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) O
2 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 Ca
2+ 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 Ca
2+ 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 Ca
2+ 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 Ca
2+ 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.
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].