Phases We are exposed to a plethora of toxins all the time. Because we are exposed daily, detoxification needs to be addressed daily. This process begins with the liver, which filters 2 quarts of blood every minute.

There are two generally accepted phases of detoxification. During Phase 1, lipid-soluble exo- or endo-toxins are taken into a series of cytochromes — think tunnels with enzymes. The enzymes catalyze reactions such as oxidation, reduction, hydrolysis, hydration, and dehalogenation, which occur in the tunnel.

What comes out are intermediary metabolites, which are less lipid soluble, but potentially more polar and highly reactive.

Assuming proper function, Phase 2 is immediately available to take these intermediary metabolites into conjugation pathways. These pathways include reactions like sulfation, glucuronidation, glutathione and amino acid conjugation, acetylation and methylation.

The original toxins are now polar and water soluble. As you can see, Phase 1 and 2 need entirely different nutrients.

Intermediary metabolites, which are highly reactive and sometimes more toxic than the original substance, are quelled by antioxidants and phytochemicals. A mixed diet for patients including lean proteins and plenty of vegetables certainly makes a positive impact on their livers to function optimally.

Additionally, in this toxic environment supplements can be very useful. Silymarin at high doses is very well tolerated. A phytosome-silybin granule was also studied and shown to provide the best bioavailability. I personally use AdvaClear from Metagenics which does contain silymarin, but also contains all the necessary Phase 1 and 2 nutrients, along with several other potent antioxidants.

Potential Issues The issues in the system are similar to what could happen on an assembly line. There are four main challenges. First, excessive exo-or endogenous toxins will obviously overtax the system. Second, either or both Phases can be slow. Third, if Phase 1 is fast or Phase 2 is slow, intermediary metabolites will build up.

The intermediary substances are highly reactive and cause premature aging. PYC has been widely studied and has shown to have promising effects in improving conditions including diabetes Spadea and Balestrazzi, ; Liu et al.

For the purposes of this review, we characterize the antioxidative activity of PYC, how this activity relates to aging, and how these mechanisms support cognitive function.

Cognition is a collective term generally referring to mental processes requiring the ability to remember and recall information and use information logically as well as abstractly and tasks that require sustained attention Budson and Price, Alterations in brain structure, neural activity, and biochemical profile are believed to contribute to the associated functional losses of reduced cognitive ability Sohal and Orr, Particularly, an increase in oxidative stress, elevated inflammation, and damage to the vasculature all play a role in age-associated cognitive decline Teunissen et al.

Oxidative stress is an imbalance in the production of free radicals [reactive oxygen species ROS ] and the antioxidant system. In the elderly, age-related oxidative stress is multifactorial, marked by increased production of free radicals, reduced activities of antioxidant enzymes, diminished antioxidant levels, and weakened repair of oxidative damage Rybka et al.

Increased production of ROS with or without decreased antioxidant defenses leads to damage of macromolecules, impaired organ function, and disease development Finkel and Holbrook, The human brain is highly susceptible to oxidative damage.

This is due to several factors, particularly because of its 1 high oxygen metabolic activity. This dynamic metabolic exchange must be stable for normal brain function. Dysfunctional oxygen metabolism is the hallmark of neurodegenerative disorders associated with cognitive decline Watts et al. The biochemical process of excessive free radical-mediated peroxidation of PUFA causes destruction to cell membranes, structure, and function Syslová et al.

Glutamate receptors are found on the surface of cells and therefore can only exert its excitatory function through extracellular fluid Zhou and Danbolt, If glutamate receptors are excessively activated, the increased glutamate can overstimulate nerve cells, depolarizing them known as excitotoxicity and eventually leading to cell death Kritis et al.

Both GPx and CAT reduce hydrogen peroxide into water and oxygen to assist in maintaining beneficial levels of ROS to prevent damage to molecular bonds, cell membranes, and DNA Basu, Additionally, essential biometals such as copper, iron, and zinc are involved in several biological processes and are essential for the survival of living organisms.

These biometals, particularly iron and copper, act by increasing the speed of chemical reactions due to their oxidizing and reducing powers redox potential Greenough et al.

This breakdown or dyshomeostasis of biometals whereby antioxidant protection is overwhelmed in favor of elevated concentration of metals leads to a state of neurotoxicity with damaging interaction to proteins, lipid peroxidation, and DNA, all evidence of increased oxidative stress in the AD affected brain Jomova et al.

Oxidative stress has been suggested to be not only an early feature of AD but also the mechanism that leads to the disease state Ansari and Scheff, They are unable to remember new information and perform complex tasks, have problems with language functions as well as visuospatial abilities, and lose the ability to make good judgments McKhann et al.

Due to these mechanisms of aging and hallmarks of neurodegenerative diseases, it may be beneficial for older individuals to consume dietary interventions with antioxidant properties to maintain cognitive function and reduce the risk of increased oxidative stress Simpson et al. In light of this, the antioxidant mechanisms of PYC are discussed below.

Due to its antioxidant and various biomodulating effects, PYC has potential benefits in improving cognitive function because it acts as a regulator and protects cells against oxidative stress by 1 being a potent free radical scavenger; 2 protecting DNA from damage; 3 increasing the synthesis of antioxidant enzymes; and 4 protecting other endogenous antioxidants vitamin C, vitamin E, and glutathione from oxidative damage Packer et al.

Demonstrating its antioxidant actions, PYC had been shown to decrease oxidative damage to DNA in children with attention deficit hyperactivity disorder Chovanová et al. In a group of patients suffering from erectile dysfunction, plasma antioxidant activity significantly increased total cholesterol, and low-density lipoprotein cholesterol decreased in response to PYC intervention Ďuračková et al.

Experiments on cultured neuroblastoma cells exposed to oxidative stress toxicity acrolein induced have showed that pre-treatment with PYC significantly diminished the ensuing cytotoxicity, protein damage, lipid peroxidation, and cell death Ansari et al. Furthermore, in animal models of dementia, PYC and vitamin E mitigated cognitive deficits and oxidative damage in the cerebral cortex and hippocampus Ishrat et al.

Clinical studies have demonstrated the antioxidant function of PYC. Researchers have also revealed additional pharmacological actions that may benefit conditions associated with cognitive impairments. One study showed that PYC not only exerts antioxidant activity but also increases plasma high-density lipoprotein and decreases serum low-density lipoprotein, indicating additional benefits on the lipid profile Stough et al.

A study of erythrocyte membrane fluidity found increased membrane surface fluidity in response to PYC as well as a further outcome of protection against lipid peroxidation either from chelating metal ions or quenching free radicals, or both Sivonová et al.

As it is known that lipoproteins are associated with cognitive impairments in the elderly Van Exel et al. PYC has also demonstrated a potential role in protecting genetic damage through its antimutagenic effects Križková et al.

Attenuation of DNA cleavage has been seen in beta-amyloid-induced apoptosis in rodent models Peng et al. However, since research into the genetic effects of PYC is in its infancy, these findings need to be further explored to determine the clinical use of these genetic mechanisms. Findings from these studies further support the multiple roles PYC may have as a potential cognitive enhancer Liu et al.

Mechanistically, PYC targets free radicals derived from both oxygen and nitrogen. While at higher concentrations nitric oxide NO is detrimental and contributes to neuroinflammation and neurodegeneration, at normal physiological levels, the role of NO is integral within the brain for neurotransmission modulates serotonin, dopamine, and norepinephrine , neuromodulation, and synaptic plasticity Dvořáková et al.

The balance of NO production within the brain is therefore integral to cognitive health. Animal experiments have demonstrated that learning and memory increase NO production within the brain Paul and Ekambaram, PYC either inhibits or increases vasodilation by assisting in the regulation of endothelial cell production of NO, which increases blood flow as well as oxygenation and transport of nutrients around the body to all organs including the brain Fitzpatrick et al.

This action of relaxing blood vessels and making them more flexible not just benefits the brain but also reduces demand on the cardiovascular system and entire body due to better circulation. The effects of PYC on stimulated macrophage cell cultures to mimic the immune response identified that the most active metabolite of PYC, M1 δ- 3,4-dihydroxyphenyl -γ-valerolactone , mediated anti-inflammatory effects by impeding nitric oxide generation and inducible nitric oxide synthase iNOS upregulation production Uhlenhut and Högger, Furthermore, M1 has been identified to accumulate in erythrocytes, monocytes, and endothelial cells with this cellular uptake and has the ability to cross the blood—brain barrier BBB possibly via the GLUTtype glucose transporter Uhlenhut and Högger, ; Kurlbaum et al.

The M1 metabolite is a by-product of PYC consumption formed in the gut from catechins Kurlbaum et al. An in vitro study utilizing cultured B16 melanoma cells found that while PYC suppressed reactive species in their assays, glutathione was enhanced Kim et al.

The most important intracellular antioxidant in the human body is glutathione GSH. GSH is a unique tripeptide made from glutamate, cysteine, and glycine found predominantly in the cytosol, mitochondria, and cell nucleus Berk et al. Interestingly, the facilitated uptake of M1 into cells involves further metabolism by conjugation with GSH in erythrocytes Kurlbaum et al.

Therefore, the antioxidative properties of PYC make it particularly novel in reducing oxidative stress in the brain than do other endogenous antioxidants, which are unable to cross the BBB Iuga et al.

Future studies are required to investigate the modulation of GSH metabolism in response to PYC administration and further elucidate the role of M1 and GSH. Interestingly, neuroimaging studies have not yet been performed as a method to investigate GSH metabolism and cognitive effects in relation to PYC administration.

Given that oxidative stress is known to affect neuroplasticity, attempts to normalize such impairments are of great therapeutic value in aging and cognition research. Neuroimaging is a non-invasive modality that may assist in answering structural, functional, and mechanistic questions, complementary to the in vivo animal, histological, and hematological studies and human clinical trials that have been discussed in response to PYC intervention.

We now review studies that have investigated the efficacy of PYC as a cognitive enhancer in humans. Figure 2 Proposed mechanism of action of PYC as a targeted therapy for preventing cognitive decline.

PYC potentially inhibits these mechanisms as represented by the x in the diagram due to its scavenging ability to free radicals and protection of proteins biomolecules against oxidative damage Packer et al.

Preliminary findings from clinical trials show promising cognitive-enhancing effects of PYC in healthy adults. Luzzi et al. Students in this study who were taking PYC also showed improvements on mood parameters alertness, contentedness, and reduced anxiety and performed significantly better on actual university exams than did the control group.

These authors found significant improvements in those who were taking PYC on mood alertness and attention and cognitive parameters episodic memory and spatial working memory and a Findings from these studies are promising, and trials with larger sample sizes are currently being conducted to confirm these potential benefits of PYC in preventing cognitive decline Stough et al.

Converging evidence suggests that the biomodulating effects of PYC improve several mechanisms that may underpin cognition including vascular, anti-inflammatory, neuroprotective, and antioxidant processes.

Research into PYC for improving cognitive function is growing with preliminary clinical studies indicating benefits on several cognitive domains including attention, memory, and executive functioning.

Research investigating the role of M1 in relation to GSH as well as the effect of PYC on brain metabolites e. Furthermore, neuroimaging techniques to investigate brain structure, function, and metabolism in response to PYC is warranted.

TS, CK, and CS all contributed to the design, writing, and editing of the manuscript. TS received an Australian Government Research Training Program Scholarship. The authors conduct studies using Pycnogenol ® that are funded by Horphag.

Horphag had no role in the preparation of the manuscript or decision to publish. Ansari, M. Protective effect of Pycnogenol in human neuroblastoma SH-SY5Y cells following acrolein-induced cytotoxicity.

doi: PubMed Abstract CrossRef Full Text Google Scholar. Oxidative stress in the progression of Alzheimer disease in the frontal cortex.

Aoki, H. Clinical assessment of a supplement of Pycnogenol ® and l-arginine in Japanese patients with mild to moderate erectile dysfunction. Basu, S. Fatty acid oxidation and isoprostanes: oxidative strain and oxidative stress.

Prostaglandins Leukot. Fatty Acids 82 4—6 , — Belcaro, G. Variations in C-reactive protein, plasma free radicals and fibrinogen values in patients with osteoarthritis treated with Pycnogenol ®. Redox Rep. Treatment of osteoarthritis with Pycnogenol ®.

Minerva Med. PubMed Abstract Google Scholar. Pycnogenol ® improves cognitive function, attention, mental performance and specific professional skills in healthy professionals aged Berk, M. N-Acetyl cysteine as a glutathione precursor for schizophrenia—a double-blind, randomized, placebo-controlled trial.

Budson, A. Memory dysfunction. Cadenas, E. Would you like to tell us about a lower price? Organika Pycnogenol Tabs Share:.

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