Punicic Acid and Its Role in the Prevention of Neurological Disorders: A Review

Claudia M Guerra-Vázquez, Mariana Martínez-Ávila, Daniel Guajardo-Flores, Marilena Antunes-Ricardo, Claudia M Guerra-Vázquez, Mariana Martínez-Ávila, Daniel Guajardo-Flores, Marilena Antunes-Ricardo

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. 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 contributes 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 deposits 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: Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; antioxidant; blood–brain barrier; conjugated linoleic acid; neurodegeneration.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Classification of the pathways involved in neurodegenerative diseases (NDs).
Figure 2
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) kinases activation (glycogen synthase kinase-3β, GSK-3β) and induces tau hyperphosphorylation, promoting the accumulation of Aβ plaques. Accumulation of Aβ oligomers causes 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 mammalian target of 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 hydroxylcholesterol (27-OHC) flows into the brain, increasing the level of α-synuclein and eventually forms Lewy bodies (LBs). Back lines indicate stimulation, while red lines indicate inhibition.
Figure 3
Figure 3
Structure of punicic acid and related isomers α-linolenic acid and linoleic acid. Chemical structures drawn in ChemDraw.
Figure 4
Figure 4
Punicic acid (PuA) biosynthesis and storage in triacylglycerol (TAG). Phosphatidylcholine (PC), Oleic acid (OA), Linoleic acid (LA), position sn2 Punicic Acid (PuA), Punicic Acid Phosphatidylcholine (Sn2-PuA PC), Fatty Acid Desaturase (FAD) 2 and FADXs, acyl-Coenzyme A (CoA), Acyl-CoA synthetase (ACS), Triacylglycerol (TAG) Phospholipid:diacylglycerol Acyltransferase (PDAT), Lysophosphatidylcholine Acyltransferase (LPCAT), n-glycerol-3-phosphate acyltransferase (GPAT), diacylglycerol acyltransferase (DGAT), sn-glycerol-3-phosphate (G3P), sn1,2-diacylglycerol (DAG), CDP-choline:1,2-diacyl-sn-glycerol cholinephosphotransferase (CPT), phosphatidylcholine: diacylglycerol cholinephosphotransferase (PDCT), phospholipase C (PLC).
Figure 5
Figure 5
Proposed punicic acid metabolism. Punicic acid is transformed into conjugated linoleic acid (CLA cis-9, trans-11) and then either β-oxidized into Conjugated Diane (CD) 16:2 or metabolized by Δ6-desaturase to become CD 18:3 to be further processed into CD 20:3 and CD 20:4. Chemical structures drawn in ChemDraw.
Figure 6
Figure 6
Schematic representation of biological effects of punicic acid (PuA) in neurological diseases (NDs). Punicic acid (PuA) acts as (1) an agonist of PPARs inhibiting the activation of nuclear factor kappa B (NF-κB) and the release of inflammatory cytokines such as TNF-alpha, and therefore, reducing neuroinflammation and tau hyperphosphorylation and conducting less Aβ formation and aggregation. (2) PuA inhibits activation of calpain and cyclin-dependent kinase 5 (cdk5), limiting the hyperphosphorylation of tau protein and conducting to less Aβ formation and aggregation. (3) PuA increases GLUT4 protein expression regulating the glucose brain metabolism, reducing insulin resistance, and reducing the hyperphosphorylation of tau proteins. (4) PuA increased the anti-oxidative properties of the PON1 complex reducing ROS generation limiting mitochondrial dysfunction and neuronal apoptosis. Lipids peroxidation. Moreover, PuA induces changes in high-density lipoproteins (HDL) lipid composition and functionality reducing the formation of oxysterols such as 27-hydroxycholesterol (27-OHC) and increasing oxidative resistance with less Aβ plaque formation. ROS: reactive oxygen species; PON1: paraoxonase 1; PPARs: peroxisome proliferator-activated receptors; HDL: high-density lipoprotein; GLUT4: insulin-sensitive glucose transporter; CH: cholesterol; BBB: blood–brain barrier; ApoE: apolipoprotein E; Glu: glucose, PuA: punicic acid. Green lines indicate stimulation, while red lines indicate inhibition.

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