deficits ↑ Claudin-5	[179]
Naringenin	tMCAO	Pre: 50 mg/kg daily for 21 days Post: 80 µM single dose	↓ Apoptosis, oxidative stress, edema, NF-κB, myeloperoxidase, nitric oxide, cytokines, neuroinflammation, glial activation, injury volume, neurological deficits ↑ Cortical neurons proliferation	[178,180]
Luteolin	tMCAO	Post: 20, 40, 80 mg/kg 0 and 12 h after ischemia	↓ Injury volume, edema, IL-1β, TNF-α, iNOS, COX-2, NF-κB, inflammation, neurological deficits ↑ Nrf2, PPARγ.	[181]
Luteolin	tMCAO	Post: 5, 10, 25 mg/kg single dose	↓ Oxidative stress, apoptosis, mRNA and protein of MMP9, infarct volume, neurological deficits ↑ PI3K/Akt	[182]
Luteolin	pMCAO	Post: 10, 25 mg/kg single dose post-ischemia	↓ MDA, Bax, oxidative stress, apoptosis, edema, infarct volume, neurological deficits ↑ SOD1, CAT, Bcl-2, claudin-5	[183]
Luteolin	pMCAO	Post: 5, 10 mg/kg 0 h and daily for 3 days survival	↓ Brain edema, TLR4, TLR5, p-p38, NF-κB infarct size, neurological deficit ↑Phospho-ERK	[184]
		Phenolic acids
Caffeic acid	tMCAO	Pre: 10, 50 mg/kg 30 min before, 0, 1, 2 h, and every 12 h for 4 days after ischemia Pre: 0.1, 1, 10 µg/kg 15 min before, single dose	↓ Neuroinflammation, leukotrienes, neuron loss, 5-lipoxygenase, astrocyte proliferation, infarct volume, brain atrophy, neurological dysfunction ↑ NO	[185,186]
Caffeic acid	pMCAO	Post: 10 µmol/kg daily for 7 days	↓ MDA, CAT, XO, oxidative stress, lipid peroxidation, infarct size, neurological deficits ↑ GSH, NO	[187]
Caffeic acid	Global ischemia	Post: 10, 30, 50 mg/kg single dose	↓ Hippocampus injury, NF-κBp65, MDA, 5-LO, oxidative stress, memory deficits ↑ SOD	[189]
Caffeic acid	tMCAO	Post: 3, 10, 30 mg/kg 0, 2 h after ischemia	↓ MMP-2, MMP-9, edema, damage in penumbra, infarct volume, sensory-motor deficits, behavioral deficits	[188]
Ferulic acid	Global ischemia	Post: 28, 56, 112 mg/kg daily for 5 days	↓ Oxidative stress, mRNA caspase 3, mRNA Bax, hippocampus apoptosis, memory impairment ↑ mRNA Bcl-2, SOD	[195]
Ferulic acid	tMCAO	Post: 50, 100, 200 mg/kg daily for 7 days	↓ Hippocampus injury, neurological deficits ↑ In hippocampus, EPO and granulocyte colony-stimulating factor	[193]
Ferulic acid	tMCAO	Post: 100 mg/kg 0 h post-ischemia Post: 100 mg/kg 2 h post-ischemia Post: 100 mg/kg 24 h Pre: 100 mg/kg 24 h before ischemia Pre: 100 mg/kg 2 h before ischemia	Pretreatment 2 h before ischemia and posttreatment 2 h after ischemia ↓ Bax, astrocytosis, infarction volume	[194]
Ferulic acid	tMCAO	Pre: 80, 100 mg/kg Post: 100 mg/kg 30 min after ischemia	↓ Superoxide radicals, ICAM-1, NF-κB, infarct size, neurological deficits	[190]
Ferulic acid	tMCAO	Post; 100 mg/kg 0 h after ischemia	↓ ICAM-1 mRNA, Mac-1 mRNA, Mac-1, 4-HNE, 8-OHdG positive cells, TUNEL positive cells, caspase 3, microglia activity, apoptosis, macrophages, oxidative stress, inflammation	[191]
Ferulic acid	tMCAO	Post: 100 mg/kg 0 h, or 30 min or 2 h after ischemia	↓ PSD-95, nNOS, iNOS, nitrotyrosine, caspase-3, apoptosis, Bax, cytochrome c, MAP kinase ↑ Gamma-aminobutyric acid type B receptor, therapeutic window	[192]
P-coumaric acid	pMCAO	Post: 100 mg/kg single dose	↓ Oxidative damage, MDA, apoptosis, caspase-3, caspase-9, edema, infarct volume, neurological deficits ↑ SOD, NRF-1	[196]
P-coumaric acid	Global ischemia	Pre: 100 mg/kg for 2 weeks before ischemia	↓ MDA, oxidative stress, hippocampal neuronal death, infarct volume, brain damage ↑ Catalase, superoxide dismutase	[197]
Chlorogenic acid	tMCAO	Post: 3, 10, 30 mg/kg 0, 2 h after ischemia Pre: 15, 30, 60 mg/kg for 1 week	↓ BBB, oxidative stress, MMP-2, MMP-9, edema, infarct volume, sensory-motor deficits, behavioral deficits	[198,199]
Chlorogenic acid	tMCAO	Post: 30 mg/kg 2 h after ischemia	↓ Cytochrome c, caspase-3, cleaved caspase-3, neurological deficits ↑ Phospho-PDK1, phospho-Akt, phospho-Bad	[202]
Chlorogenic acid	tMCAO	Pre: 15, 30, 60 mg/kg once a day for 1 week	↓ Mortality, infarction area, injury of hippocampus, cortex lesions, neurological deficit ↑ EPO, HIF-1α, NGF	[199]
Chlorogenic acid	Repeated global ischemia	Post: 20, 100, 500 mg/kg single dose	↓ Oxidative stress, apoptosis, MMPs, infarct volume, memory deficits ↑ SOD, GSH	[200]
Chlorogenic acid	Embolic strokes with rtPA	Post: 50 mg/kg 5 min, 1, 3 h after ischemia	↓ Behavioral deficits ↑ Therapeutic window	[205]
Chlorogenic acid	tMCAO	Post: 30 mg/kg 2 h after ischemia	↓ TUNEL-positive cells, caspase-3 and -7, oxidative stress, edema, infarct size, neurological damage	[201]
Chlorogenic acid	tMCAO	Post: 30 mg/kg 2 h post-ischemia	↓ Reactive oxygen species, oxidative stress, NF-κB, IL-1β, TNF-α, microglia, astrocyte activation, inflammation, cortex pathology	[204]
Chlorogenic acid	tMCAO	Post: 30 mg/kg/d 3 days after ischemia	↓ Cerebral cortex apoptosis, infarct volume ↑ Angiogenesis, VEGFA, PI3K/Akt signaling	[202]
Gallic acid	tMCAO	Pre: 50 mg/kg daily for 7 days Pre: 50 mg/kg single dose	↓ Oxidative stress, apoptosis, neuroinflammation, mitochondrial dysfunction, injury size, neurological deficits	[207,209]
Gallic acid	Global ischemia	Pre: 100 mg/kg/d for 10 days	↓ BBB injury, MDA, oxidative stress, hippocampus EEG changes, anxiety, behavioral deficits	[210]
Gallic acid	Global ischemia	Post: 25, 50 mg/kg/d for 1 week	↓ Oxidative stress, depressive symptoms	[208]
Ellagic acid	Photothrombotic model	Pre: 10, 30 mg/kg 24 h before and 0 h post-ischemia	↓ Apoptotic cells, infarct size, neurological deficits	[206]