Molecular structure, types and food sources of (n-3) and (n-6) PUFAs.
\r\n\tMass spectrometry has a significant potential to further advance the clinical analysis and be a diagnostic tool for pathology or being used in the operation room and enable fast detection of tumor's margin.
\r\n\tThis book aims to provide an insight into different application fields of mass spectrometry for clinical research and routine. Modern mass spectrometry enables analysis and quantitation of very complex samples such as serum or tissue proteome or lipidome and the mass spectrometry imaging complements tissue analysis in pathology departments.
\r\n\tFurthermore, mass spectrometry can be used in an operating room as a device for on-site detection of tumor margins and be a valuable help for the surgeon.
\r\n\t
\r\n\tMass spectrometry imaging of tissue is an advanced type of tissue analysis that complements and aids the pathology and the traditional tissue analysis by staining and optical microscopy.
Cardiovascular disease (CVD) is a substantial and growing problem in most of the developing regions of the world. Evidence from experimental, clinical and epidemiological studies has unequivocally pointed to oxidative stress as the key culprit in the pathogenesis of CVD [1, 2]. CVD continues to remain a concern in developed countries and is a growing health concern worldwide. Although death rates from CVD have decreased in many countries due to advances in the field of medicine, the prevalence of CVD risk factors continues to increase. Diet is a centrally important, modifiable risk factor in the prevention of CVD [221-224].
The protection offered by foods is probably mediated through multiple beneficial nutrients contained in these foods, including mono- and polyunsaturated fatty acids, antioxidant vitamins, minerals, phytochemicals, fibre and plant protein. In dietary practice, healthy plant-based diets do not necessarily have to be low in fat. Instead, these diets may include unsaturated fats as the predominant form of dietary fat (e.g., fats from natural vegetable oils and nuts).
Consistent evidence suggests that diets rich in fruit and vegetables and other plant foods are associated with moderately lower overall mortality rates and lower death rates from chronic diseases including CVD [3- 6]. The ‘antioxidant hypothesis’ proposes that vitamin C, vitamin E, carotenoids and other antioxidant nutrients offer protection against CVD by decreasing oxidative damage [7-9]. As evidence began to mount from animal studies and human epidemiological studies on the potential protective effects of antioxidants, excitement in both the lay and medical communities also began to increase.
There has been a global increase in the use of medicinal plants that contain significant amounts of antioxidant-rich oils, offering multiple health benefits with fewer side effects compared to their synthetic counterparts. The idea is that natural compounds, if taken in supplement form, may offer a broad and inexpensive means of decreasing the risk for CVD. Natural products, such as vegetable oils and nuts, may be viewed as a cocktail of active ingredients that often have a synergistic effect on health. The (n-3) PUFAs have been shown in epidemiological and clinical trials to reduce the incidence of CVD. Large-scale epidemiological studies suggest that individuals at risk of coronary heart disease (CHD) benefit from the consumption of plant and marine derived (n-3) PUFAs, although the ideal intake is presently unclear. Overall, in view of the prevalence of CHD, consumption of (n-3) PUFA oils should be considered as a useful complementary option for the amelioration of CVD. Several researchers have shown encouraging findings on the protective effects of some vegetable oils and nuts. However, more research needs to be done with regards to the nutrients in these vegetable oils and nuts to elucidate the protective effects against CVD progression. This chapter focuses on the beneficial roles of antioxidant-rich vegetable oils and nuts in the management of CVD, their mechanisms of action and future prospects.
The term “cardiovascular disease (CVD)” encompasses the major clinical end-points related to the heart and vascular system, including ischaemic myocardium (heart failure and angina), myocardial infarction (heart attack), cerebrovascular disease (stroke), high blood pressure (hypertension), peripheral arterial disease (ischaemia of the limbs), arrhythmias, congenital heart disease and rheumatic heart disease. The facts are unequivocal and disturbing; CVD is the leading cause of death worldwide [10-12].
Chronic diseases are disorders with a long duration and generally slow progression. They comprise four major non-communicable diseases (NCDs) as listed by the World Health Organization (WHO), namely CVD, cancer, chronic respiratory disease and diabetes [13], which are now reaching epidemic proportions in low- and middle-income countries (LIMIC) of the world [14-18]. NCDs constitute the major global health burden of the 21st century [19-20] without discriminating among age groups [21]. Chronic diseases are implicated in 35 million deaths annually worldwide and a large portion of these deaths occurs due to CVD in LIMIC [22].
There is a rising epidemic of NCDs in sub-Saharan Africa (SSA). However, as in other LIMICs, individuals in SSA suffer from the dual burdens of infectious disease and NCDs [22, 23]. Walker and colleagues [24] reported that SSA continues to suffer under the weight of infectious diseases such as HIV and malaria, as well as high rates of undernutrition. Facing these issues in conjunction with the chronic diseases that accompany high rates of overnutrition is a daunting task [25] for the health burden in Africa. SSA has a disproportionate burden of both infectious and chronic diseases compared with other parts of the world [26]. South Africa (SA) is a country of great diversity extending from highly industrialized cities with an urban advanced-economy lifestyle to remote rural areas with more traditional lifestyles. SA, like many SSA countries, is not immune to the NCD epidemic accompanied by the continued burden of undernutrition. In SA, approximately 28% of deaths annually are attributed to infectious diseases, while NCDs account for 25% of the lives lost [27]. The burden of diseases related to NCDs is predicted to rise substantially in SA over the next decade if necessary measures are not in place to combat the trend [28]. WHO estimates the burden from NCDs in SA to be two to three times higher than that in developed countries [13].
Approximately 35-65% of all deaths worldwide occur due to CVDs and death rates exceed these estimated figures owing to malnutrition and infections [29, 30]. CVDs and their risk factors are increasing in SSA [17, 31] with a high prevalence of ischaemic heart disease among men in their sixties followed by women of the same age group [17]. The common potential risk factors for NCDs are tobacco use, physical inactivity and an unhealthy diet, which all lead to CVD, diabetes and cancer [32, 33]. This burgeoning epidemic of NCDs has many root causes. Additional perpetuators of these epidemics are globalization and urbanization [34-37] with abdominal obesity contributing significantly to CVD in the SSA region [38]. Compelling evidence demonstrates a rise in mortality and morbidity from the NCDs in all strata of South African society. Leeder and colleagues [39] estimated that even without changes in the risk factor profile or the mortality rates from CVD, the demographic changes will result in a doubling of the number of cardiovascular deaths in SA by 2040. Chronic diseases such as CVD, obesity and diabetes have therefore become at least as important as infectious disease.
In summary, CVD is a substantial and growing problem in most of the developing regions of the world. The burden of NCD on the African continent and in SA in particular continues to demonstrate the potential for a sustained rise. A significant investment in the health care system and in particular the primary health care system is therefore justified. Further innovative strategies and plans are needed to address the determinants of this disease burden. However, indications still point to the paucity of community-based studies aimed at investigating NCD prevalence, incidence and risk factors. Consistent evidence suggests that diets rich in fruit and vegetables and other plant foods are associated with moderately lower overall mortality rates and lower death rates from chronic diseases including CVD [3-6]. The ‘antioxidant hypothesis’ proposes that carotenoids, polyphenols, vitamin C, vitamin E and other antioxidant nutrients afford protection against CVD by decreasing oxidative damage [7-9]. As the evidence began to mount from animal studies and human epidemiologic studies on potential protective effects of antioxidants, excitement in both the lay and medical communities also began to increase. The idea that natural compounds, if taken in supplement form, may offer a broad and inexpensive means of decreasing the risk for CVD and other age-related diseases is a very attractive hypothesis. Enthusiasm has grown to the point where people around the globe have become aware of the need to consume a diet with a high content of fruit and vegetables.
Indeed, evidence from experimental, clinical and epidemiologic studies has unequivocally pointed to oxidative stress as the key culprit in the pathogenesis of CVD [1, 2, 40, 41]. CVD continues to remain a significant problem in developed countries and is a growing health concern worldwide. Although death rates from CVD have decreased in many countries, due to advances in the field of medicine, the prevalence of CVD risk factors continues to increase. Diet is a centrally important, modifiable risk factor in the prevention of CVD [221-224].
Oxidative stress is common in many clinically important cardiac disorders, including ischaemia/reperfusion (I/R) injury, diabetes and hypertensive heart disease [42-46]. Several animal models suggest that when endogenous anti-oxidant systems are compromised, as is the case under oxidative stress conditions, exogenous antioxidant supplementation can be used for preventive and/or therapeutic intervention of CVD [42, 43, 47-49].
Fats are the most concentrated form of energy for the body. They also aid in the absorption of fat-soluble vitamins (A, D, E and K) and other fat-soluble biologically active components [50]. Chemically, most of the fats in foods are triglycerides, made up of a unit of glycerol combined with free fatty acids, each of which may be the same or different. Other dietary fats include phospholipids, phytosterols and lipoproteins associated with cholesterol [50-52]. A balanced diet, including oils and fats that supply energy and essential fatty acids is needed for good health.
The different types of fatty acids are the most important characteristics of dietary fats. According to the degree of unsaturation (double bonds and hydrogen content), fatty acids are largely classified into three major types: saturated fatty acids, monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA). A fourth form, the trans fatty acids, are mainly produced by partial hydrogenation of polyunsaturated oils in food processing but also occur naturally in animal foods in small amounts [53].
Fatty acids consist of a hydrocarbon chain with a hydrophobic methyl group at one end and a hydrophilic carboxyl group at the other end. Greek letters (α, β, γ, ω) have been used to identify the location of the double bonds in fatty acids. The “alpha” carbon is the carbon closest to the carboxyl group. The methyl group of the molecule is also referred to as the omega end and the terminal carboxyl group is located at the delta end. Current chemical numerical terms number the carbon chain form one to “n”, with n being the last carbon at the methyl end. The terms “n” and “omega” are synonymous [54].
Saturated fatty acids contain no double bond; they are fully saturated with hydrogen. The main saturated fatty acids are lauric acid (C12:0), myristic acid (C14:0), palmitic acid (C16:0) and stearic acid (C18:0). Saturated fats are found in animal-based products, such as milk, cream, butter and cheese, meat from most land animals, palm oil and coconut oil, as well as manufactured products made from these, such as pies, biscuits, cakes and pastries [55].
MUFAs are predominant in vegetable oils, such as olive oil, canola oil and peanut oil and are also found in high proportions in animal fats [56]. Much of the interest in the role of MUFA in the prevention of coronary heart disease (CHD) stems from the observed beneficial effects of the Mediterranean diet [57], which includes high consumption of olive oil. MUFAs are less susceptible to oxidation when compared to PUFAs. This in turn leads to increased availability of antioxidants in the active form and better stability of olive oil [58-61]. Olive oil also contains some antioxidant micronutrients, namely polyphenols and squalene [58, 62-64]. The main MUFA in the human diet is oleic acid (C18:1n-9), which has one double bond. MUFA intake has been associated with a slight cardioprotective effect [65]. MUFAs are known to have a beneficial effect on the serum lipid profile and thus decrease the risk of CVD [66-68]. Furthermore, these fatty acids are stable in oxidative stress conditions and are less likely to react with reactive oxygen species (ROS) when compared with PUFA [58-59]. However, studies reporting associations between dietary intake of MUFAs and CHD risk have been inconclusive [69-71].
PUFAs are naturally occurring endogenous substances, present in almost all tissues and are essential components of all mammalian cells. They are essential for survival and cannot be synthesized in the body. Hence, they have to be obtained in our diet and are therefore essential [54, 72]. There are two types of naturally occurring PUFAs in the body, the (n-6) PUFAs derived from linoleic acid (LA, C18:2) and the (n-3) PUFAs derived from α-linolenic acid (ALA, C18:3). They are categorized depending on the location of their first double bond: (n-3) PUFAs have their first double bond located at the third carbon molecule and (n-6) PUFAs at the sixth. Both of these two forms of PUFAs are metabolized by the same set of enzymes as their respective long-chain metabolites [73]. The differences between (n-3) and (n-6) PUFAs are shown in Table 1 below.
Vegetable oils are the predominant sources of alpha linolenic acid (ALA). ALA is found in legumes, flax seeds, walnuts, pinto beans, soybeans and spinach [74]. Dietary intake of ALA among Western adults is typically in the range of 0.5–2g/d [75]. The (n-6) PUFA is the main PUFA in most Western diets and is typically consumed in greater amounts than ALA [75, 76]. The evidence for a beneficial role of dietary (n-6) PUFAs is less convincing and for the purpose of this chapter we will focus on the (n-3) PUFA. The three main forms of (n-3) PUFAs are ALA, eicosapentaenoic acid (EPA, C20:5 n-3) and docosahexaenoic acid (DHA, C22:6 n-3) [77], with ALA being the simplest form. The (n-3) PUFAs are a family of biologically active fatty acids. The simplest member of this family, ALA, can be converted to the more biologically active and very long-chain (n-3) PUFAs; EPA and DHA. This process, as shown in Figure 1, occurs by a series of desaturation and elongation reactions, with stearidonic acid being an intermediate in the pathway [54, 75, 78].
Research has shown that long-chain (n-3) PUFAs protect against CVD [77, 79-82]. The cardioprotective effects of (n-3) PUFAs have long been recognized. Epidemiologic data suggest that (n-3) PUFAs derived from fish oil reduce CVD. Fish oil is a rich source of EPA (C20:5 n-3) and DHA (C22:6 n-3) (Table 1) [67, 83, 84]. The cardioprotective roles of these two forms of (n-3) PUFA are extensively reviewed by Bester and co-workers [48]. Fish oil may also reduce mortality after a cardiovascular incident, as it plays a role in reducing potentially fatal arrhythmias ([85-87]. There are several prospective studies relating the use of fish or the intake of long-chain (n-3) PUFAs to lower risk of CVD [88, 89]. Long chain (n-3) PUFAs have several beneficial cardiovascular properties, including antiatherothrombotic, antiarrhythmic, anti-inflammatory, antihypertensive and triglyceride lowering [81, 90, 91]. In summary, studies investigating the dietary roles of fatty acids demonstrate that dietary supplementation with (n-3) PUFAs decreases cardiac deaths, nonfatal cardiovascular events and all-cause mortality. These benefits are most apparent in high-risk patients. (n-3) PUFA supplementation appears to confer additional benefits in patients eating a Mediterranean diet.
The original observation is from almost 57 years ago, when Hugh M. Sinclair [92] published his observations on the negative effects of essential fatty acid deficiency on CVD. He strengthened his hypothesis by noting the low mortality rate from CHD (coronary heart disease) in Greenland Eskimos, a population consuming a high fat diet, but rich in (n-3) PUFAs [92]. Clinical studies suggest that (n-3) PUFAs reduce mortality from coronary heart disease and the rate of sudden cardiac death [92-95]. Significant antiarrhythmic effects of (n-3) PUFAs were observed in some but not all human studies on atrial fibrillation [96, 97]. In addition, animal studies show strong antiarrhythmic effects of (n-3) PUFAs [98-102].
\n\t\t\t | \n\t\t\t\t(n-3) PUFA\n\t\t\t | \n\t\t\t\n\t\t\t\t(n-6) PUFA\n\t\t\t | \n\t\t
\n\t\t\t\tMolecular structure\n\t\t\t | \n\t\t\tFirst double-bond on the third carbon counting from the methyl end (the “nth” carbon) | \n\t\t\tFirst double-bond on the sixth carbon counting from the methyl end (the “nth” carbon) | \n\t\t
\n\t\t\t\tTypes\n\t\t\t | \n\t\t\tα-Linolenic acid (ALA) [C18:3] Eicosapentaenoic acid (EPA) [C20:5] Docosahexaenoic acid (DHA) [C22:6] | \n\t\t\tLinoleic acids (LA) [C18:2] Arachidonic acid (AA) [C20:4] | \n\t\t
\n\t\t\t\tFood sources\n\t\t\t | \n\t\t\tFlaxseed oil (ALA) Canola oil (ALA) Soybean oil (ALA) Oily fish (EPA/DHA) Fish oil capsules (EPA/DHA) | \n\t\t\tCorn oil(LA) Soybean oil (LA) Sunflower oil (LA) Poultry (AA) Meats (AA) | \n\t\t
Molecular structure, types and food sources of (n-3) and (n-6) PUFAs.
The biosynthesis of (n-3) PUFA.
Long-chain (n-3) PUFAs are important constituents of all cell membranes and confer on membranes properties of fluidity and thus, determine and influence the behaviour of membrane-bound enzymes and receptors [103-107]. These PUFAs are found in abundance in the myocardium, retina, brain and spermatozoa, and are essential for the proper functioning of these tissues and growth, being important modulators of many physiological processes. The fact that these tissues have developed the cellular machinery to preferentially incorporate these minor dietary components into their membranes suggests that these PUFAs play a role in the proper function of the cell [108-110].
The fatty acid composition of myocardial membrane phospholipids, in particular, is sensitive to the type of fatty acid consumed in the diet. Studies show that indeed the myocardium and myocardial membrane phospholipids are rich in (n-3) PUFAs after fish oil consumption [111,112]. Diet-induced changes in the PUFA composition of a cell membrane have an impact on the cell’s function, partly because these fatty acids represent a reservoir of molecules that perform important signalling roles within and between cells. In particular, dietary (n-3) PUFAs compete with dietary (n-6) PUFAs for incorporation into all cell membranes [113,114]. (n-3) PUFAs modulate the expression of adhesion proteins such as selectins [115] and exert an effect by modulating the intracellular signalling pathways associated with the control of transcription factors (e.g., nuclear factor-κB) and gene transcription [116,117]. Research has shown that enrichment of monocyte membranes with (n-3) PUFAs results in the synthesis and secretion of reduced quantities of cytokines (e.g., tumour necrosis factor-α, interleukin-1β) that are involved in the amplification of the inflammatory response [117,118]. Therefore, at a cellular level, (n-3) PUFAs from fish oils can directly or indirectly modulate a number of cellular activities associated with inflammation.
Polyphenols constitute one of the most numerous and ubiquitously distributed groups of plant secondary metabolites, with more than 8000 phenolic structures currently known. Natural polyphenols can range from simple molecules (phenolic acids, phenylpropanoids, and flavonoids) to highly polymerised compounds (lignins, melanins, tannins), with flavonoids representing the most common and widely distributed sub-group [119]. These secondary plant metabolites are known to have potential antioxidant activity and radical scavenging capacity [120-124]. Polyphenols are gaining increased importance due to their beneficial effects on health. Flavonoids are the most abundant polyphenols in our diets. They can be divided into several classes according to the degree of oxidation of the oxygen heterocycle: flavones, flavonols, isoflavones, anthocyanins, flavanols, proanthocyanidins and flavanones [125]. A complication of the epidemiological observations regarding members of the flavonoid family is that subtle differences in their chemical structures can translate into marked differences in their absorption, metabolism and bioactivities [126]. South African herbal teas, rooibos (Aspalathus linearis) and honeybush (Cyclopia ssp.) are currently gaining popularity worldwide [127, 128], owing to their anti-oxidant, anti-cancer and anti-mutagenic properties [129-131]. Rooibos is a herbal tea made from the leaves and stems of the indigenous South African plant, Aspalathus linearis (Brum.f) Dahlg. (family Fabaceae; tribe Crotalarieae) [132,133]. Research has demonstrated that this herbal tea is rich in flavonoids [127, 134]. Animal studies that have investigated the cardioprotective effects of natural or synthetic flavonoids have focused mainly on the acute pharmacological activity of these compounds. For example, in vivo studies using animal models have reported acute cardioprotection obtained from intravenous injections of natural or synthetic flavonoids [135,136].
Natural vitamin E is composed of eight chemical compounds: α-, β-, γ- and δ-tocopherols and their corresponding tocotrienols. α-Tocopherol is the most active form of vitamin E in vitro. The tocopherols are saturated forms of vitamin E, whereas the tocotrienols are unsaturated and have an isoprenoid side chain. Tocopherols possess a chromanol ring and a 15-carbon tail. The presence of three trans double bonds in the tail distinguishes tocopherols from tocotrienols [137-139]. This may account for the differences in their efficacy and potency in vitro and in vivo [140,141].
Red palm oil (RPO) is a rich source of vitamin E. It contains 560–1000 parts per million of vitamin E, of which approximately 18–22% are tocopherols and 78–82% tocotrienols [142-144]. RPO has been shown to offer protection against I/R injury [42, 43, 47, 48] leading to a reduction in oxidative stress [145]. It has also been suggested that palm oil may have some anti-arrhythmogenic effects, which may reduce sudden death after ischaemic incidents [146].
Of all the vegetable oils, RPO has the highest content of tocotrienols with γ-tocotrienol the most abundant. This form of vitamin E has been demonstrated to reduce cholesterol production and platelet aggregation [147-151]. RPO may also exert a neutral or positive effect on the serum lipid profile through the effects of its fatty acid composition and tocotrienols [152-155]. Investigations into vitamin E showed that tocotrienols are more potent than tocopherols as antioxidants. The tocotrienols present in palm oil have been shown to offer protection from myocardial I/R injury in an isolated perfused rat heart model [156, 157]. Animal studies with tocopherols and tocotrienols that investigate these compounds’ potential against chronic diseases are extensively reviewed by Aggarwal and co-workers [158]. These authors argue that the evidence overwhelmingly suggests that tocotrienols may be superior in their biological properties than tocopherols and that their anti-inflammatory and antioxidant activities could prevent CVD among other chronic diseases.
Carotenoids are nature’s most widespread pigments, well known for their orange-red to yellow colours, which they impart to many fruits and vegetables. These fat-soluble phytochemicals have also received substantial attention because of their provitamin A and antioxidant roles [159]. Carotenoids are polyenoic terpenoids with conjugated trans double bonds. They include carotenes (β-carotene and lycopene), which are polyene hydrocarbons and xanthophylls (lutein, zeaxanthin, capsanthin, canthaxanthin, astaxanthin and violaxanthin) that have oxygen in the form of hydroxy, oxo, or epoxy groups [160]. The majority of the 600 carotenoids found in nature are 40 carbons in length and may be pure hydrocarbons, called carotenes, or possess oxygenated functional groups, in which case they are called xanthophylls [161]. The long-chain conjugated polyene structure accounts for the ability of these compounds to absorb visible light, but also makes them quite susceptible to oxidation. This latter property is closely related to their ability to act as antioxidants [162].
The properties and therefore functions of a carotenoid molecule are primarily dependent upon its structure and hence its chemistry [163]. In particular, the conjugated C = C double bond system is associated with energy transfer reactions, such as those found in photosynthesis [164]. In human plasma and tissues, several carotenoids have been well characterized including cyclic (such as β-carotene and α-carotene) and acyclic carotenes (such as lycopene and phytoene), together with a number of xanthophylls (such as zeaxanthin, lutein and beta-cryptoxanthin), all of which can be directly derived from dietary sources [165]. Carotenoids have generated considerable interest as several studies have suggested an inverse association between the dietary intake of carotenoids and the risk for CVD [166, 167]. Conversely prooxidant roles of these phytochemicals have also been reported [168-170].
As mentioned earlier, RPO supplementation does offer protection against myocardial I/R injury via several suggested mechanisms. Amongst the proposed mechanisms are the NO–cyclic GMP pathway, phosphorylation of mitogen-activated protein kinases and scavenging of deleterious reactive oxygen species by RPO [42, 43, 47, 48].
Investigations concerning (n-3) PUFAs show that these forms of essential fatty acids reduce the risk of sudden cardiac death as well as fatal and nonfatal myocardial infarction [171-173]. A number of mechanisms have been implicated in the protective effects of (n-3) PUFAs [174, 175]. The (n-3) PUFAs have been demonstrated as altering the transcription of specific genes. These effects are mediated by a variety of mechanisms that involve indirect (i.e., by eicosanoids, hormones) and direct nuclear effects on genes. The PUFAs (i.e., both (n-3) and (n-6) PUFAs) modulate the expression of genes involved in lipogenesis, glycolysis, production of glucose transporters, inflammatory mediators, early response genes and genes for cell adhesion molecules [176, 177].
The primary source of MUFA that lowers cholesterol levels is olive oil [178, 179]. It is evident that olive oil, due to its micronutrient content and fatty acid composition, can play a vital role in maintaining beneficial serum lipid profiles. Together with its ability to reduce systemic oxidative stress, blood pressure and inflammation, it has become an appropriate dietary supplement for lowering the risk of CHD.
Nuts are highly nutritious and of prime importance for people in several regions in Asia and Africa. Most nuts contain a great deal of fat (e.g., pecan 70%, macadamia nut 66%, Brazil nut 65%, walnut 60%, almonds 55% and peanut butter 55%). Most have a good protein content (in the 10–30% range) and only a few have a very high starch content [180]. Many nuts have also been identified as especially rich in antioxidants [181, 182]. Nuts therefore constitute one of the most nutritionally concentrated kinds of food available. Most nuts, left in their shell, have a remarkably long shelf life and can conveniently be stored for winter use [183]. Nuts are foods rich in fat, ranging from 46% in cashews and pistachios to 76% in macadamia nuts and provide 20–30 kJ/g per nut. Despite their high fat content, they are not harmful because they contain a low proportion (4–16%) of saturated fatty acids. Nearly one half of the fat content of nuts consists of unsaturated fatty acids, including both mono- (oleic acid) and poly- (linoleic and α-linolenic acid) unsaturated fatty acids (MUFA and PUFA respectively). The fatty fraction of nuts also contains plant sterols with anti-oxidants [184] and cholesterol-lowering effects [185]. Nuts are also rich sources of other bioactive macronutrients, such as protein (25% of energy) and dietary fibre, which ranges from 4 to 11g/100 g and in standard servings provide 5–10% of daily fibre requirements. They also contain significant micronutrients (Table 2), among them folate [185] antioxidant vitamins (e.g., tocopherols) and phenolic compounds [183].
\n\t\t\t\t | \n\t\t
Composition of Nuts (data from the US department of agriculture nutrient database)
By virtue of their unique composition, nuts are likely to benefit modern cardiovascular risk biomarkers, such as LDL oxidizability, soluble inflammatory molecules and endothelial dysfunction. The complex pathophysiology of atherosclerotic disease has evolved beyond the accumulation of cholesterol in the arterial wall. A series of circulating, functional, structural and genomic biological markers that reflect arterial vulnerability have been proposed as potential novel risk factors for the development of CVD (Vasan, 2006). Among them, biomarkers for oxidation [186], inflammation [187] and endothelial dysfunction [188] have received increasing attention.
Studies had shown that whole, unprocessed and unpeeled nuts have a unique composition that consists of important macro- and micronutrients, which give nuts their multiple beneficial effects on cardiovascular outcomes [189-192]. Most nut constituents have shown beneficial effects when clinically tested, in isolation or as part of enriched foods, for effects on diverse cardiovascular outcomes, including novel risk markers [189-192].
Nuts are important sources of tocopherols and phenolic antioxidants, which protect against LDL oxidation [183]. Walnuts have been shown to contain substantial amounts of melatonin, which contributed to a significant antioxidant effect in an experimental rat model [193]. In addition, a substantial fraction of nut fat comes from MUFAs, which are not susceptible to oxidation. The PUFAs are contained mainly in walnuts and are more susceptible to oxidation. However, nuts are a rich source of many antioxidants, which protect the PUFA in vivo against oxidative modification [194].
Plasma high-sensitivity CRP, an accepted measure for systemic low-grade inflammation, was a secondary outcome in several controlled nut feeding trials conducted in hypercholesterolemic subjects with almonds [195-198] or walnuts [197, 199]. Some of them have demonstrated a CRP-lowering effect [196, 197, 198]. Zhao et al., who used walnuts and walnut oil to enrich the diet in PUFA and especially ALA, showed a decrease in inflammatory markers [197] and proinflammatory cytokine production by mononuclear cells [197].
Endothelial dysfunction is a critical event in atherogenesis and is implicated both in early disease and in advanced atherosclerosis [201]. Short-term feeding studies have shown consistently that diets rich in saturated fatty acids impair endothelial function [181, 202, 203] and that even a single fatty meal rich in saturated fatty acids is followed by transient endothelial dysfunction [204, 205]. These detrimental effects can be counteracted by the administration of PUFA and other nutrients contained in nuts, such as antioxidant vitamins and arginine [179]. Another feeding trial showed that, compared with an isoenergetic Mediterranean diet with similar saturated fatty acid content, a walnut diet attenuated the endothelial dysfunction associated with hypercholesterolemia [199]. Moreover, changes in circulating levels of cellular adhesion molecules critical to leukocyte recruitment on the arterial wall also reflect endothelial dysfunction [201]. Several studies have shown that diets enriched with ALA from walnuts [197, 199, 206] reduce endothelial activation as assessed by decreased plasma cellular adhesion molecules. Walnut feeding also reduced the expression of endothelin-1, a potent endothelial activator in an animal model of accelerated atherosclerosis [207].
As the interest in incorporating nuts into the diet grows, it is important that consumers understand how to include them in a healthy diet without promoting weight gain. They are high-fat, energy dense foods and are therefore a potential threat for contributing to positive energy balance. Numerous epidemiological and clinical studies have shown that nuts are not associated with higher body weight [208, 209] or weight gain [210-215]. This could be attributed along with other potential mechanisms for the high satiety properties of nuts [216]. The enhanced satiety, which is also achieved via other mechanisms such as the decreased eating rate [217], leads to reduced energy consumption and therefore a decreased risk of weight gain and obesity.
Blomhoff et al. [190] argued that the inverse association between nut intake and cardiovascular and coronary heart diseases in epidemiological studies may, or may not, be associated with antioxidants. According to these authors, epidemiologic studies are not ideally suited for studying the role of specific nuts or biological mechanisms. Nevertheless, they are in agreement with findings supporting the theory that a complex and rich mix of nut constituents is able to offer protection against CVD and perhaps other chronic diseases [183].
Epidemiologic and clinical trial evidence has demonstrated the beneficial effect of nut consumption on coronary heart disease and its associated risk factors. The cardioprotective properties of nuts, due partially to their favourable lipid fatty acid profile (rich in unsaturated fatty acids), exceed the LDL-C lowering. Nuts, especially walnuts, contain (n-3) PUFAs, which have been shown to have a favourable impact on multiple factors related to CVD, such as inflammation, platelet function, arrhythmias, hypertriglyceridemia and nitric oxide-induced endothelial relaxation [218]. Nuts are also excellent sources of other bioactive compounds such as vegetable protein, dietary fibre, potassium, calcium, magnesium, tocopherols, phytosterols, phenolic compounds, resveratrol and arginine [179]. This unique nutrient composition explains the benefits of nut consumption for the prevention of CVD through mechanisms of oxidation, inflammation and vascular reactivity.
Investigation of the mechanisms underlying CVD showed that the disease has a complex cause beyond the accumulation of cholesterol on the arterial wall, with enhanced oxidative stress and a prominent inflammatory response. Diet has been shown to be associated with cardiovascular events. PUFAs are essential in our diet because we cannot synthesize them. They are also essential nutrients for optimal health of the cardiovascular, nervous and undoubtedly other organ systems. Dietary (n-3) PUFAs are incorporated into the cellular membranes of all tissues. The extent of incorporation into tissue membranes is dependent on dietary intake. The enrichment of membranes with (n-3) PUFAs can modulate cellular signalling events, membrane protein function and gene expression.
Interest in the possible health benefits of flavonoids has increased owing to their potent antioxidant and free-radical scavenging activities observed in vitro. There is growing evidence from human feeding studies that the absorption and bioavailability of specific flavonoids is much higher than originally believed. However, epidemiologic studies exploring the role of flavonoids in human health have been inconclusive. Some studies support a protective effect of flavonoid consumption in CVD and cancer; other studies demonstrate no effect and a few studies suggest potential harm. More recently, results from human studies provide evidence that rooibos can offer protection against oxidative stress conditions such as CVD [131,219]. In a study by Pantsi et al., the beneficial effects of dietary rooibos flavonoids were observed ex vivo in isolated perfused rat hearts. Epidemiological studies suggest that the beneficial cardiovascular health effects of diets rich in fruit and vegetables are in part mediated by their flavonoid content, with particular benefits provided by one member of this family, the flavonols [49].
Polyphenols are abundant micronutrients in our diet and evidence for their role in the prevention of degenerative diseases is emerging. Bioavailability differs greatly from one polyphenol to another, so the most abundant polyphenols in our diet are not necessarily those leading to the highest concentrations of active metabolites in target tissues. Because there are many biological activities attributed to the flavonoids, some of which could be beneficial or detrimental depending on specific circumstances, further studies in both the laboratory and with populations are warranted.
However, the fatty acid components of nuts may differently influence oxidation processes and this needs to be considered for the synergy or opposition to the effects of constituent antioxidants. There is growing evidence that dietary polyphenols in nuts, tea and wine may have anti-inflammatory effects, mediated by both their antioxidant action and modulation of signal transduction pathways, such as the nuclear transcription factor kB, with ensuing down-regulation of inflammatory genes in endothelial cells and macrophages [220]. The increased diversity and availability of sources of dietary fatty acids will likely allow the continued expansion of food products fortified with these fatty acids, a trend that may result in the attainment of the recommended dietary intake of these nutrients.
Future studies in oils should be carried out in order to elucidate the effects of oils in various models in which effects remain unknown. Little is known about the effects of nuts on a diseased heart. Studies should be performed to test whether nuts may offer protection against the severity or progression of various models of CVD.
Acute ischemic stroke (AIS) remains the second cause of death worldwide [1], despite showing a mortality rate reduction of 1.19% [2]; only in 2017, there were 6 million 167, 291 deaths; 1, 291,000 more with respect to 1997. During the same period, the survival rate increased by 0.02%; this caused an increment in the disability-adjusted life years percentage (DALYs), which went from 4.17 to 5.29% [2].
\nData from the World Health Organization (WHO) indicate that stroke represents the third cause of permanent adult disability worldwide [3], and is present in 90% of survivors. Motor deficits after stroke account for the high rates of long-lasting disability. The most common impairments are related to speech, or language and communication disorders (aphasia and dysphasia), apraxia [4], swallowing, depression, cognitive impairment, and hemiparesis of the contralateral limb [5] characterized by muscle weakness or spasticity in distal rather than proximal muscles [6]. These deficits ultimately cause chronic disability, affecting the ability to work and the patient’s independence and autonomy for performing daily life activities such as dressing or eating, ensuring they will require long-lasting care, which also deteriorates their quality of life and that of the patients’ caregivers.
\nStroke complications represent a considerable economic burden both individually and as a society; such complications are associated with a substantial increase in household expenses related to a higher requirement of medical attention, medication, lost workdays, and payment to external or additional caregivers, and in several cases, physical rehabilitation. It is estimated that the United States alone had an annual expenditure of 45.5 billion dollars during the 2014–2015 period, which is only expected to increase through 2035, according to estimations of RTI international [7].
\nIt is therefore fundamental to revisit the procedures regarding basic and clinical research points of view, as well as the most recent recommendations issued by the American Heart Association/American Stroke Association (AHA/ASA), which endorse multiple-component quality improvement initiatives including emergency department education and multidisciplinary teams with neurological management experience, thus increasing the application of fibrinolytic treatment IV.
\nThe strategies that are currently being studied in search of treatments for cerebral ischemia can be categorized into four areas: clinical care, neuroprotection, neurorestoration strategies, and rehabilitation therapy.
\nThe term neuroprotection is defined as the intentional intervention, either inhibition or modulation, that takes place at a certain point during the ischemic cascade, to intervene in a specific mechanism of damage to prevent tissue injury from increasing during the acute phase of ischemia [8]. The neurorestoration is developed through the stimulation of neurogenesis and neuroplasticity to restore the tissue and functional integrity of the neural tissue.
\nIn the clinical setting, several recanalization strategies have been explored to restore blood flow to the injured area of tissue as soon as possible, to assure the lesser damage and decrease secondary sequelae to the original lesion. Finally, physical therapy has become a rehabilitation tactic that has positively impacted the recovery of patients’ independence, autonomy, and quality of life, which is worth reviewing.
\nCerebral ischemia is caused by an abrupt and sustained occlusion of blood flow to a large artery that unties a series of biochemical alterations that are known as the ischemic cascade, Figure 1 [9]; during the development of such changes, a set of mechanisms that lead to cell death occurs: ionic imbalance and excitotoxicity, oxidative stress, and inflammation [10].
\nKey points to the pathophysiology of stroke.
The reduction of blood flow leads to a depletion in levels of glucose and O2, which alters aerobic metabolism, increasing lactic acid accumulation. Simultaneously, astrocytes use stored glycogen to provide energy to the neurons in the form of lactate [11]; but, because aerobic metabolism is interrupted at this time, lactic acid continues to accumulate, causing lactic acidosis, which causes ionic dysfunction [12]. Ionic alterations, together with Na+/K+ pump inactivity, give rise to neuronal depolarization, which leads to the opening of the Ca2+ channels and the subsequent release of excitatory neurotransmitters such as glutamate, causing increased activation of ionotropic receptors, especially NMDA, increasing the Ca2+ flux into the cell [13].
\nCa2+ is an essential protagonist within the ischemic cascade since it is capable of activating a significant amount of proteins that lead to cell death, and overproduction of free radicals; such proteins are calpains [14], endonucleases [15], calmodulin [16], and A2 phospholipase (Figure 1) [17]. Activation of these proteins leads to a further increase in free radical production and other oxidant species that directly damage structural molecules and activate inflammatory processes [18].
\nThe mitochondria are where the highest production of free radicals takes place; under normal conditions, superoxide anion (O2\n−) and hydrogen peroxide (H2O2) are produced continuously and eliminated by antioxidant enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase [19]. Alternatively, under ischemic conditions, reperfusion provides sufficient substrate for different enzymatic oxidation reactions to take place, causing an overproduction of free oxygen radicals (ROS) and the inactivation of antioxidant enzymes [20]. Concurrently, nitric oxide (NO) increases due to the activation of endothelial and neuronal nitric oxide synthases as a result of increased Ca2+ concentration, NO reacts with ROS and forms a highly toxic peroxynitric acid (ONOOH) [21].
\nFree radicals promote mitochondrial membrane permeability and allow for cytochrome c to be released into the cytosol, where the intrinsic pathway of apoptosis becomes activated, the concentration of free radicals also increases lipid peroxidation and protein denaturalization [22], DNA fragmentation, and activate several signaling pathways that lead to neural death, such as PI3K/AKT [23], Bcl2, p53 [24] and others. From the moment of the occlusion, endothelial cells express damage-associated molecular patterns (DAMPs), produce ROS and adhesion molecules that allow for their activation and that of surrounding mast cells and macrophages, which, as a consequence, release histamine, proteases, TNF-a, and chemokines [25]. The production and release of these molecules promote the blood-brain barrier (BBB) rupturing, thus causing peripheral leukocyte invasion into the injured brain parenchyma [26].
\nMicroglial cells are then activated in the non-perfused region of the brain parenchyma [27], microglial cells acquire phagocytic characteristics and a predominantly pro-inflammatory phenotype (M1), which in turn increases the release of interleukin-6 (IL-6), interleukin 1β (IL-1β), tumor necrosis factor-alpha (TNF-α), NO molecules, and prostanoids [28]. Peripheral immune cells such as neutrophils, B lymphocytes, T lymphocytes, and NK are recruited into the injured tissue, this event is thought to contribute both beneficially by inducing the release of anti-inflammatory cytokines and growth factors, and negatively by increasing the lesion through a sustained release of proinflammatory cytokines and free radicals [29].
\nWithin the process of the ischemic cascade, three points are identified that could classify as strategic to restore neuroprotection (ionic imbalance, excitotoxicity, and inflammation); nonetheless, most neuroprotective drugs act in many of the phases of the ischemic cascade, which is why they cannot be classified into a single step of neuroprotection.
\nEarly diagnosis of stroke is a predictor for better clinical outcomes [30]; therefore, its confirmation is a pressing matter for the treatment to begin as soon as possible from the recognition of symptoms onset [31]. Currently, different strategies for acute ischemic stroke are being used in the clinical setting and are part of the AHA/ASA clinical practice guidelines [32].
\nThe differential diagnosis for stroke includes transient ischemic attacks, seizure, syncope, migraine, and brain tumors [33]. To establish a correct and timely diagnosis and to determine the best course of action, the clinician must rely on laboratory testing [34] (blood glucose is usually high, total cholesterol, LDL, HDL, AST, CPK-MB), and although the gold standard for diagnosis is a cerebral angiography, clinicians try to avoid it by choosing different methods such as imaging testing, including the first-line non-contrast CT scans, CT angiography, MRI, and MRI angiography [32, 35, 36]. In the earliest stages of acute stroke, CT scans are less useful for ischemic stroke diagnosis but can rule out hemorrhagic stroke [36]. Other clinical tests such as EKG, EEG, and the National Institutes of Health Stroke Scale (NIHSS) help establish differential diagnosis and treatment plan [35].
\nSpecific and timely reperfusion treatment is essential to determine the course of the clinical outcome and to improve survival. Once the ischemic etiology has been established, and the patient is stable, treatment should start promptly. Currently, two major therapeutic strategies are being used to treat cerebral ischemia to allow for recanalization and reperfusion. The treatment of choice will depend on time to treatment and etiology of the injury; these therapies are thrombolysis using pharmacological agents and mechanical thrombectomy [35, 37, 38, 39].
\nAt present and still after decades, the FDA only approves the use of recombinant tissue plasminogen activator (rTPA), also known as alteplase, as the sole pharmacological option for recanalization [35, 39]. Alteplase initiates local fibrinolysis when administered intravenously by hydrolyzing the peptide bond in plasminogen to form plasmin [40]. The standard IV dosage is 0.9 mg/kg for 60 min, with a 10% bolus over 1 min within 4.5 h of AIS onset [31].
\nAlthough alteplase is the only drug available for thrombolysis, most stroke sufferers do not receive this drug as treatment. There usually is a delay in recognition of the symptoms and the time window in which rTPA must be administered is from 3 to 4.5 h from onset of symptoms, and benefits diminish over time [39, 41], which is why the new AHA/ASA guidelines recommend not waiting for clinical improvement before administration [32]. Also, not all patients are eligible, since candidates must be ≤80 years of age, without diabetes or stroke history, with an NIHSS score ≤ 25, not currently taking oral anticoagulation, and without radiologic evidence of ischemic injury involving more than one-third of the MCA territory [42].
\nComplications that are associated with its use are limited: BBB integrity alterations, and hemorrhagic transformation, granting that other studies have shown it to be well tolerated by patients using warfarin or other anticoagulants [38], in controversy with the new AHA/ASA guidelines that suggest it should not be administered if the patient received heparin 24 h before [32, 35, 43]. Other drugs are also available, such as aspirin, which must be delivered within 24–48 h after stroke onset. Although the guidelines emphasize that it should not be used to replace mechanical thrombectomy or IV alteplase, aspirin continues to be the choice for secondary prophylaxis [32, 44], even when the 2018 guidelines find no benefit from its use for the treatment of an ongoing AIS [32].
\nFurthermore, the FDA approves of endovascular treatments, which are reported to have a time window of up to 8 hours from the onset of symptoms [38].
\nFor patients with large vessel occlusion, less responsive to rTPA, intra-arterial therapy is recommended, since it leads to higher recanalization rates by being able to infuse the drug directly into the occluded area or the clot itself [35, 45]. About 10% of patients with AIS fall into this category, but only a few centers can perform endovascular procedures in proper conditions [46].
\nAlso, endovascular mechanical thrombectomy using contact aspiration (CA) [47], which has been described before [48], and stent retrievers (SR), especially those of new generations [49], for clot rupturing and aspiration has shown significant benefits in large vessel occlusion [50] regarding clinical outcomes and lower complication rates [49]. Notwithstanding, CA alone, without the use of a SR, is associated with a greater need for rescue treatment, and thus, worse outcomes [51]; the SR might also increase the risk for hemorrhagic transformation and neurological deficit [52].
\nIncreased costs of endovascular treatments, as well as their complexity and need for trained personnel, cause patients to have less access to them. Therefore, exploring new pharmacological therapies should be continued.
\nIn the search to find new alternatives of neuroprotective agents, a great variety of molecules have been explored that affect one or several strategic points of the pathophysiology, and that promise good results; some are mentioned below.
\nDuring the onset of AIS, glucose and oxygen concentrations decrease, and this promotes the activation of adenosine monophosphate-activated protein kinase (AMPK). This process upregulates cellular pathways that control energy metabolism through catabolic pathways such as glycolysis and lipid oxidation to increase adenosine triphosphate (ATP) production and decrease its consumption through the inhibition of gluconeogenesis. Observations have been made regarding the fact that the activation of this enzyme for short periods increases neural survival, but its activation for extended periods will lead to cell death through apoptosis, necrosis, and autophagy [53], which is why several drugs that modulate AMPK activation have been tested recently in search for beneficial effects.
\nTo mention some, metformin has been widely studied for cerebral ischemia since it possesses pleiotropic activity and modulates AMPK activation [54]. In 2016, Zhang et al. administered 7 mg/kg of metformin intraperitoneally to C57BL/6 mice for 7 days, before middle cerebral artery occlusion (MCAO). After MCAO, the authors observed that it induced neuroprotection by reducing infarct size, through lower AMPK, results that were not observed if administered for short periods of 1–3 days before MCAO, or after the occlusion; also, these benefits were not found in the case of reperfusion [55]. Also, the neuroprotective effect of metformin was observed in a global ischemia model in rats; after administration, apoptosis decreased, and mitochondrial biogenesis was induced [56]. Other experiments have demonstrated that metformin has the potential to improve memory and learning through the increase in brain-derived neurotrophic factor (BDNF) and p7056k protein [57]. On the other hand, it has also been implicated in the reduction of IL-6, IL-1β, TNF-α, and adhesion molecule levels, as well as a decrease in neutrophil infiltration [58]. Considering these results, it is crucial to clarify how this modulation is carried out since there is some controversy about the mechanism (Table 1).
\nMain neuroprotective agents in ischemia.
\n
Atorvastatin is a statin that has pleiotropic effects, since it allows angiogenesis and synaptogenesis, increases blood flow, blunts atherosclerotic plaque formation, and provides neuroprotection in cerebral ischemia model [59] by reducing aquaporin 4 expression (AQP4) [60], thus, preventing cerebral edema and the increase of infarct size. This statin has also been reported to attenuate cognitive deficit [61] through caspase 3 inhibition and avoiding neural death in the CA1 region of the hippocampus.
\nThere is also a great variety of neuroprotective drugs or molecules that act closer by modulating inflammation, through the promotion of an anti-inflammatory microglial phenotype activation; only the most representative will be mentioned below.
\nDRα1 recombinant protein linked to the MOG peptide has demonstrated the ability to decrease macrophage migration and monocyte activation through its binding to CD74, which translates to a reduction in infarct size [62]. It has also been shown that it reduces proinflammatory cytokine expression, such as IL-1β, I-17, TNF-α, and INF-ϒ, as well as lowers T lymphocyte infiltration and promotes a polarization toward an M2 phenotype macrophage activation [63].
\nCop-1 or glatiramer acetate is a copolymer formed by four amino acids (L-alanine, L-lysine, L-glutamic, and L-tyrosine) that has shown to exert neuroprotective effects by being able to reduce infarct size and improve neurological deficit [64]. Cop-1 increases the expression of IL-10, BDNF, Insulin-like growth factor-1 (IGF-1), and neurotrophin (NT-3) in the choroid plexus [65], and the cortex, which stimulates greater neurogenesis [66]. Mangin et al. and their study group obtained similar results; they reported that Cop-1 is capable of reducing COX-2, CD32, TNF-α, and IL-1β, as well as inducing greater neurogenesis and thus, reducing memory loss in mice with cerebral ischemia [67].
\nOn the other hand, food strategies have also been proposed; for example, diet-induced ketosis has demonstrated its neuroprotective effects. Xu et al. observed, in 2017, that the ketogenic diet induced a reduction in infarct size through the overexpression of transcription factors HIF-1α, pAKT, and AMPK [68]; in 2018 Stefanovic, beneficial effects of administering exogenous β-hydroxybutyrate intraperitoneally were also observed in a model of cerebral ischemia induced by endothelin-1 in rats. He reported that the ischemic penumbra cells had a diminished glucose uptake, which translated into less ROS production, astrogliosis, and neuronal death [69]. Ketone bodies or ketosis is worth further exploration since clinical trials in Alzheimer’s patients with mild cognitive decline have shown improvements in verbal memory after being treated with a ketogenic diet [73].
\nDietary administration with docosahexaenoic acid (DHA) has also proven to have anti-inflammatory and neuroprotective effects in cerebral ischemia through the reduction of proinflammatory cytokine expression, such as TNF-α, IL-1β and IL-6; even, a decrease in macrophage and microglial activation and a decrease in leukocyte infiltration to the lesion site [70]. Similar observations were made by Cai et al. who noted that macrophage, neutrophil, and T and B lymphocyte infiltration was significantly decreased, besides stimulating an anti-inflammatory macrophage (M2) activation [71]; DHA is also capable of inducing neurogenesis and angiogenesis [72], which makes it a promising molecule for future experimental research.
\nMany of the cytokines and growth factors that result from immunomodulation processes are directly involved in neurorestoration processes, the latter understood as the set of strategies that seek to reconstruct the affected neural circuits through neuroplasticity or neurogenesis [74].
\nNeurotrophins are a group of proteins that are involved in the maintenance and survival of the central nervous system [75]; this includes BDNF, NT-3, NT-4, NT-5, nerve growth factor (NGF), and IGF-1. Neurotrophins interact with two types of receptors, Trk (tyrosine kinase receptors) and the p75 receptor that belongs to the TNFR receptor family, implicated in apoptosis processes.
\nAmong the most studied neurotrophins are BDNF and NT-3; BDNF is produced by almost all brain cells and is known to participate in processes of proliferation, survival, and neuronal differentiation. Its receptors are widely distributed [76] and activate critical signaling pathways such as PLCγ, PI3K, and ERK, which ultimately lead to phosphorylation and activation of the transcription factor CREB that mediates the expression of genes that are essential for the survival and differentiation of neurons [77]. NT-3 has also been involved in the processes of cell proliferation and differentiation through the notch pathway [78], as well as participating in processes of memory and learning [76].
\nExperiments have shown that the increase of neurotrophic factors in the ischemia model is commonly related to a better functional or memory recovery and that it is usually associated with neurogenesis or neuroplasticity—as in the case of metformin, which showed an increase in BDNF expression and that induced a more significant recovery of memory and learning [57]. Also, Cop-1 was able to induce the increase of BDNF, IGF-1, and NT-3; which correlated with the increase in neurogenesis [65]; and the experiments of Luan et al. showed that patients with cerebral ischemia who presented higher levels of NGF obtained a better functional recovery at 3 months after the ischemia [79].
\nStem cell transplantation has also been linked to better neurological recovery; although clinical trials have not reported the expected results [80], basic research using stem cells has shown an increase in neurological rehabilitation and suggested mechanisms include the overexpression of BDNF and IGF-1 [81, 82], as well as immunomodulatory cytokines like IL-10, which together induce a polarization toward an anti-inflammatory M2 microglial phenotype [83].
\nIn recent years, there has been an increase in the interest of studying how the external environment has a direct effect on the structure and neuronal function, that is, on neuroplasticity [84], and that is why researchers keep studying what kind of external characteristics (specifically physical and social activity) can increase these factors and thereby obtain more significant benefits.
\nIn 2017, Chen et al. explored whether a specific type of environment stimulated the production of BDNF in rats with cerebral ischemia, and what they observed was that physical stimulation increases the expression of neurotrophic factors more than social stimulation and obtains a higher neurological recovery [85]. Mang, on the other hand, observed that the increase in BDNF after an ischemic event is determined by the type of aerobic exercise and the val66met variant of the BDNF gene [86].
\nThe effects on NT-3 have also been evaluated, and the results have been very similar; there is an increase in its levels with physical stimulation after the ischemic event and a more significant functional recovery [87]. Other proteins have also been associated with neuronal plasticity through axonal growth, such as the growth-associated protein 43 (GAP-43), which has been observed to increase when rats with cerebral ischemia undergo fastigial electrostimulation [88].
\nElectrical stimulation directly into the fastigial nucleus (FNS) has proven to be beneficial in a model of MCAO [89]. The mechanism through which FNS has shown to improve walking balance and neurological scores is due to the activation of the PKA/cAMP pathway, suppressing the expression of Rho-Kinase, and through the overexpression of GAP-43 protein [89].
\nIn this sense, experiments continue to be designed to establish the efficacy of training types and times to modulate inflammation, the production of neurotrophins, and the impact on patient mobility, as in the proposal developed by Scalzo et al. [89] that gives rise to the continued development of a well-founded physical therapy for patients with cerebral ischemia.
\nPost-stroke physical rehabilitation (PR) is of utmost importance as a non-pharmacological strategy for neuroprotection and neurorestoration but, most significantly, should be aimed at restoring and regaining motor impairment during the chronic period [90], and to promote the functional autonomy of the patient [4]. Recovery of body function assessment depends on whether the patients can perform everyday activities on their own and is measurable by several different scales such as UE-FM score for the upper extremity, and the Barthel Index for Activities for Daily Living scale [4].
\nFunctional and cognitive deficit severity is related to tissue integrity [91], and it is not clear whether recovery results from biological processes or physical rehabilitation [91, 92]. Some clinical parameters that can be observed at the bedside, such as early finger extension and shoulder abduction, can act as predictors of long-term (over 6 months) recovery after stroke [93]. Spontaneous recovery of upper and lower limbs occurs depending on the type, location, and severity of the lesion, in approximately 60–70% of cases [93] during the first 2–6 months [4, 94], period after which most people believe they have achieved maximal recovery and stop with either physical or pharmacological therapy [4, 95]. Interventions should be designed according to the stage of neurological recovery the patient is in, with the consideration that early chronicity is not a contraindication for continuing rehabilitation [4].
\nPhysical rehabilitation must start early, if possible, during the first week post-stroke [96], because there is an intensification in neuroplasticity during the early stages [91], employing different mechanisms such as the axon regeneration [88], and the higher expression of growth-promoting genes, such as GAP-43. This lesion-induced plasticity that happens during the first days post-stroke [90, 97, 98] reportedly lasts around 6 months after stroke [4, 91, 95, 97]. Also, therapy must continue after such a period, to take advantage of behavior-induced plasticity [95], which is still possible after 1 year of having had the stroke [4].
\nPR has also been proven to elicit neuroprotection and neurorestoration in other neurological disease models, such as Parkinson’s, through the upregulation of BDNF and GDNF and prevention of inflammatory response [99]. The following therapies are currently under study for neurorestorative purposes during the post-stroke chronic period:
\nEnvironmental enrichment focuses on inducing adaptation to different environments, including toys and complex tasks, to improve functional outcomes [97]. Also, this type of therapy has shown to enhance angiogenesis by increasing CD31 and VEGF [97]. Furthermore, environmental enrichment upregulates BDNF secretion, and other neurotrophic factors [85, 90].
\nWang et al. found improvements in spatial learning and memory, number of synapses, and an increase in the expression of synaptogenesis markers. GAP-43, a protein involved in neural plasticity through axonal growth, is upregulated during the first 28 days after stroke in mice exposed to environmental enrichment. Likewise, other markers involved in synaptogenesis like SYN and PSD-95 achieve better concentrations in the brains of mice treated with environmental enrichment [97].
\nFunctional electrical therapy has been used alongside other types of electrical stimulation to induce repetitive muscular contraction to mobilize certain joints [6]. Somatosensory stimulation might enhance neurorehabilitation after stroke through the stimulation of corticomotoneuronal excitability [6]. It has been proposed that this type of therapy increases muscle strength, reduces spasticity, and facilitates voluntary movements, among other motor benefits [6].
\nGuided self-rehabilitation (GSR) is a method in which the intensity of training can be increased inside the home environment. While combined with conventional rehabilitation, it has proven to be efficacious in engaging the patients in their recovery through a contract between the patient and the therapist, allowing for an increased sense of responsibility and motivation for the patients, who are required to register their progress in a diary [100]. Although not many physical therapists accept such an approach [100], positive changes have been observed after 1 year of GSR and conventional rehabilitation in ultrasound measuring of the soleus’ and medial gastrocnemius’ thickness and fascicle length, as well as clinical improvement, observed in soleus extensibility and ambulation speed [101] in chronic stroke patients.
\nConstraint-induced therapy requires constraining the non-affected limb for 90% of the waking hours, forcing the patient to use the paretic limb, inducing the increase of use-dependent plasticity, although this therapy is not practical for most of the population [6].
\nVideogame- or virtual reality-based (VRb) therapies have been under study for upper extremity functional recovery in acute and subacute or chronic patients [91, 96, 99, 102]; the rationale for such approaches is that they promote motor learning and repetitive, intense movements, and in the specific case of virtual reality, the patient is exposed to interactive visual, auditive, and proprioceptive feedback [91, 102]. Different videogame and VRb therapies have reported improvements in fine dexterity, grip strength [96], and grasp force [99] in upper extremities, and, activities of daily living [91] and cognition [102] in young and elderly patients after several weeks of rehabilitation. Better results have been observed when combined with conventional therapy, although it is still not known whether it enhances or speeds up recovery [91].
\nIn addition to continuing the search for pharmacological agents that allow the neuroprotection and neurorestoration of tissue affected by cerebral ischemia, the development of physical therapy and diet modification offers new horizons that have shown satisfactory results in the clinical setting in short times. However, it has not yet been possible to establish a protocolized treatment that can be added to the health care guidelines; so it is important to continue exploring all possible strategies to improve the quality of life of people who have suffered a cerebral infarction and that of their caregivers.
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