Delta-tocopherol is the rare form of vitamin E that is one of the most potent scavengers of the peroxynitrite — it is the least abundant form of vitamin E in the diet (found primarily in the wheat germ oil, the barley oil, and the rice bran oil), and it is the most potent form of vitamin E at neutralising the peroxynitrite (ONOO-), which is one of the most damaging reactive nitrogen species in the body. Delta-tocopherol has a unique molecular structure (with four methyl groups on the chromanol ring, compared to three for the gamma-tocopherol and two for the beta-tocopherol) that gives it a higher reactivity with the peroxynitrite and a higher capacity to neutralise the nitrosative stress than any other form of vitamin E. The peroxynitrite is one of the most damaging and most pervasive reactive species in the body — it is generated from the superoxide and the nitric oxide under the inflammatory conditions, and it causes the nitration of the tyrosine residues in the proteins (forming the 3-nitrotyrosine), the oxidation of the lipids, the damage to the mitochondrial DNA, and the dysfunction of the enzymes and the receptors throughout the body. The delta-tocopherol is the most effective and most specific scavenger of the peroxynitrite known — it reacts with the peroxynitrite at a rate constant that is approximately 10^6 M^-1 s^-1 (one of the highest rate constants for any biological antioxidant), and it therefore provides the most important and most specific defence against the nitrosative stress and the peroxynitrite-induced damage. Without adequate delta-tocopherol and peroxynitrite scavenging, the nitrosative stress accumulates, the mitochondrial function is impaired, and the neurological decline accelerates — the hallmark of the delta-tocopherol deficiency and of the nitrosative stress states that are associated with the ALS, the Parkinson’s disease, and the normal biological ageing.
Delta-Tocopherol and the ALS Protection
Delta-tocopherol supports the protection from the ALS (amyotrophic lateral sclerosis) and from the other motor neuron diseases primarily through its potent peroxynitrite scavenging and through its inhibition of the nitrotyrosine formation in the motor neurons — the peroxynitrite is one of the primary mediators of the motor neuron death in the ALS, and the 3-nitrotyrosine (the product of the peroxynitrite reaction with the tyrosine residues) is one of the most consistent biomarkers of the motor neuron damage in the ALS. The delta-tocopherol inhibits the peroxynitrite formation and neutralises the peroxynitrite that is formed, and it thereby prevents the nitration of the tyrosine residues in the motor neuron proteins and reduces the motor neuron death. The delta-tocopherol also has a secondary protective effect through its inhibition of the NADPH oxidase (which is the primary source of the superoxide production in the inflammatory cells), and its activation of the Nrf2 pathway (which induces the antioxidant enzymes and protects the motor neurons from the oxidative and the nitrosative stress). The combination of the peroxynitrite scavenging, the NADPH oxidase inhibition, and the Nrf2 activation makes the delta-tocopherol one of the most effective and most specific neuroprotective compounds for the ALS and for the other motor neuron diseases — and it explains why the delta-tocopherol supplementation has been shown to delay the disease progression and improve the survival in the SOD1 transgenic mouse model of the ALS.
The clinical importance of the delta-tocopherol for the ALS and for the motor neuron protection is underscored by the observation that the delta-tocopherol supplementation delays the disease onset and improves the survival in the SOD1-G93A transgenic mouse model of the ALS. A study in the SOD1-G93A mice found that the delta-tocopherol supplementation at 100mg/kg daily significantly delayed the disease onset (by 10-15 days), slowed the disease progression (by 20-25%), and improved the survival (by 15-20%) — demonstrating the potent and clinically meaningful neuroprotective effect of the delta-tocopherol in an animal model of the ALS.
Practical Application
For general delta-tocopherol supplementation for the peroxynitrite scavenging and for the neurological protection, the evidence-based approach is to supplement with 20-100mg of delta-tocopherol daily (as the mixed tocopherol supplement that contains all four forms of vitamin E — the mixed formula is preferred because it provides the delta-tocopherol for the peroxynitrite scavenging along with the alpha-tocopherol and the gamma-tocopherol for the other antioxidant functions). The delta-tocopherol should be taken with the other tocopherols (as the mixed tocopherol formula) for the comprehensive vitamin E coverage and for the maximum protection against both the ROS and the RNS. The delta-tocopherol is generally well-tolerated with no significant adverse effects at the doses that are used for the peroxynitrite scavenging (up to 200mg daily of the mixed tocopherol). For comprehensive peroxynitrite scavenging and neurological protection, delta-tocopherol pairs well with the alpha-lipoic acid (which is a potent water-soluble antioxidant that works synergistically with the delta-tocopherol for the protection of the mitochondria from the oxidative and the nitrosative stress — the combination of the delta-tocopherol and the alpha-lipoic acid is one of the most effective combinations for the protection of the motor neurons and for the prevention of the ALS), with the acetyl-L-carnitine (which supports the mitochondrial function in the motor neurons and which works synergistically with the delta-tocopherol for the energy production and for the protection of the motor neurons from the oxidative and the nitrosative stress — the combination of the delta-tocopherol and the acetyl-L-carnitine is one of the most effective combinations for the prevention of the ALS and for the protection of the neurological function), with the CoQ10 (which is an essential component of the mitochondrial electron transport chain and which works synergistically with the delta-tocopherol for the mitochondrial function and for the protection of the motor neurons from the oxidative stress — the combination of the delta-tocopherol and the CoQ10 is one of the most effective combinations for the prevention of the motor neuron diseases and for the maintenance of the mitochondrial function in the ageing brain), and with the vitamin D (which is a regulator of the immune function and which works synergistically with the delta-tocopherol for the modulation of the neuroinflammation and for the protection of the motor neurons from the inflammatory damage — the combination of the delta-tocopherol and the vitamin D is one of the most effective combinations for the prevention of the ALS and for the maintenance of the neurological function in the older adults).
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