TARGETED NEURAL PROTECTION (TNP-Ω)

TNP is an experimental supplement “targeted” to address adverse neural and other aging-related issues (“Alzheimer’s, Parkinson’s, Type 2-diabetes etc.).

Targeting involved a process of 1) working backward step-by step from each final adverse state of interest [e.g. Alzheimer’s Disease (AD)], and 2) identifying transition blocking interventions from meta-analyses and other systematic research reviews.

With specific regard to TNP, two integrative “prongs” were identified with emerging promise for significantly slowing-blocking several layers of significant transitions Selected B Vitamins; and Phytochemical Sources.

Targeted B-vitamins – the first prong – provides neuroprotection via several interrelated avenues of action [esp., serving to reduce plasma homocysteine (tHcy) and AD associated beta-amyloid levels.] Phytochemicals, the second prong, likewise provides protection by a spectrum of other avenues of action.

These include: antioxidant, anti-inflammatory, iron-chelation and most intriguingly by sequestering of the amyloid aggregations associated with AD, Parkinson’s, Type 2-diabetes etc.

Targeted B-vitamins – provides neuroprotection via several interrelated avenues of action serving to reduce plasma homocysteine (tHcy) and Alzheimer disease (AD) Phytochemicals — provides protection from: antioxidant, anti-inflammatory, iron-chelation and most intriguingly by sequestering symptoms associated with AD, Parkinson’s, Type 2-diabetes.

Take as directed by your healthcare practitioner, or 1 capsule with first and last meal as a dietary supplement.

TARGETED NEURAL PROTECTION (TNP-Ω™)

TNP was initially developed (~2007CE) as an experimental supplement for potentially addressing adverse neural and other aging-related issues in our friends and colleagues (some with emerging issues).

Basically, it was designed with a two-pronged approach – targeting integrations of both: Selected B Vitamins; and Phytochemical Sources.

Targeted B-vitamins – the first prong – provides neuroprotection via several interrelated avenues of action as outlined below [esp., serving to reduce plasma homocysteine (tHcy) and Alzheimer disease (AD) associated beta-amyloid levels.] Phytochemicals, the second prong as also delineated below, likewise provides protection by a spectrum of other avenues of action.

Include:

antioxidant, anti-inflammatory, iron-chelation and most intriguingly by sequestering of the amyloid aggregations associated with AD, Parkinson’s, Type 2-diabetes.

The following represents an update of the literature that supported TNPs initial development.

Ingredients

Thiamine(vitamin B1), Vitamin B6, Folic Acid, Propriety Formula: Turmeric Root, White Tea Leaf, Quercetin. Other Ingredients: Cellulose (vegetarian capsule).

Targeted B Supplementation.

Overview.

Targeted Vitamin B supplementation may serve to reduce cognitive decline via several interrelated avenues-of-action (Ganguly & Alam, 2015; Flicker et al, 2008; Mikkelsen et al., 2017). In this regard, Ganguly and Alam (2015) recently considered reductions in cardiovascular disease associated with low B levels – issues in turn often related to cognitive declines and dementia.

Alternately, Flicker et al (2008).both: noted that selected B-vitamins reduced plasma levels of beta-amyloid associated with Alzheimer’s disease (AD) and consequently concluded that may have a role in the prevention of AD.

Finally, Mikkelsen et al (2017) recently concluded that Vitamin B supplementation has been shown to improve depression outcomes – which are associated with brain atrophies (Geerlings et al., 2013).

These seemingly varied avenues-of-action each has strong interconnections with high levels of homocysteine – a focus of the historic wave of research supporting the advantages of supplementation.

Background Research. Ravaglia et al. (2005) – in their classical short-term longitudinal study — found that both high homocysteine (tHcy) and independently low folate were both risk factors for dementia and Alzheimer disease (AD).

Subsequently, Refsum et al. (2006) reported significant associations between tHcy and clinical outcomes are usually observed for tHcy levels >15 μmol/L, but for most conditions, there is a continuous concentration-response relation with no apparent threshold. Pertinently, they found that good folate or vitamin B-12 status was associated with lower tHcy levels.

Overall, their findings from HHS indicate that a raised tHcy level is associated with multiple clinical conditions; whereas, low tHcy levels are associated with better physical and mental health.

Reynolds (2006) in an integrated review noted the parallels between folate and B12 deficiencies – with supplementation on one briefly masking a deficit in the other, but then exacerbating the initial deficiency.[1] Overall Reynolds concluded “[t]here is now substantial interest in the role of folic acid, B12, and related pathways in nervous-system function and disease at all ages and the potential use of the vitamins, especially folic acid, in the prophylaxis of disorders of CNS development, mood, and cognitive decline, including some dementias.” In light of these and their own earlier findings, Refsum and colleagues (Smith et al. 2010) – in a placebo-controlled experimental trial – found brain atrophy in elderly was significantly reduced by a combination of homocysteine(tHey )-lowering B vitamins.

These included folic acid (0.8 mg/d), vitamin B12 (0.5 mg/d) and vitamin B6 (20 mg/d).

Building on this result, Douaud et al.

(2013), further found support for a reduction in gray matter atrophy, particularly in those with higher levels of homocysteine ( a finding supported by similar results in the control group, where less decline noted in those with lower vs. higher homocysteine (tHey).

The above wave of research supports the combined requirement for a range of B-vitamins, albeit some individual contributions may be noted:

Thiamine (B1) – targeted to address: (i) deficiency related effects on glucose metabolism (esp., nervous system with occasionally severe neurological symptoms; and (ii) depression effects on cognitive declines (Guilland, 2013; Mikkelsen et al, 2017).[2]

Vitamin B6 –targeted to reduce both homocysteine (tHey) and depression associated atrophies in brain size and cognitive tests (Smith et al., 2010; Douaud et al., 2013; Geerlings et al., 2013).

Folic Acid –targeted to reduce risk of Alzheimer’s and dementia (Ravaglia et. (2005); Refsum et al., 2006; Smith et al., 2010; Douaud et al. (2013),) Vitamin B12 – targeted to reduce depression and cognitive deficit, particularly with dietary deficits (Refsum et al, 2006; Smith et al., 2010; Douaud et al., 2013; Mikkelsen et al., 2017). Also intriguingly, there is emerging evidence that it blocks AD-associated amyloid fibrillation in vitro (Alam et al., 2017).

Clearly targeted B supplementation is associated with reduce homocysteine and associated cognitive decline albeit it may be via any of several interrelated avenues-of-action (e.g., Ganguly & Alam, 2015; Flicker et al, 2008; Mikkelsen et al., 2017; Alam et al. 2017).

Targeted Phytochemical Supplementation

Overview. Targeted phytochemical supplementation may – as with targeted B vitamins – also serve to reduce cognitive decline via several interrelated avenues-of-action (Porat et al. 2006; Letenneur et al., 2007; Kumar & Khanum, 2012; Vauzour, 2012; 2014; Lakey-Beitia et al., 2015).

In this regard, for example, Kumar and Khanum (2012) have noted that curcumin has > 10 neuroprotective beneficial effects for the nervous system in animal model including protection of neurons against ischemic cell death, and thereby ameliorating behavioral deficits [arguably by antioxidant and anti-inflammatory actions as noted by Lakey-Beitia et al., 2015).[3] Additionally, in-vitro and animal models show it is a strong candidate for protection or treatment of major age related neurodegenerative diseases (e.g., AD, Parkinson’s, Type-2 Diabetes as well as Stroke and many other age-related diseases).

[4] At the same time, Kumar and Khanum note “[c]urcumin has been shown to reverse chronic stress-induced impairment of hippocampal neurogenesis and increase expression of brain-derived neurotrophic factor (BDNF) in an animal model of depression.” Alternately, Vauzour (2012) points toward specific avenues broadly underlying phytochemical effects across their underlying sources.

Altogether, traditional reviews have tended to highlight the antioxidant, anti-inflammatory and iron-chelation as avenues of action. In contrast, Porat et al. (2006) systematically review – especially the in-vitro evidence – the inhibition of amyloid fibril formation by polyphenols with structural similarity and aromatic interactions as a common mechanism; while, pointing to the epidemiological and in-vivo experimental support (e.g., Yang et al., 2005). Porat et al. (2006) also note the disassociation of antioxidant and (IC-50) fibril formation that suggested our later targeted combination of phytochemical sources.

Background Research. Letenneur and colleagues (2007) – in their seminal epidemiological study – reported that [polyphenol and other] flavonoid intake was significantly associated with a reduction in cognitive decline over a 10-year period in an aging population (>65y).

Their study, which adjustment for age, sex, and educational level, strongly raised the possibility that dietary flavonoid intake was associated with better cognitive evolution.

This research, in part informed by earlier research, encouraged waves of further epidemiological studies, but also in-vitro and most interesting intervention studies.

In a later integrative review covering much of this, Rodriguez-Mateos et al (2014) observe that “over the last decade, a vast and growing research literature has indicated that(poly)phenols may exert particularly powerful actions on …cognition and may reverse age-related declines in memory and learning.

In addition, growing evidence also indicates that (poly) phenols may inhibit the development of Alzheimer’s disease-like pathology and counteract age-related cognitive declines possibly via their ability to interact with the cellular and molecular architecture of the brain responsible for memory…”

The above waves of research very broadly support the health benefits of phytochemicals, albeit some specific sources are especially relevant to the targeted application:

Curcumin – targeted for its wide-spectrum of effects. In this regard, Lakey-Beitia et al. (2015) have, in addition to the multitude of other avenues of action delineated above, observed that curcumin blocks amyloid linkages thereby preventing the formation of AD plaques (pointing to protective effects (re: Parkinson’s, Type-2 Diabetes as well as Stroke and many other age-related diseases).

More directly focused on mental health (as also addressed above), Kumar and Khanum note “[c]urcumin has been shown to reverse chronic stress-induced impairment of hippocampal neurogenesis and increase expression of brain-derived neurotrophic factor (BDNF) in an animal model of depression.

With regard to curcumin, the evidence altogether supports Rodriguez-Mateos et al (2014 broad summary (re: polyphenols) “inhibit… disease-like pathology and counteract age-related cognitive declines possibly via their ability to interact with the cellular and molecular architecture of the brain responsible for memory…”

White Tea (Camellia Sinensis) – targeted also for its wide-spectrum of effects.

In this regard, Dias et al. (2013) have noted that white tea, the least processed, is ascribed to have the highest content of phenolic compounds among teas.

As above with curcumin, “[t]ea polyphenols, especially catechin derivatives, are potent antioxidant agents, with positive effects on human health.”

Their “…ability to scavenge free radicals, thereby inhibiting oxidative-stress …[serves to block]..development of several human diseases such as CVD, DM, neurodegenerative disorders and certain types of cancer.

Pointing to protective effects post-stroke and other hypoxia-related conditions in this regard, Chen et al (2016) have noted that catechin prevents hypoxia/reperfusion-evoked cell death in microglial cells.

White-tea also shares with Curcumin that ability to block amyloid linkages (with prospective prevention of AD, Parkinson’s etc.).

Especially interesting, in this regard, among its phenolic compounds is Epigallocatechin gallate (ECGC) which has a remarkably low (IC-50 = 0.18) for Beta-amyloid -40 (See Porat et al., 2006, Table 1). Hence, again the evidence altogether supports Rodriguez-Mateos et al (2014 broad summary ( re: polyphenols) “inhibit… disease-like pathology and counteract age-related cognitive declines possibly via their ability to interact with the cellular and molecular architecture of the brain responsible for memory…”

Quercetin – targeted for apparent capabilities to reduce risks of both short and long-term stress disease risks (respiratory, oxidative stress, and amyloid-related ).

In this regard, our initial interest was provoked by early viral reduction effects seen in-vitro which signaled possible reductions in upper respiratory infections ( UTRIs ) that often lead to physical then cognitive declines in the elderly.

Importantly, this initial in-vitro suggestion was later supported both in: studies of UTRI reductions following intense exercise (Nieman et al., 2007; Davis et al., 2008); and in a community level study where reductions in URTI total sick days and severity were seen particularly in

middle-aged and older subjects…who rated themselves as physically fit (Heinz et al, 2010). Interestingly Costa et al. (2016) have recently noted that in addition to direct antioxidant effects, “quercetin may also act by stimulating cellular defenses against oxidative stress.

[5] Two such pathways include the induction of Nrf2-ARE and induction of the antioxidant/anti-inflammatory enzyme paraoxonase 2 (PON2).

Further, quercetin has been shown to activate sirtuins (SIRT1), to induce autophagy, and to act as a phytoestrogen, all mechanisms by which quercetin may provide its neuroprotection.”

Finally, as curcumin and white-tea, quercetin shares the ability to block amyloid linkages (with prospective prevention of AD, Parkinson’s etc.).

Especially interesting it has demonstrated one of the lower IC-50s (= 0.24) for Beta-amyloid -40 (See Porat et al., 2006, Table 1).[6] Hence, again the evidence for quercetin altogether supports Rodriguez-Mateos et al (2014 broad summary ( re: polyphenols) “inhibit… disease-like pathology and counteract age-related cognitive declines possibly via their ability to interact with the cellular and molecular architecture of the brain responsible for memory…”

Clearly targeted phytochemical supplementation is associated with reductions in cognitive decline albeit via a wide spectrum of avenues-of-action including the blocking, if not reduction, of amyloid aggregations associated with AD, Parkinson’s, Type 2-diabetes and a host of other diseases.

Concluding Remarks

TNP-α, as described above, was designed (~2007CE) using a two-pronged approach that targeted integrations of both: Selected B Vitamins; and Phytochemical Sources. Targeted B-vitamins – the first prong – was designed to provides neuroprotection via several interrelated avenues of action as outlined above [esp., serving to reduce plasma homocysteine (tHcy) and Alzheimer disease (AD) associated beta-amyloid levels.]

Targeted phytochemicals, the second prong, alternately was designed to provide protection by a spectrum of other avenues of action.

These included: antioxidant, anti-inflammatory, iron-chelation and most intriguingly by sequestering of the amyloid aggregations associated with AD, Parkinson’s, Type 2-diabetes.

Our two-pronged approach – as revealed in the bodies of subsequent research outlined above – was remarkable in its anticipation of a formulation that has remained consistent with the bodies of emerging research over the last decade.

We consequently remain confident in our recommendations of TNP-α for potentially addressing adverse neural and other aging-related issues in our friends and colleagues.

References

Alam PA, Siddiqi MK, Chaturvedi SK, Zaman M & Khan RH (2017). Vitamin B12 offers neuronal cell protection by inhibitingAβ-42 amyloid fibrillation. International Journal of Biological Macromolecules; 99, 477-482.

Arts, I. C., & Hollman, P. C. (2005). Polyphenols and disease risk in epidemiologic studies. The American journal of clinical nutrition, 81(1), 317S-325S.

Bittner, A.C. & Sakuragi, Y. (2006). Intra-Individual Ergonomics (I2E): Framework and Future. Proceedings 50th Annual Meeting Human Factors and Ergonomics Society, pp. 2533-2537 (CD-ROM). Santa Monica, CA: Human Factors and Ergonomics Society.

Costa, L. G., Garrick, J. M., Roquè, P. J., & Pellacani, C. (2016). Mechanisms of neuroprotection by quercetin: counteracting oxidative stress and more. Oxidative medicine and cellular longevity

Vol. 2016, Article ID 2986796, 10 pages http://dx.doi.org/10.1155/2016/2986796

Chen, C. M., Wu, C. T., Yang, T. H., Chang, Y. A., Sheu, M. L., & Liu, S. H. (2016). Green Tea Catechin Prevents Hypoxia/Reperfusion-Evoked Oxidative Stress-Regulated Autophagy-Activated Apoptosis and Cell Death in Microglial Cells. Journal of agricultural and food chemistry, 64(20), 4078-4085.

Davis J, Murphy E, McClellan J, Carmichael M, & Gangemi J. (2008). Quercetin reducessusceptibility to influenza infection following stressful exercise. Am J Physiol :Regul Integr Comp Physiol;295 :R505 –509.

Dias TR, Tomás G , Teixeira NF, Alves MG, Oliveira PF & Silva BM (2013) White Tea (Camellia sinensis (L.)): Antioxidant Properties and Beneficial Health Effects. Int J Food Sci Nutr Diet. 2(2), 19-26. doi : dx.doi.org/10.19070/2326-3350-130005 Douaud, G., Refsum, H., de Jager, C. A., Jacoby, R., Nichols, T. E., Smith, S. M., & Smith, A. D. (2013).

Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment. Proceedings of the National Academy of Sciences, 110(23), 9523-9528.

Flicker, L., Martins, R. N., Thomas, J., Acres, J., Taddei, K., Vasikaran, S. D. et al. (2008). B-vitamins reduce plasma levels of beta amyloid.

Neurobiology of aging, 29(2), 303-305.

Ganguly, P., & Alam, S. F. (2015). Role of homocysteine in the development of cardiovascular disease. Nutrition Journal, 14, 6. http://doi.org/10.1186/1475-2891-14-6

Geerlings, M. I., Sigurdsson, S., Eiriksdottir, G., Garcia, M. E., Harris, T. B., Sigurdsson, T et al. (2013). Associations of current and remitted major depressive disorder with brain atrophy: the AGES-Reykjavik Study. Psychological Medicine, 43(2), 317–328.

http://doi.org/10.1017/S0033291712001110

Guilland, J.C (2013). Vitamin B1 (thiamine). La Revue du praticien , 63(8), 1074-1075.

Heinz, S. A., Henson, D. A., Austin, M. D., Jin, F., & Nieman, D. C. (2010). Quercetin supplementation and upper respiratory tract infection: A randomized community clinical trial. Pharmacological research, 62(3), 237-242.

Kumar, G. P., & Khanum, F. (2012). Neuroprotective potential of phytochemicals. Pharmacognosy reviews, 6(12), 81.

Lakey-Beitia J, Berrocal R, Rao KS. & Durant AA. (2015). Polyphenols as therapeutic molecules in Alzheimer’s Disease through modulating Amyloid pathways. Mol Neurobiol; 51: 466-479. doi :10.1007/s12035-014-8722-9

Letenneur, L., Proust-Lima, C., Le Gouge, A., Dartigues, J. F., & Barberger-Gateau, P. (2007). Flavonoid intake and cognitive decline over a 10-year period. American journal of epidemiology, 165(12), 1364-1371.

Mikkelsen, K., Stojanovska, L., Prakash, M., & Apostolopoulos, V. (2017). The effects of vitamin B on the immune/cytokine network and their involvement in depression. Maturitas, 96, 58-71.

Nakayama H, Tsuge N, Sawada H, & Higashi Y (2013). Chronic intake of onion extract containing quercetin improved postprandial endothelial dysfunction in healthy men. J Am Coll Nutr; 32: 160-164.

Nieman DC, Henson DA, Gross SJ, Jenkins DP, Davis JM, Murphy EA, et al. (2007). Quercetin reduces illness but not immune perturbations after intensive exercise. Med Sci Sports Exerc;39:1561–1569.

Oulhaj, A., Jernerén, F., Refsum, H., Smith, A. D., & de Jager, C. A. (2016). Omega-3 fatty acid status enhances the prevention of cognitive decline by B vitamins in mild cognitive impairment. Journal of Alzheimer’s Disease, 50(2), 547-557.

Porat, Y., Abramowitz, A., & Gazit, E. (2006). Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism. Chemical biology & drug design, 67(1), 27-37.

Ravaglia, G., Forti, P., Maioli, F., Martelli, M., Servadei, L.et al., F. (2005). Homocysteine and folate as risk factors for dementia and Alzheimer disease. The American J of clinical nutrition, 82(3), 636-643.

Refsum, H., Nurk, E., Smith, A. D., Ueland, P. M., Gjesdal, C. G.et al. (2006). The Hordaland Homocysteine Study: a community-based study of homocysteine, its determinants, and associations with disease. J Nutrition, 136(6), 1731S-1740S.

Reynolds, E. (2006). Vitamin B12, folic acid, and the nervous system. Lancet Neurology, 5(11), 949-960.

Russo, M., Spagnuolo, C., Tedesco, I., Bilotto, S., & Russo, G. L. (2012). The flavonoid quercetin in disease prevention and therapy: facts and fancies. Biochem Pharm, 83(1), 6-15.

Smith, A. D., Smith, S. M., De Jager, C. A., Whitbread, P., Johnston, C. et al.. (2010). Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PloS one, 5(9), e12244.

Vauzour, D. (2012). Dietary polyphenols as modulators of brain functions: biological actions and molecular mechanisms underpinning their beneficial effects. Oxidative medicine and cellular longevity, 2012. doi :10.1155/2012/914273

Vauzour D (2014) Effect of flavonoids on learning, memory and neurocognitive performance: relevance and potential implications for Alzheimer’s disease pathophysiology. J Sci Food Agric, 94:1042–1056

Wald DS, Kasturiratne A, Simmonds M (2010) Effect of folic acid, with or without other B vitamins, on cognitive decline: Meta-analysis of randomized trials. Am J Med 123(6):522–527.

Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA, Cole GM (2005) Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem;280:5892–5901.

[1] This latter finding strongly argues for co-supplementation of B12 and folate in targeted applications.

[2] Guilland (2013 notes that mild deficiencies are common in the general population (esp. during pregnancy and after protracted vomiting, as well as with a spectrum of medications.

[3] Chen et al. (2016) – not surprising in light of Porat et al (2006) – a show very similar effects for tea extracts, albeit with more focus on the details of the avenues of phytochemical action.

[4] Lakey-Beitia et al. (2015) have, in addition to other avenues of action, noted that curcumin blocks amyloid linkages preventing the formation of AD plaques, which broadly applies across Parkinson’s, Type 2 Diabetes and other amyloid diseases for green tea, quercetin and other phyto -polyphenols as earlier suggested by Porat et al (2006).

[5] Antioxidant effects are reflected in a range of long turn performance, health and well-being enhancements (e.g., Bittner & Sakuragi, 2006). In keeping with this, profound postprandial effects have been recently demonstrated with chronic intake of onion extract containing quercetin (Nakayama et al., 2013).

[6] The ECGC component of white tea (with IC-50 = 0.18) would appear slightly superior, but ECGC is a fraction of white tea; whereas, quercetin is the total fraction.

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