2020 Volume 69 Issue 10 Pages 1147-1161
To present a systematic review of published studies in databases such as PUBMED, REDALYC, SCIELO, DIALNET, SCOPUS, EBSCO and CONRICYT related to the role-played by the components present in the vegetable oil of grape seed (Vitis vinífera) and the prevention or delay in the onset or progression of neurodegenerative diseases. The analysis of the research revealed that neurodegenerative diseases causes alterations in consciousness or in the nervous system leading to severe damage in neuronal cells, these pathologies are considered gradual and progressive. Various syndromes manifest the degenerative diseases of the nervous system; in some of them the predominant symptom is the progressive dementia. Among the components of the diet that in numerous epidemiological studies have shown an inverse association are vitamins, minerals, carotenoids, polyunsaturated fatty acids and polyphenols, the latter being the ones addressed in this document. There is an important evidence that a nutritional support based on polyunsaturated fatty acids and antioxidants can be applied to subjects with a history of neurodegenerative conditions in order to act as neuroprotectors. This requires the determination of the nutritional benefits of these nutrients or of nutraceuticals for the health of this group of patients.
The reactive oxygen species (ROS) and free radicals originated in biological systems are capable of oxidizing cellular proteins, nucleic acids, and lipids leading to premature aging, mutagenesis and carcinogenesis 1) . Food vegetable products provide a wide variety of active compounds called secondary metabolites, which have antioxidant, antitumor activity, and immunostimulatory properties 2) ; the deterioration of cells in the human body can occur due to the lipid peroxidation present in aerobic cells, between the interaction of free radicals and polyunsaturated fatty acids, however, it is not the only factor that intervenes 3) , 4) . The Vine seeds (Vitis vinifera L.) have been studied due to their active properties that contain the phenolic compounds, flavonoids, and phenolic acids. Presented substances in the seeds have a variety of biological effects: antioxidants, captures of free radical, anti-inflammatory, antihypertensive, antimutagenic, antineoplastic, antiviral, antibacterial, antiulcer stomach, anti-tumor, healing, anti-hyperglycemic, cardioprotection, anti-hepatoxic or anti eye cataract, and sunscreens; these properties are related to the reactivity of the phenol group and have been tested in vitro, in vivo, in animals and in humans 5) . The phenolic components presented in Vitis vinifera are organic substances with functions of both as immunological defense, and as protection against reactive oxygen species, since they have in their structure one or more aromatic rings which they manage to sequester the free radicals presented its antioxidant activity depends on the number and location of the hydroxyl groups contained in its structure. Grape seed oil contains E vitamin (tocopherols), phenolic compounds, and fatty acids; antioxidants are acting in the prevention of aging, heart disease, and cancer since they prevent reactive oxygen species (ROS) cause damage in to DNA and oxidative reactions carried out by free radicals. According to the analyzes made on the grape seed, it has been determined that linoleic acid (omega-6) is present in the 62.81%, 65.34% for conventional and organic oil, in addition, to other fatty acids such as palmitic acid (C16:0), palmitoleic (C16:1), stearic (C18:0), oleic (C18) ; the content of alpha-tocopherol, delta-tocopherol and gamma-tocopherol have values above the FAO/WHO table (2015), both for organic and conventional oils 6) , 7) . The seeds have monomeric phenolic compounds such as gallic acid, catechin, epicatechin, gallocatechin, oligomers such as procyanidins and anthocyanidins 8) , 9) , 10) , 11) .
Neurodegenerative conditions induce alterations in consciousness or in the nervous system that cause severe damage to neuronal cells, these pathologies are considered gradual and progressive 12) ; degenerative diseases of the nervous system are manifested by various syndromes and in some of them the predominant symptom is progressive dementia 12) , 13) . Now at day, neurodegenerative diseases are classified based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) 14) , within this are Parkinson’s Disease (PD), Alzheimer’s Disease (AD), Huntington’s Disease (HD), Dementia and Amyotrophic Lateral Sclerosis (ALS). All these pathologies have a multifactorial etiology, mainly environmental, of aging; and family history, where the genes involved in each condition have been reported (see Table 1) ; this genetic origin is related to several involved mechanisms, of interaction between genes and molecular pathways 15) , 16) , 17) , 18) , 19) , 20) , 21) , 22) , 23) , 24) , 25) , 26) , 27) , 28) , 29) , 30) .
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Parkinson’s disease (PD) is the most common form of dementia with the highest prevalence in the world after Alzheimer’s disease 31) , 32) ; PD is a neurodegenerative disease characterized by its slow development and manifested around 60 to 85 years old 33) , there are early cases, before 50 years, there are even reports of cases of extreme peculiarity, very early onset, whose appearance oscillates at approximately 20 years. The cardinal signs of PD are akinesia, tremor at rest, stiffness, increased muscle tension and resistance to movement and instability of the posture due to loss of balance, which leads to frequent falls, some other symptoms may occur as bradykinesia and dysarthria 34) , 35) . Alzheimer’s disease (AD) is clinically characterized as a cause of dementia present in senior people, patients may present anxiety and depression. It is a disease whose pathogenesis is complex because it can occur in an inherited way, or in an environmental way as a result of multifactorial aging process. The AD is a neurodegeneration characterized by protein deposits to the neurons, which is the accumulation of amyloid peptide surrounded by degenerated nerve endings, as well as intracellular neurofibrillar alterations due to phosphorylation in the “tau" cytoskeletal protein 36) , 37) , 38) . This accumulation of proteins occurs intracellularly in the “tau" for formed protein and the extracellular accumulation is β-amyloid, both leading to the degradation of neurofibrillar tangles and amyloid plaques, causing inflammation and dysfunction of brain cells 39) , 40) . In addition, oxidative stress in neurodegenerative diseases has been widely described from the reduction of the defense mechanism in the formation of radicals free oxygen in a physiological way derived from mitochondrial respiration, immune response and the reduction of inflammatory processes associated with aging 41) , 42) .
For to genetic causes, mutations in the genes of presenilins 1 and 2 have been described in the gene that codes for the β-amyloid precursor protein, and in the apoE gene. Other risk factors are the presence of head trauma, exposition to chemical compounds, atherosclerosis, osteoarthritis and depression 12) , 13) , 14) , 31) , 32) . Huntington’s disease (HD) is a neurodegenerative disorder that has a characteristic that affects neuroanatomic and neurophysiological to the language, from the moment it is caused by the destruction of a specific subpopulation of gabergic neurons of the caudate nucleus, this process of progressive cell death results in an alteration of motor control and various behavioral and intellectual deficits, which can lead to chronic depression, irritability and aggressiveness 43) , 44) . Genetically speaking, HD is due to an anormal expansion of the CAG triplet in the sequence of the HTT gene which becomes pathogenic when 34 repetitions are exceeded and a direct correlation between the length of the repeated segment and the precocity manifests the disorder 45) . Dementia refers to the severe damage of intellectual functions, dementia disorders are caused by abnormal pathological processes (of a genetic or vascular nature, among others). They can affect both young people and the elderly, the course of dementia in young people usually leads to a much faster cognitive decline even in weeks in contrast to the decline presented in the elderly, which can last for years. An essential characteristic of Dementia consists in the development of multiple cognitive deficits that include memory impairment and at least one of the following cognitive impairments: aphasia, apraxia, agnosia or an impaired ability to perform 46) , 47) , 48) , 49) , 50) . About to Amyotrophic Lateral Sclerosis (ALS), is a degenerative disease of motor neurons, it is characterized by a loss of capacity and motor activity, the main cause is the degeneration of neurons, ranging from damage to upper motor neurons in gray nuclei and cerebral cortex and inferior in the gray columns of the spinal cord and brain stem 51) , 52) , 53) . Some pathological features include thickening of the proximal area of motor axons due to abnormal cross-linking and disorientation of neurofilaments cytoplasmic neuronal inclusions similar to Lewy bodies, fragmentation of the Golgi apparatus, as well as Wallerian axonal degeneration 54) , 55) , 56) .
The pharmacological treatments available for neurodegenerative diseases are symptomatic and do not alter the course or progression of the disease, they also produce adverse reactions in patients, having a limited scope; therefore, it is necessary to develop alternative therapies for the treatment and reduction of the progress of these diseases 57) .
The brain has a high oxidative metabolism that becomes the main target organ when is affected in the state of uncontrolled stress, the high concentration of cortisol not only lead to damage the brain cells, but also accelerate neurodegenerative disorders of the brain, decreasing growth factors, causing the release of proinflammatory cytokines that leads to the presence of oxidative stress. Between 50-60% of the lipids that make up the brain are unsaturated fatty acids that make it susceptible to lipoperoxidation and the formation of secondary compounds such as acrolein, malondialdehyde and isoprostanes 57) . The formation of lipoperoxidation can cause cell dysfunction and the death of neurons, this oxidation causes alterations in the protein structures favoring the development of neurodegenerative diseases, it also has a low concentration of antioxidant enzymes, such as: superoxide dismutase, catalase, and glutathione peroxidase. The production of reactive oxygen species (ROS) by cells of the central nervous system (CNS), occurs through microglia cells considered as CNS macrophages for their ability to remove waste substances and damaged structures, when are activated they release ROS as O2 － and H2O2 as well as a whole series of cytokines, the latter can induce the microglia to release more ROS or produce the expression of the enzyme inducible nitric oxide synthase (iNOS), which produces reactive species derived from nitrogen (nitric oxide) 57) , 58) , 59) , 60) , 61) , 62) , 63) . The oxidative stress of Alzheimer’s disease significantly increases the levels of Malondialdehyde (MDA), as the lipids contained in the brain oxidize, mainly polyunsaturated fatty acids, being more susceptible to oxidative cell damage due to the high level of oxygen consumption and the post- mitotic neurons and form lipid peroxides, the latter are unstable and decompose forming carbonyl compounds, and contribute to the formation of MDA 64) , 65) .
In multiple epidemiological studies the benefits of the antioxidant activity of grape juice have been reported in relation to the reduction of oxidative stress, inflammations, and the protection of diseases such as cancer, cardiovascular diseases, and dermal disorders 66) . In many of them is emphasized that proanthocyanidins are powerful antioxidants that mediate many biological activities, such as anti-inflammatory, anti-diabetic, cardiovascular protections, anti-cancer, antiviral activities, and play a role in immunomodulation 5) .
The vegetable oil from Vitis vinifera has organic acids, mainly malic acid, oxalic acid and tartaric acid 67) ; and polyphenolic compounds that have a classification in six subgroups among which we can find: flavonols, flavones, isoflavones, anthocyanins, flavanones and flavanols, highlighting mainly the so-called flavan-3-oles, particularly catechin and epicatechin, these are associated with inhibition of arterial thrombosis, anti-inflammatory activity, reduction of total cholesterol and lipoprotein low density in vivo as part of its antioxidant capacity. In addition, the oil contains resveratrol, it is known that resveratrol inhibits the nuclear factor κB, involved in the toxicity of β-amyloid which is responsible for generating Alzheimer’s disease 68) , 69) . This same compound has proven to be a repressor of the p53 gene, thus preventing neuronal apoptosis and its oxidative damage, there is evidence that treatments with resveratrol decreases brain damage caused by ischemia, hemorrhages, seizures and epilepsy, thus serving as an alternative to the treatment and prevention of neurodegenerative conditions such as Alzheimer’s disease, Parkinson and Huntington 70) , 71) , 72) , 73) , 74) . Bazan in 2016, showed that Vitis vinifera oil contains as a major component omega-6, functioning as well as a platelet antiaggregant preventing thrombotic diseases or strokes 75) .
However, one of the aspects to consider in the ingestion of Vitis vinifera is its assimilation in the organism, mainly because resveratrol is rapidly metabolized (less than 2h) in the liver and intestinal epithelial cells in glucuronic acid conjugates and of the phenolic sulfate group that are then eliminated 73) , 76) , because resveratrol has a low bioavailability that limits its biological and pharmacological benefits, the whole process that this compound has to go through the blood brain barrier to reach the brain where it is. It has demonstrated its neuroprotective effects. Therefore, methods with greater assimilation in the organism, of this compound, have been developed in recent years through nanotechnology as described by Loureiro, In which they developed a targeted therapeutic system for intravenous administration of resveratrol and extracts of Seed and grape skin using solid lipid nanoparticles by crossing the blood-brain barrier in an in vitro model, demonstrating that the synthesized nanoparticles are capable of encapsulating the extracts and can be functionalized to cross the barrier 40) .
Studies have been conducted in animals and in vitro models with promising results of the use of Vitis vinifera as shown in Table 2 40) , 70) , 71) , 72) , 73) , 74) , 75) , 76) , 77) , 78) , 79) , 80) , 81) , 82) , 83) , 84) , 85) , 86) , 87) , 88) , 89) , for example, in the study conducted by Borai et al. 68) , it was shown that polyphenol-based treatment has a beneficial therapeutic effect against the neurobehavioral and neurochemical changes associated with Alzheimer’s dementia, through regression in the neurodegenerative characteristics of dementia from Alzheimer in the rat model intoxicated with Al, induced by AlCl3 by reducing brain damage and improving functional outcome, in the Behavioral T maze test and confirmed by kite testing and histopathological investigations. Also, Ma and collaborators in animal models observed that the polyphenols of the flavones of Vitis vinifera, can promote synaptic plasticity and indirectly affect the expression of cholinergic neurotransmitters, which can be a mechanism of Vitis vinifera protection in rats with Alzheimer’s disease by improving protein expression of p-CREB, BDNF and SYT1 in hippocampus rat, depending on the dose 76) .
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In the study conducted by Li and collaborators reported that the selected grape seed polyphenol extract can adequately interferes with the assembly of tau peptide in neurotoxic aggregates, in addition to a significantly slowing of the development of Alzheimer’s tau neuropathology in the mouse model brain TMHT of AD through mechanisms associated with the attenuation of the signal kinase 1/2 of the extracellular signal receptor in the brain 90) . Also, they reported in previous studies of in vitro physical biochemistry and in vivo preclinical studies where grape seed polyphenol extract interfering with tau fibrillation and attenuate tau phosphorylation mediated by ERK1/2 in Thr181 and Ser396/400/404. Therefore they suggest that grape seed polyphenol extract is highly tolerated in rodents and humans, being bioavailable in the brain 90) .
As final considerations, we can say that today the main sources of polyunsaturated fatty acids of the omega-3 type could act as antioxidants are cold-water fish, however, environmental conditions have caused a decrease in the recommendation of the consumption; together with the adoption of lifestyles characterized by high consumption of tobacco, presence of heavy metals in food and beverages, alcohol, and sedentary lifestyle, has caused an increase in the diseases that now, we consider public health problems. This has led to look for new alternatives, the most viable is the consumption of vegetable origin oils present in a greater availability to the population, and at lower cost, in addition to the fact that among their nutritional properties they are free-cholesterol, trans-type fats, and not interact with other nutrients. The consumption of grape seed oil can be considered as a prevention and treatment option in neurodegenerative or cardiovascular diseases, the mechanism of action, tissue specificity, administration dose, and duration of this treatment has not yet been understood, it is an objective that should be proposed in the medium term, in view of this, they require a greater number of investigations that significantly could determine the nutritional benefits of these nutrients, or of nutraceutical foods for the health of the population.
The authors declare no conflict of interest.
