Honey and Its Ingredients in Post-Ischemic Neurodegeneration Treatment: History
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Contributor:
Ryszard Pluta
,
Barbara Miziak
,
Stanisław J. Czuczwar

Neurodegeneration of the brain after ischemia is a major cause of severe, long-term disability, dementia, and mortality, which is a global problem. These phenomena are attributed to excitotoxicity, changes in the blood–brain barrier, neuroinflammation, oxidative stress, vasoconstriction, cerebral amyloid angiopathy, amyloid plaques, neurofibrillary tangles, and ultimately neuronal death. In addition, genetic factors such as post-ischemic changes in genetic programming in the expression of amyloid protein precursor, β-secretase, presenilin-1 and -2, and tau protein play an important role in the irreversible progression of post-ischemic neurodegeneration. Numerous studies have shown that the high contents of flavonoids and phenolic acids in honey have antioxidant, anti-inflammatory, anti-apoptotic, anti-amyloid, anti-tau protein, anticholinesterase, serotonergic, and AMPAK activities, influencing signal transmission and neuroprotective effects.

  • brain ischemia
  • Alzheimer’s disease proteinopathy
  • honey
  • excitotoxicity
  • neuroinflammation
  • apoptosis
  • amyloid
  • tau protein
  • neurodegeneration

1. Introduction

Ischemic stroke is a disease characterized by high mortality, morbidity, recurrence, and low cure rate [1]. Worldwide, ischemic stroke is the leading cause of severe long-term disability and the second leading cause of death (5.5–6.0 million) after ischemic heart disease [2][3][4][5][6][7][8]. Ischemic stroke, caused by occlusion of an artery leading to the brain, is the most common form of stroke, accounting for roughly 85–90% of all strokes [3][5][8][9][10][11]. The incidence of stroke increases with age in both men and women [7], but in some countries, especially India and China, the incidence of stroke in people under 40 has recently increased, representing a serious problem for public health [12]. In the coming years, the global trend of extending life expectancy will cause a parallel increase in the incidence of stroke.
Approximately 70% of ischemic strokes and 87% of stroke-connected deaths and disability-adjusted life years occur in low- and middle-income countries [13]. In these countries, the number of ischemic stroke cases has more than doubled in the last four decades [13]. In contrast, over the last forty years, the incidence of ischemic stroke decreased by 42% in developed countries [13]. Ischemic stroke occurs on average 15 years earlier and causes more deaths in people in developing countries compared to people in developed countries [14]. As many as 84% cases of ischemic strokes in developing countries die within three years of stroke, compared with 16% in developed countries [13]. Current epidemiological statistics evaluate that approximately 14–17 million people suffer from ischemic stroke annually, of whom approximately half die within a year [2][3][4][5][6][7][8][15]. It is now believed that one in six people in the world will suffer a stroke in their lifetime [15]. It is also known that the number of post-ischemic patients all over the world has reached approximately 33 million [2][6]. Interestingly, in the 21st century, the number of cases of ischemic stroke in young adults has increased to about 2 million per year [16]. Due to aging and obesity among adults in the European community, it is estimated that by 2025, the incidence of stroke in this group will increase to 1.5 million [16].
There has been a global decline in age-adjusted mortality and stroke rates for the last 25 years, but the total number of stroke cases has increased as life expectancy has increased [10]. Ischemic stroke is the most common cause of brain ischemia in humans in developed countries, and the number of cases is 10 times higher than that of hemorrhagic stroke, while in developing countries this difference is much smaller [10]. Although ischemic stroke death rates are dropping, it is believed that up to 50% of stroke-connected deaths can be attributed to improper preventive or medicinal management of modifiable risk factors [10]. The risk of recurrence of ischemic stroke during the first month of recirculation is high; 1 in 25 patients have been shown to have a repeated stroke in this time frame [10]. According to the latest forecasts, the number of ischemic stroke cases will increase to 77 million in 2030 [2][6]. If the tendency of growing ischemic stroke indicators in the world continues, by 2030 there will be about 12 million deaths worldwide, 70 million patients will suffer a stroke, and more than 200 million disability-adjusted life years will be recorded annually [6].
Despite progress in diagnosis and symptomatic treatment of ischemic stroke, it is calculated that the number of strokes will more than double by 2050, and long-term disability following stroke will increase in equal measure due to demographic shift and the growing amount of stroke survivors [17][18]. It is estimated that 30–40% of ischemic strokes cases are cryptogenic, i.e., they have no known cause [9]. Symptoms usually vary depending on the extent of the stroke and the area of the brain affected, and include sensory and motor dysfunctions that are often permanent. Approximately 30–50% of stroke survivors do not return to functional independence [9].
Brain ischemia has been shown to trigger a sequence of phenomena called the “ischemic cascade” that can last from minutes to days [9][19]. These phenomena include energy failure, excitotoxicity, oxidative stress, disruption of the blood–brain barrier, neuroinflammation, and ultimately cell death [8][9][20]. Ischemic lesions cause cortical and subcortical infarcts, white matter damage, cerebral amyloid angiopathy, and microbleeds [21][22][23]. This additionally causes hypoperfusion, ischemia of adjacent structures, chronic neuroinflammation, accumulation of amyloid plaques and neurofibrillary tangles, gliosis, neuronal death, and finally brain atrophy [24][25][26][27][28][29][30]. Post-ischemic neurodegeneration commonly involves injury to the following brain regions: the cerebral cortex, temporal lobe, hippocampus, amygdala, entorhinal cortex, and parahippocampus. After ischemia, these regions are involved in memory and cognitive deficits, and their progressive neurodegeneration also triggers behavioral changes. Since most regions affected by pathology are related to both cognition and behavior, this makes behavioral changes strongly correlate with cognitive dysfunction. Ischemia-related cognitive impairment ranges from mild to severe, occurring in about 35–70% of survivors one-year post-stroke, with higher rates seen soon post-stroke [31][32][33][34][35][36]. Approximately 20% of patients with mild cognitive impairment post-stroke make a full recovery, with the highest rate of recovery seen soon after insult [36][37]. However, cognitive improvement without returning to pre-stroke levels is more common than fully recovery [36][38][39]. Interestingly, the risk of developing dementia in the future increases after ischemic brain damage, even in patients with transient cognitive impairment [36][40]. Brain ischemia has been shown to speed up the beginning of dementia by 10 years [41]. Approximately 8–13% of patients experience dementia soon after a first ischemic stroke and more than 40% after a second ischemic stroke [6][35][41]. In addition, the estimated progress of dementia in patients surviving 25 years post-stroke is approximately 48% [24][41].
It should be emphasized that patients experiencing an ischemic stroke have significant implications for caregivers, society, and the economy, especially in developing countries where the projected increase in the incidence of stroke is the highest. Not surprisingly, the socioeconomic influence of strokes is huge and increasing over time, with an annual cost in the EU of EUR 38 billion in 2012, EUR 45 billion in 2015 and EUR 60 billion in 2017 [42].
In view of the above data, there is an urgent need to develop new therapies capable of preventing or reducing brain ischemia related to Alzheimer’s disease proteinopathy damage. Currently, there are no causal treatments available that could prevent the disease or effectively treat its sequelae. It is understood that ischemic prophylaxis should be started as early as possible to reverse the natural progression of the disease. Currently, of course, reperfusion remains the only and immediate therapeutic option in ischemic stroke. At the present, despite limited effectiveness, thrombolysis with recombinant tissue plasminogen activator (rtPA) and thrombectomy are used in the therapy of acute stroke [5]. Less than 10% of ischemic stroke cases receive rtPA treatment [43]. However, the clinical profit is less than three percent due to the restricted time window for optimal medical therapy and the potential for extensive bleeding following drug administration [44][45]. In addition, reperfusion strategies, despite their limited effectiveness, are applicable only to a small percentage of patients due to the short time window of therapy, contraindications, and costs connected with maintaining the infrastructure for performing procedures [5]. In addition, the possibility of further therapeutic intervention after reperfusion procedures in the form of a neuroprotective effect is now proposed. Neuroprotection is not an alternate to thrombolytic treatment and thrombectomy, but aims to brake alternations in brain parenchyma and preclude the spread of damages to adjacent areas or structures. The idea of neuroprotection is promising in preclinical studies but has not been translated into clinical success [46][47]. A fresh notable example is nerinetide, which interferes with postsynaptic density protein 95, an excitatory neuronal protein. In experimental studies, it has shown promise in the therapy of cerebral ischemia, but has not shown treatment advantages in human stroke [47]. One of the reasons why neuroprotective strategies fail is that they mainly target neuronal cells. It should be added that the brain is composed of different cells, i.e., astrocytes, microglia, oligodendrocytes, endothelial cells, and pericytes, all of which influence the function and survival of neuronal cells by releasing different substances that act either positively or negatively. These cells are under-studied as therapeutic targets in post-ischemic stroke, but understanding of their post-ischemic behavior, both harmful and beneficial, continues to grow and is being intensively studied.

2. Therapeutic Potential of Honey and Its Ingredients in Post-Ischemic Neurodegeneration

Honey administered orally before and after brain ischemia reduced damaged pyramidal neurons in the hippocampus, and significantly improved spatial learning and memory performance [48][49].
Quercetin and its glycosides, including isoquercetin, have a beneficial effect on pathological changes in various models of ischemic brain injury [50][51][52][53][54][55][56][57][58]. 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 [50][51][52][53][54][55][56][57][58]. It is suggested that the factor Nrf2 may be involved in the antioxidant and anti-apoptotic effects [50][51][52][53][54][55][56][57][58].
Myricetin has been studied for multiple medical effects, including anti-apoptotic, anti-inflammatory, and antioxidant properties [59][60]. Studies have shown that myricetin works against brain damage after local ischemia [59][60][61]. Among the proposed molecular mechanisms of myricetin action, inhibition of p38 MAPK and enhancement of AKT and Nrf2 factors have been indicated [60][62].
A protective effect has been demonstrated with kaempferol in transient local cerebral ischemia in rats, e.g., in reducing amyloid protein precursor [63][64][65]. Studies indicate that treatment with kaempferol after ischemia prevents the development of neuroinflammation by reducing the activation of NF-kB/RelA and STAT3 [63][64][65].
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 [66][67][68]. In addition, naringin, a naringenin-7-O-glycoside, prevented brain microvascular thrombosis in spontaneously hypertensive rats [69].
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 [70][71][72][73].
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 [74][75][76][77][78]. The neuroprotection provided by this substance was probably mediated by the inhibition of 5-lipoxygenase and both antioxidant and anti-inflammatory effects [69][74][75][76][77][78].
The beneficial effect of ferulic acid was confirmed in animal models of global and local brain ischemia [79][80][81][82][83][84]. 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 [69][79][80][81][82][83][84]. 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 [81].
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 [85][86].
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 [87][88][89][90][91][92][93]. 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 [89]. 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 [69][94].
Another honey ingredient, ellagic acid, had a protective effect after experimental ischemic brain injury by affecting the regulation of Bcl-2/Bax activity [95].
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 [96][97][98][99][100]. 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 [100]. Gallic acid has been documented to interrupt the vicious cycle of oxidative stress during brain injury due to ischemia [96][97][98][99][100].
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 [101] and ischemia-related brain neurodegeneration of Alzheimer’s disease proteinopathy [64][65][66]. Additionally, naringenin, quercetin, naringin, ellagic acid, and caffeic acid also decrease tau protein phosphorylation in the brain in models of Alzheimer’s disease [101]. Honey components reduce the expression of genes involved in amyloidogenic neurodegeneration, such as amyloid protein precursor, β-secretase, and presenilin 1 [101][102][103][104]. 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 [102][103]. 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 [101]. 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 [101]. 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 [105] and reduces the production and accumulation of amyloid in the form of plaques [106][107]. 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 [104][108][109]. Chlorogenic acid, ellagic acid, caffeic acid, gallic acid, myricetin, naringenin, quercetin, and kaempferol lower the level of acetylcholinesterase [101] like curcumin analogs in an experimental model of amnesia [108][109]. Additionally, caffeic acid and gallic acid also reduce level of butyrylcholinesterase [101]. It has also been shown that the action of chlorogenic acid leads to a reduction in memory and cognitive deficits in humans [110]. 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.
Table 1. Activity of honey and selected its flavonoids and phenolic acids in various models of brain ischemia.
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 [48][50]
    Flavonoids    
Quercetin tMCAO Post: 20 mg/kg/d for 3 days ↓ Oxidative stress,
necrosis, apoptosis, brain edema, brain injury, neurological deficits		 [54]
Quercetin pMCAO Post: 30 mg/kg single dose ↓ Brain injury [51]
Quercetin Photothrombotic model Post: 25 µmol/kg every 12 h for 3 days ↓ BBB injury, brain edema, neurological deficits
↑ Functional outcomes		 [53]
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 [52]
Quercetin tMCAO Pre: 10 mg/kg 30 min before ↓ Neurological deficits, behavioral changes
↑ Parvalbumin expression		 [58]
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		 [56]
Quercetin tMCAO Pre: 10 mg/kg 30 min before ↓ Infarct volume, neurological deficit
↑ Protein phosphatase 2A		 [55]
Quercetin tMCAO Post: 10, 30, 50 mg/kg at the onset of reperfusion ↓ BBB injury, ROS, infarct volume, neurological deficit [59]
Quercetin pMCAO Pre: 10 mg/kg 1 h before ↓ Intracellular calcium overload, glutamate excitotoxicity, caspase-3. [57]
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		 [60]
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		 [63]
Myricetin tMCAO Pre: 25 mg/kg for 7 days ↓ Excitotoxicity, oxidative stress, inflammation, apoptosis [62]
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 [64][65][71]
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		 [68]
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		 [67][70]
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.		 [71]
Luteolin tMCAO Post: 5, 10, 25 mg/kg single dose ↓ Oxidative stress,
apoptosis, mRNA and protein of MMP9, infarct volume, neurological deficits
↑ PI3K/Akt		 [72]
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		 [73]
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		 [74]
    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		 [75][76]
Caffeic acid pMCAO Post: 10 µmol/kg daily for 7 days ↓ MDA, CAT, XO, oxidative stress, lipid peroxidation, infarct size, neurological deficits
↑ GSH, NO		 [77]
Caffeic acid Global ischemia Post: 10, 30, 50 mg/kg single dose ↓ Hippocampus injury, NF-κBp65, MDA, 5-LO, oxidative stress, memory deficits
↑ SOD		 [79]
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 [78]
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		 [85]
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		 [83]
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 [84]
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 [80]
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 [81]
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		 [82]
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		 [86]
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		 [87]
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 [88][89]
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		 [92]
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		 [89]
Chlorogenic
acid		 Repeated global ischemia Post: 20, 100, 500 mg/kg single dose ↓ Oxidative stress,
apoptosis, MMPs, infarct volume, memory deficits
↑ SOD, GSH		 [90]
Chlorogenic
acid		 Embolic strokes with rtPA Post: 50 mg/kg 5 min, 1, 3 h after ischemia ↓ Behavioral deficits
↑ Therapeutic window		 [95]
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 [91]
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 [94]
Chlorogenic
acid		 tMCAO Post: 30 mg/kg/d 3 days after ischemia ↓ Cerebral cortex apoptosis, infarct volume
↑ Angiogenesis, VEGFA, PI3K/Akt signaling		 [92]
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		 [97][99]
Gallic acid Global ischemia Pre: 100 mg/kg/d for 10 days ↓ BBB injury, MDA, oxidative stress, hippocampus EEG changes, anxiety,
behavioral deficits		 [100]
Gallic acid Global ischemia Post: 25, 50 mg/kg/d for 1 week ↓ Oxidative stress, depressive symptoms [98]
Ellagic
acid		 Photothrombotic model Pre: 10, 30 mg/kg 24 h before and 0 h post-ischemia ↓ Apoptotic cells, infarct size, neurological deficits [96]
P2VO—permanent occlusion of both common carotid arteries, tMCAO—transient middle cerebral artery occlusion, pMCAO—permanent middle cerebral artery occlusion, BBB—blood–brain barrier, ROS—reactive oxygen species, Nrf2—nuclear factor erythroid 2-related factor 2, HO-1—heme oxygenase 1, STAT3—signal transducer and activator of transcription 3, NF-κB p65—nuclear-kappa B factor p65, NOD2—nucleotide-binding oligomerization domain containing 2, RIP2—receptor-interacting-serine/threonine-protein kinase 2, MMP-9—matrix metallopeptidase-9, IL-1β—interleukin-1 beta, IL-6—interleukin-6, MDA—malondialdehyde, p38 MAPK—p38 mitogen activated protein kinase, GSH/GSSG—glutathione/glutathione disulfide, SOD—superoxide dismutase, AKT—protein kinase B, TNF-α—tumor necrosis factor-α, MAPKs—mitogen-activated protein kinases, ERK—extracellular signal-regulated kinase, iNOS—inducible nitric oxide synthase, COX-2—cyclooxygenase-2, PPARγ—peroxisome proliferator-activated receptor gamma, PI3K—phosphatidylinositol 3-kinase, CAT—catalase, TLR4—toll-like receptor 4, p-p38—phospho-p38, XO—xanthine oxidase, NO—nitric oxide, 5-LO—5-lipoxygenase, EPO—erythropoietin, ICAM-1—intercellular adhesion molecule 1, NRF1—nuclear respiratory factor 1, VEGFA—vascular endothelial growth factor A, EEG—electroencephalography. ↓—decrease, ↑—increase.

This entry is adapted from the peer-reviewed paper 10.3390/molecules28155624

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