Punicic Acid And Its Role in The Prevention Of Neurological Disorders: A Review Part 2

3. Punicic Acid

In nature, the most abundant source of punicic acid (PuA) is pomegranate (Punica granatum), with the final amount depending on the fruit genotype. 

With the development of genetic technology, more and more people are paying attention to the relationship between genes and memory. Research shows that genes have a great influence on human intelligence and memory.

First, genetic variation can affect a person's intelligence level. Intelligence is closely related to human brain structure and function, and these characteristics are affected by genes. For example, some genes affect the brain's neurotransmitter levels, which can affect the brain's learning and cognitive abilities. So if some people have these beneficial genetic variants, they may have higher intelligence than others.

Secondly, genes can also affect a person's memory. Some genes affect a person's hippocampus, an important brain region closely related to memory function. Some people may be genetically gifted with better hippocampal structure, and they may learn from experiences more easily than others, retaining information and applying it to later situations.

In addition, genes can also affect people's learning styles and memory strategies. Certain genes may promote attention and concentration, traits that aid memory. In addition, some genes may also affect people's emotional state, thereby affecting learning and memory. For example, some people may inherit genes that make them more anxious, which may interfere with their learning and memory of new information.

However, although genes can influence intelligence and memory, this does not mean that all people are genetically limited. Environment and experience are equally important. Lifestyle and experience are key to developing and improving intelligence and memory. Through endless study and practice, people can improve their intelligence and memory abilities and constantly surpass themselves.

In general, genes are part of human intelligence and memory, but they are not all. By creating a conducive external environment and following a healthy lifestyle to enhance memory and intelligence, people can make themselves better and more successful. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche deserticola can also promote the growth and repair of nerve cells, thus enhancing the connectivity and function of neural networks. These effects can help improve memory, learning, and thinking speed, and may also prevent the development of cognitive dysfunction and neurodegenerative diseases.

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However, other sources include Momordica balsamina, Ecballium elaterium, Fevillea trilobata, and some species from the Trichosanthes genus, such as T. kirilowii, T. anguina, T. bracteata, T. nervifolia [14,19,51]. 

Punicic acid, also known as octadecatrienoic acid or trichosanic acid (C18H30O2), possesses a molecular weight of 278.43 g/mol, a melting point of 44–45 ◦C, and an octanol–water partition coefficient (X LogP) of 6.4. Moreover, it was reported that punicic acid has a molar refractivity and polarizability value of 89.64 m3/moL and 35.91 Å3, respectively [52]. 

PA exhibits a pKa value of 4.99 (strongest acidic), as it can act as a donator of one hydrogen [53,54]. It is a conjugated linolenic acid isomer with structural similarities to α-linolenic and linoleic acids [54] (Figure 3). Among the main described characteristics of punicic acid is its ability to scavenge hydroxyls, metal chelation, and reduce properties [15].

Biosynthesis of punicic acid begins with the de novo synthesis of fatty acids inside the plant's plastid, mostly palmitic (16:0), stearic (18:0), and oleic acids (18:1∆9cis) (Figure 4). Fatty acids are conjugated on phosphatidylcholine (PC) to undergo desaturations and conjugations in the position sn2 of PC. 

Oleic acid-PC (OA 18:1∆9cis) is processed into linoleic acid-PC (LA 18:2∆9cis,12cis), which in turn is transformed into Punicic Acid-PC by fatty acid desaturase (FAD) 2 and fatty acid desaturases group X (FADXs), respectively. 

Newly synthesized fatty acids are then converted into acyl-Coenzyme A by the action of Acyl-CoA synthetase to act as acyl donors in triacylglycerol (TAG) biosynthesis inside the endoplasmic reticulum (ER) before being stored in cytoplasmic lipid droplets.

The main challenges of using PSO or punicic acid for health applications are chemical instability and limited water solubility [55]. Since fatty acids such as punicic acid are molecules highly unsaturated, they are susceptible to degradation due to oxidation, light, or thermal treatments. Likewise, because punicic acid is poorly soluble in water and only a small fraction can be slowly absorbed by the body, the bioavailability of this molecule is very low and exhibits a rapid metabolism to conjugated linoleic acid (CLA), limiting its use in commercial or therapeutic [56]. 

To overcome these challenges, researchers have explored different strategies such as the synthesis of precursor molecules and the design of specific delivery systems to protect the active drug. 

Modifications on the chemical structure can protect the molecule's active sites from biological degradation and therefore improve its stability. Esterification of punicic acid showed an improvement of 30% in the oxidative stability of monodispersed punicic acid compared to its free form. Likewise, this chemical modification of punicic acid significantly improved its water solubility and bioaccessibility [55]. 

On the other hand, encapsulation is the most used technique to protect drugs from environmental and chemical degradation. In this sense, spray-drying microencapsulation of pomegranate seed oil using succinylated taro starch demonstrated 61% encapsulation efficiency with an improvement in oxidation stability and a significant delivery of PSO in the small intestine [57]. 

Likewise, PSO nanoemulsions have shown improved stability under stress conditions such as osmotic stress and extreme pH values [58]. Mizrahi et al. [59] reported that nanoemulsions of pomegranate seed oil exhibited strong neuroprotective effects by reducing lipid oxidation and neuronal loss. 

Recent technological advances allowed the development of novel delivery systems, which not only protect the drug but also exhibit an efficient release in the target site, improving the bioavailability and biological activity of this by the modification of the pharmacokinetics parameters [60,61]. 

Improved physical and peroxidation stability of PSO at different temperatures (4 ◦C and 25 ◦C) was achieved by the incorporation of beeswax and propolis wax during the fabrication of PSO nanostructured lipid carriers. 

After 40 days of storage time, PSO nanostructured lipid carriers at 4 ◦C showed peroxidation levels significantly lower than at 25 ◦C. Likewise, the antioxidant activity of these systems, measured by DPPH free radical-scavenging activity, showed to be stable throughout the storage period regardless of temperature conditions [62]. 

Moreover, the combination of PSO with other therapeutic drugs or nutraceuticals was shown to improve the pharmacokinetic parameters and biodistribution profile of the latter [63,64]. 

The biological benefits of PSO and punicic acid also attracted the food industry's interest in designing and offering consumers more healthy products through the enrichment of polyunsaturated acids of the different food matrices [65–68]. These approaches can be really useful in the development of food products with enhanced nutritional quality or even for the development of food supplements that contribute to preserving human health [69]. 3.1. 

Punicic Acid Metabolism Lipids are abundant in the brain, and they perform a variety of structural functions such as neurogenesis, signal transduction, neural communication, membrane compartmentalization, synaptic transmission, and regulation of gene expression [70]. 

Punicic acid (PuA) is metabolized into circulating conjugated linoleic acid CLA via a saturation reaction [71–74]. CLA is mostly processed in the liver into neutral lipids and phospholipids, respectively. CLA isomers c9,t11, and t10,c12 are metabolized via desaturation and elongation reactions while maintaining their conjugated diene structure [75]. 

Both isomers are processed differently; t10,c12 CLA is readily beta oxidized to Conjugated Diane (CD) 16:2 and delta 6 desaturated to CD 18:3, while c9,t11 CLA appears to be metabolized into CD 20:3 (Figure 5). CD 18:3, 20:3, and 20:4 are mainly incorporated into phospholipids CLA. At the same time, CD 18:3 and CD 20:3 are distributed into neutral lipids [76]. 

In humans, it was observed that punicic acid is transformed into c9,t11 and incorporated into tissues such as plasma, and red blood cell mass, and is partially beta-oxidation in peroxisomes to produce CD 16:2 [72,75]. In rats, CLA was measured mainly in the liver, kidney, adipose tissue, mammary tissue, plasma, heart, and brain, with only small traces of punicic acid being found in liver and heart tissue [71,76]. 

A study measured the concentration of CLA in human plasma after daily intake of 0.8 g, 1.6 g, or 3.2 g of c9,t11 CLA in capsules and found that the metabolites CD 18:3 and 16:2 were promptly incorporated linearly, while 20:3 reached a plateau at 1.6 g/d [75].

A study in rats demonstrated that after 40 days of rich in punicic acid supplementation with PSO rich in punicic acid at concentrations of 1%, 2%, and 4% CLA was found in serum, liver, heart, and kidney, respectively, and some traces of PuA were found in the liver and heart. In the brain, PSO consumption was shown to decrease thiobarbituric acid reactive substances (TBARS) levels, which are used to determine lipid peroxidation, but neither PuA nor CLA was detected in this tissue [71]. However, other studies confirmed the presence and metabolism of CLA in the brains of both rats and humans [76–78]. 

CLA metabolites may be able to reach the brain through incorporation into very-low-density lipoprotein (VLDL) [76], produced by the intestine and liver, and be absorbed into the brain by the very-low-density lipoprotein receptor (VLDLR) [79]. 

However, it is also likely that low-density lipoprotein (LDL) and the low-density lipoprotein receptor (LDLR), as well as the fatty acid translocase (FAT/CD36), are involved in the transport of CLA through the blood–brain barrier (BBB), as it is the case with most PUFAs [80,81]. Astrocytes and endothelial cells, two major components of the BBB, are the major contributors to the transportation of PUFAs from the circulation to the brain [82]. 

Astrocytes participate in the synthesis of eicosanoids [76] and play an important role in CLA metabolism [79]. CLA isomers c9,t11, and t10,c12 are effectively incorporated and metabolized in rat brain and human astrocyte cell culture. 

However, because beta-oxidation of CLA is more efficient in the brain than in other tissues, CLA concentrations in the brain are low. Therefore, it is believed that the incorporation of CLAs is tissue-specific [76]. 

Low CLA concentrations in the brain could be the result of the preference of the cerebral tissue for other fatty acids, against the selection of fatty acids with trans double bonds, or the presence of the blood–brain barrier, poor incorporation of phospholipids, and low supply. Additionally, the incorporation of CLA in the brain is lower than in other tissues [71,76].

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