The technical field generally relates to nutritional health supplements, and more particularly to nutritional health supplements for the brain.
The brain is the center of the nervous system in all vertebrates and most invertebrates. As the core of the nervous system and the organ that governs the function of all other organs, less than optimum or diminished brain function impacts all aspects of health and well-being. Accordingly, brain health maintenance and re-enforcement of brain defense mechanisms, which include short- and long-term support of the brain's fight against neuroinflammation, is a key component to maintaining and further enhancing health and well-being. Neuroinflammation is inflammation of nervous tissue, including the brain and spinal cord, and is initiated by many different conditions, diseases and injuries that affect the brain such as concussion, stroke, cancer, infections of blood, brain, and other organs, autoimmunity and autoimmune brain diseases including multiple sclerosis and other demyelinating diseases, migraine and other primary and secondary headache disorders, neurodegenerative diseases including Parkinson's Disease, Huntington's Disease and Amyotrophic Lateral Sclerosis and other motor neuron diseases, and dementia syndromes, including Alzheimer's Disease and Chronic Traumatic Encephalopathy.
Concussion, typically defined as a mild traumatic brain injury, affects both the brain's structural and metabolic organization and provokes intense neuroinflammation. The symptoms, signs, and long-term consequences of neuroinflammation resulting from concussion derive from pathophysiological events at the cellular level. This multifaceted injury includes both a primary injury and secondary injury to the cellular constituents of the brain. It is considered that primary structural injury results in a loss of structural integrity and death to cells and axons. Prevention is typically the focus for avoidance or minimization of primary structural injury, although alternatives are also sought.
The secondary injury of concussion occurs due to multiple, parallel, interacting and inter-dependent biological reactions initiated by the primary injury. These pathophysiological events are immediate, cumulative, progressive, and cascading in nature, and can result in progressive degeneration of the meninges, cortical, grey, and white matter structures of the brain. These secondary injury reactions are considered to underlie the vulnerability to repeated concussions, persistence of symptoms in some individuals, the long-term neurological sequelae that may occur after single or repeated concussions, and the progressive neurodegeneration that may occur in some individuals.
Accordingly, it is desirable to support the brain's defense mechanisms that counter both the primary and secondary injury reactions of concussion and its potentially devastating short term and long-term effects. It is also desirable to support the brain's defense mechanisms that support the brain's fight against neuroinflammation to maintain and further enhance health and well-being. Furthermore, other desirable outcomes, features and characteristics will become apparent from the subsequent description, taken in conjunction with this background.
In accordance with an exemplary embodiment, a nutritional health supplement is provided that includes, but is not limited to, an antioxidant that delays neuronal death under excitotoxic conditions, a neuroprotective agent having antioxidant, anti-inflammatory, and anti-apoptic properties, and a neuroprotective agent that is a precursor for glutathione synthesis.
In accordance with another exemplary embodiment, a nutritional health supplement is provided that includes, but is not limited to, an antioxidant that delays neuronal death under excitotoxic conditions, a neuroprotective agent that is a precursor for glutathione synthesis, a NAD+ precursor, a ketone body or ketone precursor, and an antioxidant with free-radical species-deactivating properties.
In a further exemplary embodiment, a nutritional health supplement is provided that includes, but is not limited to, riboflavin, N-acetyl cysteine (NAC), nicotinamide riboside, betahydroxybutyrate or a betahydroxybutyrate precursor, and glutathione.
The various embodiments will hereinafter be described in conjunction with the following drawing figures, wherein like numerals denote like elements, and wherein:
As used herein, the word exemplary means serving as an example, instance, or illustration. The following detailed description is merely exemplary in nature and is not intended to limit the invention or the application and uses of the invention. Any embodiment described herein as exemplary is not necessarily to be construed as preferred or advantageous over other embodiments. The embodiments described in this Detailed Description are exemplary embodiments provided to enable persons skilled in the art to make or use the invention and not to limit the scope. Furthermore, there is no intention to be bound by any expressed or implied theory presented in this document.
The use of numerical values in the various ranges specified in this application, unless expressly indicated otherwise, are stated as approximations as though the minimum and maximum values within the stated ranges were both preceded by the word “about”. Thus, slight variations above and below the stated ranges can be used to achieve substantially the same results as values within the ranges. Moreover, in the disclosure of these ranges, a continuous range is intended, covering every value between the minimum and maximum values, including the minimum and maximum end points of the range. In general, the term “about” means +/−10% from the stated value.
A nutritional health supplement is provided in accordance with an exemplary embodiment. In another exemplary embodiment, the nutritional health supplement is a nutritional brain supplement, and in yet another embodiment the nutritional health supplement is a brain supplement that contains ingredients that work in a complementary and symbiotic manner to treat the pathological reactions that result from concussion, otherwise referred to as a mild traumatic brain injury.
The natural products of the nutritional health supplement are safe and effective for neuroprotection, including, but not limited to, attenuation or mitigation of brain injury. This includes the attenuation or mitigation attributed to concussion, such as because of metabolic and inflammatory secondary injury events. In addition, the combination of supplement ingredients is designed and formulated to at least reduces, and typically prevents, the persistence of symptoms in vertebrates and most invertebrates, of injuries such as concussion. While the following description is directed to concussion, there is no intent to limit the application or use of the nutritional health supplement to only concussion and the application and use is applicable to numerous health and neurological conditions.
The pathological mechanisms initiated after concussion are immediate, cumulative, sequential, and in the cases of inflammation and neurodegeneration, persistent and progressive. Current attempts to investigate the treatment of concussion typically isolate and target a single mechanism of this complex, sequential, and progressive multi-modal injury and do not appreciate that the mechanisms result in a cascading effect wherein the mechanisms build on each other and display a temporal profile. As explained in more detail below, altered membrane and cellular ionic homeostasis leads to excitotoxicity with excessive release and reduced uptake of glutamate, calcium sequestration and mitochondrial dysfunction. Mitochondrial dysfunction leads to oxidative stress, the generation of reactive oxygen species, a reduction in energy production, the failure of membrane pumps, worsening ionic homeostasis, depletion of essential metabolites that are responsible for the production of neurotransmitters and neurotrophic factors, activation of genes that lead to programmed cell death, and eventually cell death. The primary and secondary neural injury results in microglial activation, the release of cytokines, and neuroinflammation. Neuroinflammation leads to axonal destruction, microtubule dissociation, tau aggregation and deposition which leads to cell death and further inflammation. These events have a temporal profile and may progress at different rates in different areas of the brain that are affected differentially by the diffuse and multifocal nature of the brain injury after the traumatic impact. The various embodiments of the nutritional health supplements contemplated herein comprise a unique combination of ingredients that are strategically selected to symbiotically interfere with each step in this cascade. Therefore, the embodiments have a synergistic effect, enhance the protection of uninjured but neighboring tissue, rescue vulnerable tissue that is destined for cell death and permanent injury, and enhance the repair of injured tissue.
In more detail, the pathogenesis of concussion is initially induced by a mechanical injury that sets into motion a series of complex secondary pathological mechanisms that occur both sequentially and in parallel. This cascade of sequential, interdependent and parallel pathological reactions is initiated immediately after the injury and can persist and progress over an indefinite period of time. The persistence of these mechanisms can lead to progressive neuronal, axonal, and glial cell death which can result in persistent symptoms and progressive neurodegeneration.
Referring to
Continuing with
At least five interdependent pathological reactions occur as a result of the initial cascades of depolarization, calcium influx, and mitochondrial dysfunction/oxidative stress. These five reactions include excitotoxicity, calcium-mediated toxicity, free radical toxicity, neuroinflammation, and neurodegeneration. Referring to
Calcium-mediated toxicity 60 is mediated by activation of a number of enzymes 54, including phospholipases, endonucleases, and proteases such as calpain, which damage the cell membrane, the cytoskeleton of the cell, and DNA. This calcium influx also activates apoptosis genes 54, normally responsible for programmed cell death, which now results in premature cell death 28.
Free radical toxicity 70 is characterized by the production of reactive oxygen species 72 (ROS) and reactive nitrogen species (RNS), including free radicals, peroxide, and superoxide, as a result of mitochondrial dysfunction 18 and oxidative stress 30. In addition to the generation of these oxidizing molecules, oxidative stress 30 may also be associated with a significant decrease in the effectiveness of antioxidant defenses, including and especially glutathione. The harmful effects of ROS on the cell include damage to DNA, RNA and proteins, lipid peroxidation (oxidation of free fatty acids and membrane lipids), and induction of apoptosis or programmed cell death. Lipid peroxidation leads to the production of reactive aldehydes 72 such as malondialdehyde and 4-hydroxynonenal, the latter of which causes damage to cellular constituents similar to ROS. Overall, while cells can overcome the negative effects associated with oxidative stress if the disturbance is mild, moderate or severe oxidative stress, as may occur after concussion, can trigger apoptosis, cell death, or cell necrosis.
Referring to
With continued reference to
Head injury, concussion, and repetitive head impacts have been demonstrated to be a major risk factor for Alzheimer's disease, dementia, and tauopathies, including Chronic Traumatic Encephalopathy (CTE). All of the pathological cascades described above may lead to the breakdown and destruction of the cytoskeletal architecture of axons and dendrites, including the microtubules that are responsible for axonal transport of neuropeptides and neurotransmitters that are responsible for synaptic communication between neurons. Persistent inflammation after concussion and repetitive head impacts also may lead to progressive neurodegenerative disease. Neuroinflammation is detectable in the earliest stages of Alzheimer's disease. The neuronal toxicity associated with inflammation makes it a potential mediator in the pathogenesis of Alzheimer's disease. Injured neurons also lead to further glial activation and a feed-forward cycle of glial activation and neuronal injury resulting in progressive neurodegeneration leading to the development of Alzheimer's disease or CTE in predisposed individuals.
Neuroinflammatory cytokines and reactive microglia exacerbate tau pathology and contribute to the spreading of tau in animal models of Alzheimer disease and other tauopathies, including CTE. Increased neuroinflammation, including an increase in inflammatory cell (CD68) density and enhanced microglia reactive morphology is associated with more severe tau pathology in the cortex of humans with neuropathologically diagnosed CTE. Increased neuroinflammation is also related to the risk of being diagnosed with dementia and this relationship is mediated by tau. Increased neuroinflammation as a consequence of concussion, especially after repetitive head impacts, appears to play an important role in the development of tau pathology in CTE. The interdependence of the various cascades involved in the brain injury after concussion is underscored by the participation of reactive oxygen species (ROS) and calcium-induced activation of calpain, caspases, and apoptosis genes in neuroinflammation and neurodegeneration. The cleavage of tau by Caspases results in aggregation of tau fragments which promote neuronal injury and neurodegeneration.
In the setting of a diffuse injury, as exists after concussion, a neuron in one location may differ from a neuron in another location with regard to the evolution of this pathological cascade. It is therefore imperative that a treatment contain various ingredients that target different mechanisms at different stages in this pathological cascade. This prevents later stage pathological mechanisms from being initiated if the sequence is terminated early and rescues other cells that may already be in a later stage of this pathological cascade. A treatment that contains various ingredients that target different mechanisms at different stages in this pathological cascade therefore will act in a complementary and synergistic fashion.
Accordingly, in an exemplary embodiment, a nutritional health supplement includes, but is not limited to, an antioxidant that delays neuronal death under excitotoxic conditions, a neuroprotective agent having antioxidant, anti-inflammatory and anti-apoptic properties, and a neuroprotective agent that is a precursor for glutathione synthesis. In another exemplary embodiment, a nutritional health supplement includes, but is not limited to, an antioxidant that delays neuronal death under excitotoxic conditions, a neuroprotective agent that is a precursor for glutathione synthesis, a NAD+ precursor, a ketone body or ketone precursor, and an antioxidant with free-radical species-deactivating properties.
In an exemplary embodiment, the antioxidant that delays neuronal death under excitotoxic conditions comprises riboflavin. Riboflavin is a B-vitamin and powerful antioxidant. It is readily absorbed and is required for normal cellular functioning. As illustrated in
In an exemplary embodiment, a daily dose of the nutritional health supplement includes riboflavin in an amount of about 100 mg to about 600 mg, for example, about 150 mg to about 550 mg, such as about 200 mg to about 500 mg. In another exemplary embodiment, riboflavin is present in a daily dose of the nutritional health supplement contemplated herein in an amount of about 250 mg to about 450 mg, for example, about 300 mg to about 400 mg, such as about 400 mg.
As noted above, in another embodiment, the nutritional supplement comprises a neuroprotective agent having antioxidant, anti-inflammatory and anti-apoptic properties. While any neuroprotective agent having antioxidant, anti-inflammatory and anti-apoptic properties is contemplated herein, an example of a suitable neuroprotective agent having antioxidant, anti-inflammatory and anti-apoptic properties comprises resveratrol. Resveratrol (3,5,40-trihydroxystilbene, RV) is a natural polyphenol belonging to the phytoalexin family that is found in grapes and a variety of medicinal plants. Resveratrol facilitates a wide spectrum of biological functions and exerts protective effects against neurological damage, including stroke, spinal cord injury and neurodegenerative diseases. Referring to
Two brain structures prominently affected in head trauma are the cortex and the hippocampus, which play a role in the processing of spatial memory and learning. The loss of neurons in the hippocampus contributes to the impairment of learning and memory following concussion. Thus, impairment of cognitive function has long been thought to be the result of rapid cell death following concussion. Concussion increases neuronal cell death in both the hippocampus and leads to long-term neurobehavioral effects of trauma-increased anxiety and deterioration of cortex and hippocampal-dependent memory. Resveratrol administration after the trauma ameliorates the histopathological and behavioral consequences of trauma, especially in the hippocampus.
In an exemplary embodiment, resveratrol is present in a daily dose of the nutritional health supplement contemplated herein in an amount of about 250 mg to about 500 mg, for example, about 300 mg to 500 mg, such as about 350 mg to 500 mg. In another exemplary embodiment, resveratrol is present in a daily dose of the nutritional health supplement contemplated herein in an amount of about 400 mg to about 500 mg, for example, about 450 mg.
The nutritional supplement further comprises a neuroprotective agent that is a precursor for glutathione synthesis in accordance with an embodiment, as noted above. N-acetyl cysteine or N-acetyl L-cysteine (NAC) is an example of a neuroprotective agent suitable for use in the nutritional supplement contemplated herein. NAC exerts neuroprotective effects that are mediated by antioxidant and anti-inflammatory effects. Without wishing to be bound by theory, the antioxidant and anti-inflammatory effects of NAC are likely the result of inhibition of NAC-induced nuclear factor-κB-activated pathways that include cytokine cascades and phospholipid metabolism. NAC also appears to preserve mitochondrial function, particularly in hippocampal neurons. Referring to
In an exemplary embodiment, NAC is present in a daily dose of the nutritional health supplement contemplated herein in an amount of about 400 mg to about 4000 mg, for example, about 400 mg to about 3500 mg, such as about 400 mg to about 3000 mg. In another exemplary embodiment, NAC is present in a daily dose of the nutritional health supplement contemplated herein in an amount of about 400 mg to about 2500 mg, for example, about 400 mg to about 2,000 mg, such as about 400 mg to about 1500 mg. In another exemplary embodiment, NAC is present in a daily dose of the nutritional health supplement contemplated herein in an amount of about 500 mg to about 1300 mg, for example, about 600 mg to about 1200 mg.
In accordance with another exemplary embodiment, the nutritional health supplement as contemplated herein includes, but is not limited to, a NAD+ precursor. Examples of NAD+ precursors suitable for use in the nutritional supplement contemplated herein include niacin, nicotinamide (NAM), and nicotinamide riboside (NR). All tissues produce NAD+ from nicotinamide (NAM) or the recently identified NAD+ precursor, NR. Niacin, NAM and NR are neuroprotective soluble B3 vitamins that improve recovery of neurological function after brain injury.
NAD+ is the reduced version of the coenzyme nicotinamide adenine dinucleotide (NAD). The NAD coenzymes NAD+, NADH, NADP+ and NADPH are the central regulators of metabolism and are required for fuel oxidation, ATP generation, gluconeogenesis, ketogenesis, production of pentose phosphates, heme, lipids, steroid hormones and detoxification of free radical species. The reduction of NAD+ in the post-concussion period reduces the production of brain derived neurotrophic factor (BDNF) by silencing its gene. BDNF is the brain's primary neurotrophic factor and is responsible for promoting growth, differentiation, survival, and expansion of neurons and is implicated in synaptic plasticity and neuroplasticity. It is therefore beneficial in the neural repair and neuroplasticity required for recovery from concussion. NAD+ is important in regulating ATP synthesis in the brain and in the recovery process after brain trauma, since ATP is required to power the membrane Na+/K+ ATPase pumps that restore ionic homeostasis and membrane potential that are necessary for the recovery and survival of cells after concussion. Neuronal death from concussion occurs in part due to the excessive activation of poly (ADP-ribose) polymerase-1 (PARP-1), which results in NAD+ depletion and energy failure. As illustrated in
Different enzymatic pathways, which are expressed to variable degree in different cell types, are responsible for converting each of the forms of vitamin B3 into NAD+. These enzymatic pathways also respond differently to cellular stress. In preclinical studies of concussion, the enzyme nicotinamide phosphoribosyl transferase (Nampt) that catalyzes the conversion of nicotinamide to NAD+, is inhibited after concussion, whereas the expression of the enzymes NRK1 and NRK2 that convert NR to NAD+ is increased. This increased expression occurs in injured central and peripheral neurons. As a result, NR increases NAD+ levels to a degree that is not possible with niacin and nicotinamide.
In addition, while nicotinamide is an NAD+ precursor, it also inhibits the activity of sirtuins. Sirtuins are a family or proteins that play a role in energy metabolism, stress resistance, inflammation, aging, DNA repair, and programmed cell death. On the other hand, NR increases the activity of sirtuins and may therefore enhance neuroprotection beyond what is achievable with niacin and nicotinamide.
In an exemplary embodiment, NR is present in a daily dose of the nutritional health supplement contemplated herein in an amount of about 300 mg to about 1,000 mg, for example, about 350 mg to about 950 mg, such as about 400 mg to about 900 mg. In another exemplary embodiment, NR is present in a daily dose of the nutritional health supplement contemplated herein in an amount of about 450 mg to about 850 mg, for example about 500 mg to about 800 mg, such as about 500 mg to about 750 mg.
The nutritional health supplement contemplated herein includes, but is not limited to, a branched chain amino acid (BCAA), in accordance with an exemplary embodiment. Referring to
Clinical studies have demonstrated that endogenous levels of BCAAs are reduced in individuals that sustain a concussion relative to healthy controls, suggesting that the metabolic cascade that ensues after brain injury influences BCAA metabolism. Concussion alters BCAA levels and the BCAA supplementation of the nutritional health supplement contemplated herein positively influences concussion recovery with no adverse side. The proteins derived from BCAAs also serve to maintain the integrity of the transport machinery that allow for axonal and dendritic transport of neurotransmitters that become compromised as a result of the inflammatory cascades that occur after concussion. The neurotransmitter proteins generated from BCAAs also maintain the integrity of synaptic connections and therefore of the neural network. In this way, BCAAs mitigate the compromise to neuronal function imposed by multiple pathological mechanisms that occur after concussion 142.
In an embodiment, the BCAA, which can be, for example, L-leucine or other branched chain amino acids, is present in a daily dose of the nutritional supplement contemplated herein in an amount of about 1 mg to 5,000 mg, for example, about 100 mg to about 4,500 mg, such as about 200 mg to about 4,400 mg. In another embodiment, the BCAA is present in a daily dose of the nutritional supplement contemplated herein in an amount of about 300 mg to about 4,300 mg, for example, about 400 mg to about 4,200 mg, such as about 500 mg to about 4,100 mg. In another embodiment, the BCAA is present in a daily dose of the nutritional supplement contemplated herein in an amount of about 700 mg to about 3,900 mg, for example about 800 mg to about 3,800 mg, such as about 900 mg to about 3,700 mg. In another embodiment, the BCAA is present in a daily dose of the nutritional supplement contemplated herein in an amount of about 1,000 mg to about 3,600 mg, for example, about 1,100 mg to about 3,500 mg, such as about 1,200 mg to about 3,400 mg. In another embodiment, the BCAA is present in a daily dose of the nutritional supplement contemplated herein in an amount of about 1,300 mg to about 3,300 mg, for example, about 1,400 mg to about 3,200 mg, such as about 1,500 mg to about 3,100 mg, In another embodiment, the BCAA is present in a daily dose of the nutritional supplement contemplated herein in an amount of about 1,600 mg to about 3,000 mg, for example, about 1,700 mg to about 2,900 mg, such as about 1,800 mg to about 2,800 mg. In another embodiment, the BCAA is present in a daily dose of the nutritional supplement contemplated herein in an amount of about 1,900 mg to about 2,700 mg, for example, about 2,000 mg to about 2,600 mg, such as about 2,100 mg to about 2,500 mg. In another embodiment, the BCAA is present in a daily dose of the nutritional supplement contemplated herein in an amount of about 2,200 mg to about 2,300 mg, for example, about 2,225 mg to about 2,275 mg, such as about 2,500 mg.
In another exemplary embodiment, the BCAA, which can be, for example, L-valine, L-isoleucine, a combination thereof, or other branched chain amino acids, is present in a daily dose of the nutritional supplement contemplated herein in an amount of about 1 mg to about 2,500 mg, for example about 50 mg to about 2,450 mg, such as about 100 mg to about 2,400 mg, In another embodiment, the BCAA is present in a daily dose of the nutritional supplement contemplated herein in an amount of about 150 mg to about 2,350 mg, for example, about 200 mg to about 2,300 mg, such as about 250 mg to about 2,250 mg. In another embodiment, the BCAA is present in a daily dose of the nutritional supplement contemplated herein in an amount of about 300 mg to about 2,200 mg, for example, about 350 mg to about 2,150 mg, such as about 400 mg to about 2,100 mg. In another embodiment, the BCAA is present in a daily dose of the nutritional supplement contemplated herein in an amount of about 450 mg to about 2,050 mg, for example, about 500 mg to about 2,000 mg, such as about 550 mg to about 1,950 mg. In another embodiment, the BCAA is present in a daily dose of the nutritional supplement contemplated herein in an amount of about 600 mg to about 1,900 mg, for example, about 650 mg to about 1,850 mg, such as about 700 mg to about 1,800 mg. In another embodiment, the BCAA is present in a daily dose of the nutritional supplement contemplated herein in an amount of about 750 mg to about 1,750 mg, for example, about 800 mg to about 1,700 mg, such as about 850 mg to about 1,650 mg. In another embodiment, the BCAA is present in a daily dose of the nutritional supplement contemplated herein in an amount of about 900 mg to about 1,600 mg, for example, about 950 mg to about 1,550 mg, such as about 1,000 mg to about 1,500 mg. In another embodiment, the BCAA is present in a daily dose of the nutritional supplement contemplated herein in an amount of about 1,050 mg to about 1,450 mg, for example, about 1,100 mg to about 1,400 mg, such as about 1,150 mg to about 1,350 mg. In another embodiment, the BCAA is present in a daily dose of the nutritional supplement contemplated herein in an amount of about 1,200 mg to about 1,300 mg, for example, about 1,225 mg to about 1,275 mg, such as about 1,250 mg.
In accordance with an exemplary embodiment, the nutritional supplement contemplated herein includes, but is not limited to, a neuroprotective agent that mitigates glutamate-mediated excitotoxicity and calcium influx. In one embodiment, the neuroprotective agent is an omega-3 fatty acid. In another embodiment, the neuroprotective agent is the omega-3 fatty acid docosahexaenoic acid (DHA). While the neuroprotective agent will be described below with reference to DHA, it will be appreciated that other neuroprotective agents that mitigate glutamate-mediated excitotoxicity and calcium influx may be suitable for use in the nutritional supplement contemplated herein.
DHA is an omega-3 long-chain polyunsaturated fatty acid (LCPUFA) that is highly concentrated in the central nervous system (CNS). As illustrated in
The neuronal content of DHA is reduced after concussion and the structural injury, neuronal death, and neurological consequences of a concussion increase when neuronal levels of DHA are low. Prophylactic supplementation with DHA mitigates brain white matter damage and enhances the protection of the cytoskeletal elements and architecture of brain axons after a concussion 1008. DHA mitigates against the neuronal and axonal damage after concussion as measured by serum neurofilament light, a highly sensitive and specific biomarker for concussion-related brain injury. Further, animals supplemented with DHA demonstrate enhanced resilience to concussion and multiple TBIs, similar to that which would be observed in repetitive sports-related concussive injuries.
Physical activity, particularly that which is long in duration and high in intensity, affects plasma phospholipid composition, which is an important consideration for athletes. The neuroprotective effects of supplemental DHA demonstrate the greatest efficacy when administered at a dose of approximately 3.6 g in a 90-kg athlete. While athletes with greater height, weight, and body mass index, including American Football players, may require a higher dose, athletes of smaller stature and body mass may only require about 2 g/day.
In an exemplary embodiment, DHA is present in a daily dose of the nutritional health supplement contemplated herein in an amount of about 200 mg to about 4,000 mg, for example, about 700 mg to about 3,500 mg, such as about 1,200 mg to about 3,000 mg. In another exemplary embodiment, DHA is present in a daily dose of the nutritional health supplement in an amount of about 1,700 mg to about 3,500 mg, for example, about 2,000 mg to about 3,000 mg, such as about 2,000 mg to about 2,500 mg. In another exemplary embodiment, DHA is present in a daily dose of the nutritional health supplement in an amount of about 2,000 mg.
In accordance with another exemplary embodiment, the nutritional health supplement as contemplated herein includes, but is not limited to, a ketone body or ketone precursor. Ketone bodies (ketones), such as beta-hydroxybutyrate (BHB), acetoacetate, and acetone, or ketone precursors, such as ketone salts, for example, sodium, potassium, magnesium and/or calcium salts of BHB, and ketone esters, such as D-beta-hydroxybutyrate/D-1,3-butanediol and acetoacetate/D/L 1,3-batanediol, represent an alternative to glucose for cerebral metabolism and are the only endogenous fuels that can contribute significantly to cerebral energy metabolism. Cerebral metabolism of glucose has been demonstrated to be altered after concussion and elevated levels of glucose has been associated with poor outcome after concussion. Ketones have been demonstrated to be neuroprotective in several models of concussion. Ketones alter and improve mitochondrial metabolism and their oxidation generates more ATP than glucose or fatty acid metabolism, while also generating fewer reactive oxygen species (ROS).
In animal studies evaluating the ketogenic diet (KD) for concussion, ketones have been shown to increase ATP, decrease neuronal death, decrease edema, and improve cell survival under stressful conditions of ischemia and hypoxia. Ketones also decrease glutamate synthesis, reduce apoptosis (programmed cell death), and increase brain-derived neurotrophic factor. These metabolic properties of ketones are thought to contribute to their neuroprotective potential after concussion and other traumatic brain injuries. The administration of exogenous ketones, in the form of ketone esters or salts, represents a treatment strategy to rapidly increase ketones in the body to be used an energy source for cerebral metabolism and as treatment to reduce the inflammation and anti-excitotoxity while improving cerebral blood flow and energy production after a concussion. Moreover, studies suggest that after acute brain injury, cerebral uptake of ketones increases significantly, and there is both experimental and clinical evidence that administering ketones to patients with cerebral injury may provide significant benefit. While the ketone body will be described below with reference to BHB, it will be appreciated that other ketone bodies and precursors may be suitable for use in the nutritional supplement contemplated herein. It is to be appreciated herein that reference to BHB herein also refers to BHB precursors. Referring to
In an exemplary embodiment, BHB or a BHB precursor is present in a daily dose of the nutritional health supplement contemplated herein in an amount of about 500 mg to about 11,000 mg, for example, about 550 mg to about 10,000 mg, such as about 600 mg to about 9,000 mg. In another exemplary embodiment, BHB or a BHB precursor is present in a daily dose of the nutritional health supplement in an amount of about 650 mg to about 8,000 mg, for example, about 700 mg to about 7,000 mg, such as about 750 mg to about 6,000 mg. In another exemplary embodiment, BHB or a BHB precursor is present in a daily dose of the nutritional health supplement in an amount of about 800 mg to about 5,000 mg, for example, about 850 mg to about 4,000 mg, such as about 900 mg to about 3,000 mg. In another exemplary embodiment, BHB or a BHB precursor is present in a daily dose of the nutritional health supplement in an amount of about 950 mg to about 2,500 mg, for example, about 1,000 mg to about 2,000 mg.
In an exemplary embodiment, the nutritional supplement contemplated herein comprises, but is not limited to, a mitochondrial dysfunction mitigator with antioxidant and anti-inflammatory properties. While any mitochondrial dysfunction mitigator with antioxidant and anti-inflammatory properties is contemplated herein, an example of a suitable mitochondrial dysfunction mitigator with antioxidant and anti-inflammatory properties is curcumin and/or a curcumin derivative, for example, tetrahydroxycurcumin, or a combination thereof. Curcumin is a golden pigment and the biologically active ingredient from the spice herb turmeric. Tetrahydroxycurcumin is the active metabolite that gives curcumin its therapeutic properties. In the setting of concussion, as illustrated in
In an exemplary embodiment, the curcumin or tetrahydroxycurcumin is present in a daily dose of the nutritional health supplement contemplated herein in an amount of about 500 mg to about 2000 mg, for example, about 500 mg to about 1500 mg, such as about 500 mg to about 1000 mg. In another exemplary embodiment, curcumin or tetrahydroxycurcumin is present in a daily dose of the nutritional health supplement contemplated herein in an amount of about 500 mg to about 950 mg, for example, about 500 mg to about 900 mg, such as about 500 mg to about 850 mg. In another exemplary embodiment, curcumin or tetrahydroxycurcumin is present in a daily dose of the nutritional health supplement contemplated herein in an amount of about 500 mg to about 800 mg, for example, about 500 mg to about 750 mg, such as about 500 mg to 700 mg. In another exemplary embodiment, curcumin or tetrahydroxycurcumin is present in a daily dose of the nutritional health supplement contemplated herein in an amount of about 500 mg to 650 mg, for example, about 500 mg to about 600 mg, such as about 500 mg to about 550 mg. In another exemplary embodiment, curcumin or tetrahydroxycurcumin is present in a daily dose of the nutritional health supplement contemplated herein in an amount of about 500 mg
The nutritional health supplement contemplated herein comprises, but is not limited to, an antioxidant with free-radical species-deactivating properties, in accordance with another exemplary embodiment. While various antioxidants with free-radical species-deactivating properties are suitable for use in the nutritional health supplement contemplated herein, in an exemplary embodiment, the antioxidant with free-radical species-deactivating properties comprises glutathione. Referring to
In an exemplary embodiment, S-acetyl glutathione is present in a daily dose of the nutritional health supplement contemplated herein in an amount of about 500 mg to about 4000 mg, for example, about 500 mg to about 3500 mg, such as about 500 mg to about 3000 mg. In another exemplary embodiment, S-acetyl glutathione is present in a daily dose of the nutritional health supplement contemplated herein in an amount of about 500 mg to about 2500 mg, for example, about 500 mg to about 2000 mg, such as about 500 mg to about 1500 mg. In another exemplary embodiment, S-acetyl glutathione is present in a daily dose of the nutritional health supplement contemplated herein in an amount of about 500 mg to about 1000 mg.
In accordance with another exemplary embodiment, a method for attenuating or mitigating a brain injury is provided. The method comprises administering a therapeutically effective amount of a nutritional health supplement to a vertebrate or invertebrate. In an embodiment, the nutritional health supplement comprises an antioxidant that delays neuronal death under excitotoxic conditions, a neuroprotective agent having antioxidant, anti-inflammatory, and anti-apoptic properties, and a neuroprotective agent that is a precursor for glutathione synthesis. In another exemplary embodiment, the nutritional health supplement comprises an antioxidant that delays neuronal death under excitotoxic conditions, a neuroprotective agent that is a precursor for glutathione synthesis, a NAD+ precursor, a ketone body or ketone precursor, and an antioxidant with free-radical species-deactivating properties. In yet another exemplary embodiment, the nutritional health supplement comprises an antioxidant that delays neuronal death under excitotoxic conditions, a neuroprotective agent that is a precursor for glutathione synthesis, a NAD+ precursor, a ketone body or ketone precursor, a BCAA, and an antioxidant with free-radical species-deactivating properties. In a further exemplary embodiment, the nutritional health supplement comprises an antioxidant that delays neuronal death under excitotoxic conditions, a neuroprotective agent having anti-oxidant, anti-inflammatory, and anti-apoptic properties, a neuroprotective agent that is a precursor for glutathione synthesis, a NAD+ precursor, a ketone body or ketone precursor, a BCAA, a neuroprotective agent that mitigates glutamate-mediated excitotoxicity and calcium influx, a mitochondrial-dysfunction mitigator with anti-oxidant and anti-inflammatory properties, and an antioxidant with free-radical species-deactivating properties.
It will be appreciated that the exemplary embodiments of the nutritional health supplements contemplated herein can be presented and administered to oneself or to another vertebrate or invertebrate in any suitable form. For example, the nutritional health supplements contemplated herein can be in the form of a solid such that it can be administered or ingested orally as a pill, tablet, capsule, chewy or gummy supplement, gum, powder, for example, to be mixed in a liquid or drink, or the like. Alternatively, the nutritional health supplements as contemplated herein can be in the form of a liquid, so as to be administered subcutaneously, intravenously, as a liquid oral spoonful or shot, or via intranasal administration. Of course, other methods of administration of the nutritional health supplements contemplated herein also may be used, such as, for example, transdermally. It also will be understood herein that the term “daily dose” refers to one or more administrations of the nutritional health supplement, for example, one or more pills, one or more tablets, one or more liquid spoonfuls or shots, etc. in a 24-hour period.
As noted above, the natural health supplements contemplated herein are effective for both the attenuation and mitigation of brain injury. Accordingly, the administration of the nutritional health supplements can be affected before activity that may result in a concussion, for example, a sport, during activity that potentially could result in a concussion, and/or as soon as possible upon a suspected or confirmed concussion. For example, in one embodiment, one of the exemplary embodiments of the nutritional health supplement contemplated herein is taken in a daily dose for a period, such as, for example, two weeks, one month or the like, prior to the participation in a high-risk activity, or a series of high-risk activities, such as a sports season.
In another embodiment, a nutritional health supplement as contemplated herein is administered in discrete daily doses during periods of exposure to repetitive hits to the head, such as during a sports season. Exposure is highest in numerous contact and non-contact sports during practice and game activities. Youth and adult athletes who participate in contact sports sustain hundreds to thousands of hits to the head during an athletic season, depending on the sport and position of play. In the absence of symptoms or signs of concussion, these “sub-concussive” hits result in both functional and structural injury to the brain. Sub-concussive hits (or silent concussions) initiate the same pathophysiological events of a symptomatic concussion. Sub-concussive hits result in the same long-term neurological consequences as symptomatic concussions. Therefore, the daily use of an exemplary embodiment of the nutritional health supplement as contemplated herein during this exposure period will optimize the health of the brain, and enhance the protection of the brain, mitigate the damage to brain tissue, and enhance the repair mechanisms necessary because of these silent brain injuries.
In another embodiment, a nutritional health supplement as contemplated herein is administered in daily doses as soon as possible upon a suspected or confirmed concussion. Restoration of normal metabolic activity takes approximately 30 days after a single concussion. For example, a nutritional health supplement as contemplated herein is administered immediately or as soon as possible after a concussion and taken in daily doses for 30 days after a single concussion, or 60 days if there is a second concussion with 30 days after the first. The immediate administration after the contact is optimal. However, administration within 24 hours can substantially mitigate the injury and enhance the speed of recovery. Benefits of the nutritional health supplements contemplated herein may also be observed if the supplements are taken after 24 hours of the injury.
The various embodiments of the nutritional health supplement as contemplated herein can be taken in series at various times with respect to a potential or actual concussion. In one exemplary embodiment, a nutritional health supplement as contemplated herein comprising an antioxidant that delays neuronal death under excitotoxic conditions, a neuroprotective agent having anti-oxidant, anti-inflammatory, and anti-apoptic properties, and a neuroprotective agent that is a precursor for glutathione synthesis is taken before and/or during the period of exposure to repetitive hits to the head, such as during a sports season, to optimize the health of the brain, and enhance the protection of the brain. In another embodiment, a nutritional health supplement as contemplated herein comprising an antioxidant that delays neuronal death under excitotoxic conditions, a neuroprotective agent that is a precursor for glutathione synthesis, a NAD+ precursor, a ketone body or ketone precursor, and an antioxidant with free-radical species-deactivating properties is taken before and/or during the period of exposure to repetitive hits to the head, such as during a sports season, to optimize the health of the brain, and enhance the protection of the brain.
After a concussion, administration of this embodiment of the nutritional supplement is halted and an embodiment of the nutritional health supplement comprising an antioxidant that delays neuronal death under excitotoxic conditions, a neuroprotective agent having anti-oxidant, anti-inflammatory, and anti-apoptic properties, a neuroprotective agent that is a precursor for glutathione synthesis, a NAD+ precursor, a ketone body or ketone precursor, a BCAA, a neuroprotective agent that mitigates glutamate-mediated excitotoxicity and calcium influx, a mitochondrial-dysfunction mitigator with anti-oxidant and anti-inflammatory properties, and an antioxidant with free-radical species-deactivating properties is administered for approximately 30 days after a single concussion. Alternatively, an embodiment of the nutritional health supplement comprising an antioxidant that delays neuronal death under excitotoxic conditions, a neuroprotective agent that is a precursor for glutathione synthesis, a NAD+ precursor, a ketone body or ketone precursor, a BCAA, and an antioxidant with free-radical species-deactivating properties is administered for approximately 30 days after a single concussion. Restoration of normal metabolic activity takes approximately 30 days after a single concussion. Therefore, this nutritional health supplement is administered immediately or as soon as possible after a concussion and taken for 30 days after a single concussion, or 60 days if there is a second concussion with 30 days after the first.
As can be appreciated from the foregoing, description, these natural components that form the basis of the nutritional health supplements as contemplated herein address numerous factors of excitotoxicity, calcium-mediated toxicity, free radical toxicity, neuroinflammation, oxidative stress, protein synthesis, and neurodegeneration that are specifically stated herein. Additional benefits are not provided in the interest of brevity and clarity, and the stated, implied, and unstated benefits are applicable to other conditions, characterized by neuroinflammation, including concussion, stroke, cancer, infections of blood, brain, and other organs, autoimmunity and autoimmune brain diseases including multiple sclerosis and other demyelinating diseases, migraine and other primary and secondary headache disorders, neurodegenerative diseases including Parkinson's Disease, Huntington's Disease and Amyotrophic Lateral Sclerosis and other motor neuron diseases, and dementia syndromes, including Alzheimer's Disease and Chronic Traumatic Encephalopathy (CTE).
The following combinations are not exhaustive and provided only as exemplary embodiments. It will be appreciated that many other embodiments with various combinations of ingredients and amounts of ingredients are possible and are contemplated herein.
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
A nutritional health supplement for attenuating or mitigating concussion including, per daily dose of the nutritional health supplement:
This application is a U.S. National-Stage entry under 35 U.S.C. § 371 based on International Application No. PCT/US2020/023696, filed Mar. 19, 2020, which was published under PCT Article 21(2) and which claims priority to U.S. Provisional Application No. 62/853,520, filed May 28, 2019, U.S. Provisional Application No. 62/915,768, filed Oct. 16, 2019, and U.S. Provisional Application No. 62/947,729 filed Dec. 13, 2019, all herein incorporated by reference in their entireties.
Filing Document | Filing Date | Country | Kind |
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PCT/US2020/023696 | 3/19/2020 | WO |
Number | Date | Country | |
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62853520 | May 2019 | US | |
62915768 | Oct 2019 | US | |
62947729 | Dec 2019 | US |