Polyphenols Mediate Neuroprotection in Cerebral Ischemic Stroke: History
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Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Salaheldin Abdelraouf Abdelsalam
,
Kaviyarasi Renu
,
Hamad Abu Zahra
,
Basem M. Abdallah
,
Enas M. Ali
,
Vishnu Priya Veeraraghavan
,
Kalaiselvi Sivalingam
,
Larance Ronsard
,
Rebai Ben Ammar
,
Devanathadesikan Seshadri Vidya
,
Palaniyandi Karuppaiya
,
S. Y. Al-Ramadan
,
Peramaiyan Rajendran

Stroke is one of the main causes of mortality and disability, and it is due to be included in monetary implications on wellbeing frameworks around the world. Ischemic stroke is caused by interference in cerebral blood flow, leading to a deficit in the supply of oxygen to the affected region. It accounts for nearly 80–85% of all cases of stroke. Oxidative stress has a significant impact on the pathophysiologic cascade in brain damage leading to stroke. In the acute phase, oxidative stress mediates severe toxicity, and it initiates and contributes to late-stage apoptosis and inflammation. Oxidative stress conditions occur when the antioxidant defense in the body is unable to counteract the production and aggregation of reactive oxygen species (ROS).

  • ischemia stroke
  • oxidative stress
  • gallic acid
  • resveratrol
  • quercetin
  • kaempferol
  • mangiferin
  • epigallocatechin
  • pinocembrin

1. Introduction

Stroke is a cerebrovascular disease, mainly caused by atherosclerosis. It interrupts the supply of blood, which, in turn, causes an oxygen deficit [1]. The acute symptoms of stroke include dizziness, weakness, nausea, aphasia, hemiplegia, a loss of coordination, and a loss of vision. Stroke is the second leading cause of death in the world and one of the major causes of infirmity in adults, particularly in developing (12.8%) and developed countries (8.7%) [2][3]. Studies have also revealed an association between oxidative stress and various risk factors of ischemia stroke (IS), including cigarette smoking, in addition to hypertension, diabetes mellitus, hyperlipidemia, and obesity. Consequently, there is a huge number of relevant studies that have assessed the disease ontology and explored effective diagnostic measures and therapies. Some researchers have reported the positive effects of nutrient antioxidants on ischemic stroke [4][5][6]. Polyphenols are antioxidants that fight cancer. In pathological conditions, such as cancer, polyphenols are powerful antioxidants that mitigate oxidative stress. Free radicals can be scavenged by polyphenols. Essentially, there are more conjugated systems, aromatic rings, and hydroxyl groups in a different part of the molecules [7]. Humans consume these compounds in foods, such as fruits, cereals, and vegetables. Polyphenols can also prevent degenerative diseases. Research on polyphenols has been delayed due to their complex structure. Polyphenols are the most common antioxidants in our diet [8][9][10]. The action of these molecules is to inhibit oxidative change in low-density lipoprotein, which is the basic mechanism of endothelial lesions in atherosclerosis. Researchers have discovered that polyphenols are good for cardiovascular diseases, osteoporosis, neurodegenerative diseases, cancer, and diabetes [11]. Figure 1 shows the basic structures of some common neuroprotective polyphenols.
Figure 1. Effects of gallic acid on ischemic stroke (image created using biorender.com (accessed on 21 October 2022)).

2. Decreased Blood Flow Contributes to the Pathogenesis of Ischemic Stroke

Evidence from Mayhan et al., 2022, suggests that dysfunctional potassium channels may play a role in the etiology of vascular abnormalities and behavioral/cognitive disorders in the brain. Changes in the responsiveness of cerebral arterioles in response to the activation of essential vasodilator mechanisms may underlie the observed anomalies in brain function and, hence, impact the control of cerebral blood flow in response to metabolic demand variations (neurovascular coupling) [12]. Basal tone and variations in the diameter of cerebral arteries/arterioles and, hence, cerebral blood flow have been demonstrated to be regulated in response to several stimuli through ATP-sensitive potassium channels (KATP) and calcium-activated potassium channels (BK) [13]. The smooth muscles of blood vessels, including the arteries and arterioles of the brain, have been found to contain KATP channels [14]. After cerebral ischemia/reperfusion injury and in a number of other disease conditions, investigations have demonstrated that the dilation of cerebral arterioles in response to the activation of KATP channels changes. Basal tone in the cerebral arteries and arterioles can be modulated by BK channels. Dilating cerebral blood vessels in response to various agonists/physiological stimuli is mostly dependent on the activation of BK channels. The regulation of cerebral blood flow may be severely compromised if cerebral arteries are unable to respond normally to KATP and BK channel activation, especially under conditions of elevated metabolic demand. Impaired responses of cerebral arterioles to eNOS- and nNOS-dependent agonists could be attributed to an increase in oxidative stress. Large cerebral and coronary arteries are particularly susceptible to the negative effects of oxidative stress on K+ channel activity [15]. Superoxide is a critical modulator of diet-induced hyperhomocysteinemia-related cerebral vascular dysfunction and vascular hypertrophy. These results suggest that mild hyperhomocysteinemia may be an independent risk factor for cerebrovascular disease and ischemic stroke, and they may help provide a molecular basis for these observations in clinical practice. Future efforts to prevent the cerebral vascular consequences of hyperhomocysteinemia may target superoxide-dependent pathways, together with homocysteine-lowering medications, such as folic acid supplements [16]. Increased superoxide production from NAD(P)H oxidase activation is one mechanism by which aging reduces the eNOS-dependent responsiveness of cerebral arterioles and reduces oxidative stress [17]. Ischemic stroke results from a combination of factors, including oxidative stress, blood flow in the cerebral area, and dilated cerebral blood vessels [15].
Brain neutrophil infiltration and ischemia damage are both reduced in animals lacking ICAM-1 or treated with techniques that block ICAM-1 [18]. Additionally, blocking E-selectin is linked to better neurological outcomes [19]. When the brain suffers from ischemia, neutrophils are one of the earliest types of leukocytes to arrive on the scene. In addition to generating cytotoxic chemicals, neutrophils can clog blood vessels, reducing blood flow to the brain during reperfusion and, thus, worsening brain I/R injury. There have been a number of studies showing that preventing neutrophil infiltration into the brain reduces I/R harm [20]. The brain’s resident immune cells, called microglia, play a crucial role in regulating homeostasis and the immune response. There is evidence to suggest that there are two ways in which phagocytosis, the production of neuroinflammatory mediators that are harmful to cells, and activated microglia contribute to brain I/R injury. Damaged neurons, infiltrating leukocytes, activated astrocytes, microglia, and endothelial cells all contribute to the production of cytokines/chemokines in the aftermath of brief focal cerebral ischemia [21]. By activating microglia, upregulating the production of adhesion molecules, and driving pro-apoptotic signaling, pro-inflammatory cytokines, such as IL-1, TNF-, and IL-6, all contribute to brain I/R injury [22]. By contrast, anti-inflammatory cytokines, such as IL-1ra, IL-4, and IL-10, reduce pro-inflammatory cytokines and their receptor expression and downstream signaling to dampen inflammation after an ischemia event. There is an uptick in pro-inflammatory cytokines and chemokines, pointing to a potential for vascular inflammation [23]. This reduction of blood flow increases vascular inflammation and leads to ischemic stroke.

3. Oxidative Stress and Stroke

The central nervous system (CNS), microglia, and astrocytes are key sources contributing to the generation of reactive nitrogen species (RNS) and ROS, which regulate synaptic and nonsynaptic transmission between neurons and glia [24][25]. ROS and RNS stimulate the long-term potentiation of synaptic transmission, essential for memory. Moreover, studies have indicated age-related changes in superoxide in regulating synaptic ductility, learning, and forming memories. The brain is known to be at high risk following an increase in RNS and ROS caused by decreased neuron antioxidant enzymatic activity and (1) increased peroxidizable lipid concentration, (2) O2 consumption, and (3) iron levels, which act as pro-oxidants, inducing oxidative stress under pathological conditions [26][27]. To that end, it has been reported that the production of ROS has a significant impact on the brain on exposure to ischemic attack and reperfusion.
However, the three major routes of physiological ROS production, in general, remain significant during a stroke (Figure 1). The glycolytic pathway and Krebs cycle are responsible for the generation of these reduced coenzymes, which undergo oxidative phosphorylation to generate ATP molecules [28]. However, with a decreased oxygen supply, the metabolism slows down the electron transport chain (ETC) while enhancing the formation of superoxide ions from complexes I and III [29]. Additionally, mitochondria absorb the Ca2+ ions entering the neurons, causing the depolarization of the membrane and the impairment of ETC, which leads to a higher production of free radicals and the production of ATP. The combination of Ca2+ and ROS assists in the opening of the mitochondrial permeability transition pore (MPTP), and the resulting membrane leakage causes the energy deprivation and complete depolarization of mitochondria. MPTP may further disrupt the mitochondria, resulting in the production of ROS, cytochromes, and Ca2+ in the cytosol, which causes cell damage and apoptosis [30][31][32]. During neuronal ischemia, it is challenging for mitochondria to maintain a sufficient level of ATP, as the cell membrane ion pumps use an extensive amount of ATP to counteract the influx of Ca2+ and Na+ mediated by the N-methyl-D-aspartate (NMDA) receptor [33][34][35]. ROS oxidizes the thiol groups present in the adenine nucleotide transporter aggravated by the ROS-mediated consumption of GSH, and this impairs the movement of ATP from the mitochondria into the cytosol. Consequently, a vicious cycle is formed between the increased ATP demand and the reduced capacity for production and delivery, resulting in a decrease in energy, membrane ion flux, and cell death.
Free radicals have a high reactivity and a short half-life, making it difficult to measure them directly. There is an indirect way to demonstrate the production of free radicals, which is by measuring the products of a reaction between free radicals and other molecules, including DNA, lipids, proteins, and antioxidant levels [36]. Rodents, such as rats and mice, are commonly used laboratory species for research on brain ischemia. Their cranial circulatory anatomy is similar to that of humans, their physiological factors are easy to control, and histopathology enables analyses of ischemic pathogenesis and tissue infarction. Numerous experimental and clinical observations in various animal studies have indicated a higher free-radical production during all forms of ischemic injury (Table 1). However, there are limited data for such a correlation in humans due to methodical issues in measuring free radicals.
Table 1. Effects of polyphenols on stroke in animal studies.

Name of the Polyphenol

Mode of Study

Major Findings

Refs.

Resveratrol

Mouse and Rat

Oxidative stress inhibition, anti-inflammation, brain damage and apoptosis inhibition

[37][38][39][40][41][42][43][44][45][46][47][48][49][50][51]

Gallic acid

Mouse and Rat

Oxidative stress reduction, anti-inflammation

[52][53][54]

Quercetin

Mouse and Rat

Oxidative stress inhibition, MMP9 reduction

[55][56][57][58][59]

Kaempferol

Mouse and Rat

Oxidative stress inhibition, anti-inflammation, mitochondrial dysfunction suppression

[60][61][62][63][64]

Mangiferin

Mouse and Rat

Oxidative stress inhibition, anti-inflammation

[65][66][67][68][69][70][71]

Epigallocatechin

Mouse and Rat

Oxidative stress inhibition, anti-inflammation

[72][73][74][75][76][77][78][79][80]

Pinocembrin

Mouse and Rat

Oxidative stress inhibition, anti-inflammation

[81][82][83][84][85][86][87][88]

4. Effects of Polyphenols on Stroke

The dietary consumption of polyphenols from different sources of plants provides protection against the morbidity and mortality caused by cardiovascular diseases. Polyphenols from different plant sources provides protection against stroke in humans, animals, and in vitro studies [89]. Polyphenols have different pharmacological and biochemical effects. Some polyphenols have anti-inflammatory, antioxidant, and anti-proliferative effects. Oxidative stress plays an important role in cerebral ischemia. Polyphenols provide protection against neurodegenerative diseases with cerebral ischemia by reducing ROS and apoptosis, thereby acting as therapeutic agents against stroke [90]. Polyphenols are found in plant products, and they help in the defensive response against various kinds of stresses, including physical damage and ultraviolet radiation. It has also been observed that phenolic antioxidants inhibit the oxidation of lipids and other molecules, which helps to provide protection against free radicals [91][92][93]. Moreover, the type of conjugate and the polyphenol structure can determine the antioxidant capability. This might be the reason behind the better performance of particular polyphenols in scavenging superoxides, while others can scavenge highly reactive radicals, such as peroxynitrite, derived from oxygen. Certain polyphenols can chelate iron and possibly prevent the free-radical formation caused by iron. In the last decade, researchers have taken a keen interest in the potential neuroprotective effects of polyphenols, such as grape and wine polyphenols, against cerebral ischemia [94][95]. Polyphenols play an important role in providing protection against ischemic stroke, as they protect neurons by decreasing oxidative stress through the inhibition of LPO and NO and by decreasing inflammation [96]. Polyphenols reduce vascular risk factors, such as atrial fibrillation, during a stroke. Moreover, they protect the brain by augmenting different mechanistic pathways; for example, honokiol has been found to have anti-thrombotic effects [97]. Polyphenols decrease the production of ROS by inhibiting oxidase, reducing superoxide production, inhibiting the formation of OxLDL, proliferating VSMC, inhibiting migration, reducing platelet aggregation, and providing protection against mitochondrial oxidative stress. Therefore, polyphenols provide protection against ischemic heart disease and stroke [98].
In preclinical models, when polyphenols are administered after the induction of stroke, they exert neuroprotective actions, delaying the progress of brain damage, as well as the recovery of stroke [99][100]. Polyphenols exhibit their neuroprotective effects at the mechanistic level by acting on various targets at the same time. These compounds are strong antioxidants, with hydroxyl groups and neutrophilic centers functioning as ROS scavengers and metal chelators. Certain polyphenols can also initiate transcription factors associated with antioxidant-responsive element pathways, including erythroid 2-related factor 2 (Nrf2) [101][102][103]. Therefore, they promote the activity of antioxidant enzymes, such as superoxide dismutase (SOD), heme oxygenase-1 (HO-1), catalase, glutathione reductase, and glutathione-S-transferase. Various polyphenols can interact with pro-apoptotic (Bax and Bad) and anti-apoptotic (Bcl-2 and Bcl-XL) members of the Bcl-2 family, p53, mitogen-activated protein kinases (MAPKs), and protein kinase B (AKT) [104][105][106][107]. The previous literature has shown that polyphenols can modulate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), the Toll-like receptor (TLR), and arachidonic acid pathways. This decreases the formation of tumor necrosis factor α (TNF-α), interleukin (IL)-1β, IL-6, IL-1, and IL-8, along with cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and nitric oxide (NO) [101][108][109].

This entry is adapted from the peer-reviewed paper 10.3390/nu15051107

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