Punicic Acid And Its Role in The Prevention Of Neurological Disorders: A Review Part 1

Abstract: 

Millions of people worldwide are affected by neurodegenerative diseases (NDs). NDs are characterized by progressive damage and death of nerve cells accompanied by high levels of inflammatory biomarkers and oxidative stress conditions. 

Neurodegenerative diseases, such as Alzheimer's disease and dementia, are common diseases we face today. These diseases will cause neuron death and brain cell atrophy in the patient's brain, causing cognitive decline. Memory is one of the most significantly affected areas.

However, even in the face of these disease threats, we should not give up investing in and working on our mental health. Research shows that an active lifestyle, mental health, and intellectual exercise can delay the progression of neurodegenerative diseases to a large extent and maintain good memory.

For example, aerobic exercise and brain training can improve brain structure and function and delay cognitive function degradation. A nutritious, balanced diet, adequate sleep, and social interaction are also important factors in maintaining good health and can help prevent neurodegenerative diseases and preserve memory.

Other scientists believe that both self-efficacy and emotional balance can help us retain our memory. For example, seeing ourselves solve a problem or accomplish a goal makes us feel more confident and happy, and these feelings can help us maintain our mental health, which in turn helps maintain good memory.

In daily life, we can also perform some simple training to help improve memory. For example: remembering phone numbers, birthdays, names, and other information, reading articles aloud, and recalling the contents are all very effective methods.

Although neurodegenerative disease is a serious disease, it also reminds us to maintain good living habits and a positive attitude to ensure our mental health and memory, and make our lives healthier, more fulfilling, and better! It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory because Cistanche deserticola is a traditional Chinese medicinal material that has many unique effects, one of which is to improve memory. The efficacy of Cistanche deserticola comes from the multiple active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health through a variety of pathways.

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Punicic acid, the main bioactive component of pomegranate (Punica granatum) seed oil, is an omega-5 isomer of conjugated α-linoleic acid that has shown strong anti-oxidative and anti-inflammatory effects that contribute towards its positive effect against a wide arrange of diseases. Punicic acid decreases oxidative damage and inflammation by increasing the expression of peroxisome proliferator-activated receptors. 

In addition, it can reduce beta-amyloid deposit formation and tau hyperphosphorylation by increasing the expression of GLUT4 protein and the inhibition of calpain hyperactivation. Microencapsulated pomegranate, with high levels of punicic acid, increases antioxidant PON1 activity in HDL. Likewise, encapsulated pomegranate formulations with high levels of punicic acid have shown an increase in the antioxidant PON1 activity in HDL. 

Because of the limited brain permeability of punicic acid, diverse delivery formulations have been developed to enhance the biological activity of punicic acid in the brain, diminishing neurological disorders symptoms. 

Punicic acid is an important nutraceutical compound in the prevention and treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease.

Keywords: antioxidant; conjugated linoleic acid; blood–brain barrier; Alzheimer's disease; Parkinson's disease; Huntington's disease; neurodegeneration.

1. Introduction

Some of the most prevalent diseases that can cause loss of independence in older populations are neurodegenerative diseases (NDs), which are becoming more frequent. The neurodegenerative process is the progressive loss of function or death of central nervous system cells, causing an increase in motor and cognitive impairments with time [1]. 

Among the most prevalent NDs are Alzheimer's Disease (AD) and frontotemporal dementia, Parkinson's Disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), and multiple spinocerebellar ataxias. AD incidence in the population aged 85 and over is about 30%, while PD is around 2% in people above 65 years old, and ALS reported 1–2 cases per 100,000 people yearly, and the incidence is expected to soar as the population ages [2]. 

Therefore, there is a need for the implementation of new preventive measures and the development of novel treatments for the early stages of neurodegeneration. The World Health Organization estimates that the global social cost of dementia is USD 818 billion, equivalent to 1.1% of the world's gross domestic product. The prevalence of AD in Latin America is as high as 8.5%. 

Moreover, it is expected that by 2030 about 65.7 million will live with dementia and around 115.4 million by 2050 [3]. The mortality and people's disability caused by these neurological disorders have increased, hence, considering them a global public health challenge. As the incidence is expected to soar as the population ages, finding new solutions and strategies for the treatment of neurodegenerative diseases is a goal of increasing urgency. Because oxidative damage and inflammation are key pathways in the development of neurodegeneration, phytochemicals with elevated antioxidative and anti-inflammatory properties are being investigated to aid in the prevention of neurodegeneration and halt disease progression. 

The pomegranate (Punica granatum) is an ancient and adaptable fruit originally from Western Asia that belongs to the Punicaceae family. It is cultivated throughout the world, including Middle Eastern, Asian, European, and American countries, mainly in subtropical and tropical areas under variable climatic conditions [4,5]. Approximately 50% of the total weight of the fruit corresponds to the peel, which is an important source of phenolic compounds, minerals, and complex polysaccharides. Meanwhile, the edible part of the pomegranate fruit consists of arils (40%) rich in water, sugars, pectin, and seeds (10%) [6]. 

Pomegranate seeds contain many components such as polyphenols and fatty acids that contribute to their beneficial effects. Pomegranate Seed Oil (PSO) represents around 12% and 20% of the total seed weight [7]. PSO contains 14 fatty acids, the most abundant of which is punicic acid 50–80% [7–9], followed by linoleic acid (13–20%), palmitic acid (6–9%), stearic acid (2–3%), oleic acid (8–9%), linolenic acid (0.06–0.08%), and arachidic acid (0.68–0.90%) [9]. 

Punicic acid, PSO's main bioactive component, was shown to achieve a potent anti-oxidative effect that contributes towards its positive effect against a wide range of diseases such as osteoporosis, has anti-obesity properties, increases the expression of antioxidant and lipid metabolism-related genes, and modifies the composition and function of high-density lipoprotein (HDL) [10–13]. 

Punicic acid is an omega-5 isomer of conjugated α-linolenic acid (CLnA) and exhibits structural similarities to conjugated linoleic acid (CLA) [12]. By itself, punicic acid possesses a wide spectrum of biological effects such as anti-inflammatory, anti-diabetic, anti-obesity, anti-proliferative, and anti-carcinogenic properties [14,15]. The main biological mechanism described for punicic acid involves the modulation of the differential expression of peroxisome proliferator-activated receptors (PPARs), which control the expression of genes involved in cell differentiation and proliferation, regulate enzymes involved in lipids metabolism, and glucose homeostasis. 

In addition, PPARs are closely related to the activation and production of pro-inflammatory biomarkers [16–19]. While the antioxidant and anti-inflammatory properties of punicic acid may provide beneficial effects on the treatment of NDs, the way it interacts in different pathways related to the progression of NDs may give it advantages over other anti-oxidative nutraceuticals. 

This review aims to present an overview of the current knowledge about the potential benefits of punicic acid in neurological disorders and the molecular mechanism involved in its effects.

2. Main Pathways Involved in Neurological Disease

Even though all NDs have different pathology and symptomatology, their pathways share some common traits. A conceptual model classifying the different pathways involved in neurodegeneration was developed considering four major models of action [20] (Figure 1). 

In general, pathways that contribute to neuron survival and degeneration include: (1) intracellular mechanisms such as apoptosis [21], autophagy [22], mitochondrial function, oxidative damage, and repair [23], ubiquitin/proteasome [24], (2) local tissue environment such as cell adhesion [25], endocytosis, neurotransmission [26], prions/ transmissible factor [27], (3) systemic environment such as inflammation/immune response [28], lipid/endocrine metabolism [29], brain vasculature [30], (4) and mechanisms related to aging [31], for instance, epigenetics [32], neurotrophic factors [33], and telomeres [34]. All these components are highly related and interact with each other to modulate the neurodegenerative process (Figure 2).

2.1. Intracellular Mechanism

Among intracellular mechanisms related to neuron survival and degeneration, DNA damage and defective repair are the most common hallmarks that many NDs with features of progressive movement disorders share. 

A high concentration of reactive oxygen species (ROS) can cause accumulation of oxidative DNA damage in its sequence and epigenetic modifications [24]. Altered gene expression could cause loss of normal neural function and progressively trigger programmed cell death and neuronal loss [22]. Mitochondria is the major source of cellular ROS production, and it was found that oxidative damage can promote α-synuclein aggregation and affect amyloid-β (Aβ) and other proteins related to aging and ND [22,35]. In long-living, non-mitotic cells such as neurons, ROS abundance causes oxidative stress and impairment of antioxidant defenses, resulting in dysfunction of the mitochondria and initiation of cell death cascade [36]. 

Multiple studies relate the effects of nitric oxide and ROS with NDs, including nitration of Lewis bodies in Lewis body dementia and Alzheimer's Disease (AD), nitration of α-synucleins in patients with multiple system atrophy, widespread nitrates tau proteins in AD, and frontotemporal dementia with Parkinsonism. Decreased levels of nitric oxide contribute to the upregulation of Aβ in the cerebrovascular system, and nitric oxide inhibition delays the progression of Parkinson's Disease pathology [37]. 

Likewise, Tumor Necrosis Factor-alpha (TNF-α) is a pro-inflammatory cytokine related to the pathogenesis of ND through systemic inflammation [38]. Anti-TNF-α therapies were proposed by several studies to diminish AD pathology, decrease amyloid deposition, and diminish neuronal impairment [39]. In addition, brain insulin resistance was described as a factor to induce cognitive impairments and neurodegeneration. 

Insulin brain levels are reduced during aging and Alzheimer resulting in the inhibition of several phosphatases involved in Tau dephosphorylation resulting in the deposition and accumulation of extracellular amyloid-β (Aβ) plaques [40,41].

Figure 2. Schematic representation of shared physiopathological hallmarks in neurodegenerative diseases (NDs): (1) Mitochondrial dysfunction due to oxidative stress, aging, or because of genetic or environmental factors damage, resulting in the excessive production of ROS, which can activate p53 and the Bax (apoptotic regulator) translocation that allows the release of cytochrome C (Cyt C) Figure 2. 

Schematic representation of shared physiopathological hallmarks in neurodegenerative diseases (NDs): (1) Mitochondrial dysfunction due to oxidative stress, aging, or because of genetic or environmental factors damage, resulting in the excessive production of ROS, which can activate p53 and the Bax (apoptotic regulator) translocation that allows the release of cytochrome C (Cyt C) leading the (Cas 9) and caspase 3 (Cas3) activation, resulting in DNA damage and cell death or (2) Apoptosis. 

Likewise, excessive ROS production also leads to oxidative stress and (3) Lipid Peroxidation, which can lead to protein aggregates such as α-synuclein as well as misfolded amyloid β peptide, the latter becoming an amyloid β (Aβ) plaque affecting neuron signaling induced by (4) Cholinergic Insufficiency. In turn, accumulation of Aβ plaque induces (5) Microglia Activation with the concomitant release of (6) Inflammatory Cytokines and produces neuroinflammation. 

On the other hand, (7) Dysregulation of Ca2+ because of neuronal membrane depolarization could induce synaptic deficits and promote the accumulation of Aβ plaques, and (8) Neurofibrillary Tangles through calpain activation. In addition, sustained calcium inflow results in over-activation of neuronal nitric oxide synthase (nNOS), with the increase in nitric oxide synthesis leading to oxidative stress/nitrosative stress and generalized brain inflammation. Moreover, ROS accumulation induces (9) kinase activation (glycogen synthase kinase-3β, GSK-3β) and induces tau hyperphosphorylation, promoting the accumulation of Aβ plaques. 

Accumulation of Aβ oligomers causes the removal of insulin receptors (IRS) from the cell surface, inducing a (10) Neuronal Insulin Resistance and inhibiting the activation of glucose transporter type 4 (GLUT 4). Dysfunctional insulin signaling brings the mammalian target of the rapamycin (mTOR) pathway down and results in (11) Autophagy failure to accumulate Aβ plaques. 

Finally, the synthesized cholesterol binds apolipoprotein E (APOE) to form APOE– cholesterol (APOE–CH) particles. APOE–CH particles are internalized into neurons, and the free cholesterol is metabolized to 24-hydroxycholesterol (24-OHC), which subsequently passes through the blood–brain barrier (BBB) and enters into plasma, while plasma (12) 27 hydroxyl cholesterol (27-OHC) flows into the brain, increasing the level of α-synuclein and eventually forms Lewy bodies (LBs). The back lines indicate stimulation, while the red lines indicate inhibition.

2.2. Local Tissue Environment

The progressive aggregation of misfolded proteins that severely affect the local tissue environment, creating damage, is a pathological feature that characterizes neurodegenerative diseases [42]. These misfolded proteins are subjected to protein degradation, such as proteasome-mediated. Inhibition of protein degradation pathways leads to the formation of protease-resistant, thus, decreasing the propagation of aggregated proteins that promote the misfolding of cell proteins [43]. 

Likewise, autophagy is the main mechanism responsible for removing protein aggregates, dysfunctional cellular organelles, and pathogens to maintain cellular homeostasis. Accumulation of immature autophagic vacuoles (AVs) as a consequence of a disrupted autophagy process is a common characteristic observed in the brain of Alzheimer's patients. 

It was shown that the mammalian target of rapamycin (mTOR) signaling is inhibited in the cortex and hippocampus of adult AD model mice. Brain insulin resistance induces alterations in the insulin/insulin-like growth factor (IGF-1)-PI3K (phosphoinositide 3-kinase class I)-Akt pathway, resulting in the aberrant activation of mTOR signaling, which negatively regulates autophagy induction [44–46].

2.3. Systemic Environment

Changes in the systemic environment such as inflammation are common in neurodegenerative diseases such as AD and Parkinson's Disease (PD) and can cause, along with oxidative stress, perturbances in the proteome composition of High-Density Lipoprotein (HDL) [47]. Circulating HDL provides resilience to cerebrovascular dysfunction in AD, which plays an important role in brain metabolism and homeostasis, dampening the clearance of Aβ and tau and thus leading to the formation of neuritic plaques and neurofibrillary tangles [48].

2.4. Aging Mechanism

The composition of fatty acids and fluidity of brain membranes change with age. Polyunsaturated Fatty Acids (PUFAs) such as docosahexaenoic acid (DHA, 22:6 n-3) and arachidonic acid (AA, 20:4 n-6) are the most abundant and important PUFAs in the brain and play a critical role in aging and neurodegeneration. In the elderly, DHA and AA decrease in membranes of the orbitofrontal cortex. Specific DHA deficiency might be caused by an age-related reduction in enzyme activity involved in the regulation of DHA synthesis, uptake, and assembly into brain phospholipids (Zhang et al., 2018). 

Meanwhile, high dietary consumption of omega-3 and omega-6 PUFAs is favorable for the memory of healthy older human adults. This process is mediated by the integrity and preservation of the white matter microstructure of the fornix in the brain (Zamroziewicz et al., 2017). Several PUFAs such as DHA and AA are being studied for the development of new treatments against NDs and neurodegeneration [49,50]. 

Punicic acid (18:3, ∆9cis, 11trans, 13cis, n-5) is a promising candidate whose mechanism of action is yet to be completely understood. The following section will refer to the characteristics and mechanisms of interest of punicic acid and their potential relation with the prevention of NDs.

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