Successful Functional Recovery from Traumatic Brain Injury Utilizing Thymus Extract

*There are currently no effective treatments for TBI.

Abstract

Traumatic brain injury (TBI) is one of the leading causes of death worldwide. Trauma survivors suffer from a variety of long lasting health consequences. TBI patients who do not meet the daily recommended allowance for keen nutrients, have a higher risk of mortality, longer hospital stays, and poor neurological scores. We sought to evaluate the potential therapeutic benefits of nutritional supplements derived from bovine thymus gland, which can deliver a variety of nutrients and bioactive molecules…inducing production of serum, IGG antibodies against neuronal and glial antigens, which may explain…the potency of a nutritional supplement containing nuclear fraction of bovine thymus in enhancing the functional recovery from TBI.

Abbreviations

• TBI – Traumatic brain injury
• mTBI – Mild traumatic brain injury
• BBB – Blood brain barrier
• AD – Alzheimer’s disease

TBI is a result of mechanical force trauma to the head that causes close to 30% of all deaths, occurs in approximately 70 million people, worldwide, yearly, and is referred to as a silent epidemic. Depending on the nature of the impact and injury, TBI varies from a mild concussion to a severe, disabling, and long lasting condition…inducing symptoms that range from brief unconsciousness, and amnesia to coma and prolonged central nervous system dysfunction. Approximately 5 million people In the United States alone, suffer from lasting consequences of this injury. TBI, including repetitive TBI is one of the most significant non-genetic, and non-age-related risk factors for Neurodegenerative diseases, such as chronic traumatic encephalopathy, Alzheimer’s disease, a DN like dementia, and even brain cancer.

The consequences of TBI, however, extend well beyond the brain, health, and cognitive function and affect other organ systems. Due to the complex nature of the pathology, which involves Neuro degeneration, formation of lesions, disruption of blood, brain barrier… And because of the poor regenerative capacity of the brain, TBI treatments need to target multiple sailor and molecular pathways and processes to date. There are no approved effective treatments for TBI, besides hospitalization, often in the intensive care units, surgery, and palliative or symptomatic care aimed at neurorehabilitation.

TBI is known to induce the production of IgG class Auto antibodies against Eno and gel antigens, presumably driven by the breakdown of the BBB and release of brain, specific proteins circulating IgG antibodies against neural, and Leo antigens may also indicate Neuro degenerative disease, nervous system, injury, and inflammatory response, Contributing to poor recovery from the injury. This is particularly relevant to repetitive mild traumatic brain injury and consequent TE because the immune system is activated continuously, due to repeated BBB disruption and cascades of cytotoxic events. However, when auto antibodies are induced in response to antigens presented food, the immune response against these food, derived antigens, in most cases, can be suppressed through an oral tolerance mechanism. in fact, induction of immune tolerance is one of the proposed novel approaches to treating Neuro determinative diseases, TBI, and also surgical brain injury, where delivery of nervous system antigens through oral, nasal mucosa, or intravenous roots, were shown to reduce inflammation and offer Nuro protection.

Nutritional support is considered a plausible approach to Amelia rating, and possibly preventing, the long-term consequences of head injury. The current consensus is that advanced official planning for patience with TBI needs to start promptly after the injury as it improves their survival and recovery rates. This is supported by extensive pre-clinical and clinical evidence showing that vitamins, minerals, antioxidants, and dietary supplements, improve various aspects of recovery from TBI … Naturally occurring molecular matrices are often more bioavailable, compared to individual, natural or synthetic supplements. However, the general nutritional value of foods we concern has been gradually declining due to declining soil, quality, the use of herbicides and pesticides as sub, optimal farming, practices, and large percentages of the world populations are deficient and multiple vitamins and minerals. in addition, meat and plant materials, deliver, distinct types of bioactive molecules, such as peptides and nucleic acids, which regulate a variety of biological processes, and these molecules are likely to differ between meats and plants due to the similar cellular compositions of these foods.

Desiccated thymus and thymus gland extracts — cytoplasmic (thymus tm) and nuclear (thymex PMG tm) provided by Standard Process, Inc. (Palmyra, WI, USA). Cytoplasmic and nuclear extracts were made from frozen raw bovine glands and dried on site using Standard Process Inc. proprietary processes. All test products are in powder form and are suitable for consumption by animals and humans. These extracts have been commercially available as dietary supplements in the United States since the early 1950s. The nuclear fraction of bovine thymus, particularly its concentrated form, may carry unique bioactive components with significant impact on gene regulation that could explain, in part, the enhancement of functional recovery.

Signaling pathways implicated in TBI, pathology and recovery are modulated by thymus extract supplementation

Brain injury, induces changes in many cellular and molecular pathways that respond to tissue damage and support healing and recovery. We therefore used ingenuity pathway analysis to evaluate which canonical signaling pathways are affected alone, and can be modulated by thymus extract, supplementation, and the extent to which each of the thymus extract impacts individual pathways in relation to the vehicle – sham group. we find that the number of signaling pathways significantly altered and thymus extract supplementation differs dramatically. Extract containing the thymus nuclear fraction, exert, pronounced effects on hippocampal gene expression patterns. Only the one thymus extract supplementation significantly improves recovery. Resveratrol, however, was found to be beneficial in the context of recovery from TBI.

Extract derived from bovine thymus contain antigens found within the nervous system, and their oral supplementation increases serum levels of IgG antibodies against those antigens

An increase in some autoantibodies against neural, and glial antigens is part of a pathological process, observed in several Neuro degenerative diseases, and with brain injury, and exacerbates the damage to the nervous system. However, when antigens, delivered in food elicit auto antibody production, the immune response can be suppressed through an oral tolerance mechanism, Which involves initial production of IGM antibodies against given antigens, and later, transition to production of IgG, antibodies against the same antigens, which can confer long-term suppression of the immune response. When antigens delivered in food, are identical or highly homologous to those that are normally not present in circulation at high levels, and are released from the brain tissues on injury, the circulating IgG antibodies induced through ingestion of food would prevent the immune system attack on cells that carry those antigens this reducing inflammation.

Thymus gland develops from Neuro, dermal tissue, later serves as a Neuro endocrine function, and is known to express neuronal and glial antigens.

The specific extract derived from bovine thymus fights antigens found within the nervous system. This oral supplementation increases serum levels of IgG antibodies against those antigens

“An increase in autoantigens is part of pathological process, observed in several Neurodegenerative diseases and with brain injury, and exacerbates the damage to the nervous system. However, when antibody production is solicited by antigens, delivered in food, the immune response can be suppressed through an oral tolerance mechanism, which involves initial production of antibodies against given antigens, and later, transition to production of IgG antibodies against the same antigens. This can confer long-term suppression of the immune response. When antigens delivered in food, are identical, or highly homologous to those that are normally not present in circulation at high levels, and are released from the brain tissues, upon injury, the circulating IgG antibodies induced through ingestion of food would prevent the immune system attack on cells that carry those antigens, reducing inflammation.”

Thymus gland develops from neuroectodermal tissue, later serves as a neuroendocrine function, and is known to overcome neural antigens. These antibodies wage war against those antigens and could be induced after oral supplementation.

Despite the high prevalence and long lasting consequences of TBI, effective treatments for this condition are still lacking, while timely, nutritional support and intervention are considered essential for reducing the risk of death and poor neurological outcomes. “In this study, we assess the potential benefit of bovine thymus gland TNF extract supplementation in acute head injury which recapitulates many common TBI symptoms observed, and is validated for experimental reliability by numerous research groups. This work reveals possible cellular and molecular mechanisms that may underline nutrition mediated improvement and acceleration of the recovery from TBI. Previous studies have demonstrated that TBI significantly impairs the vestibular-motor function in the early phase, following injury, and this effect diminishes, or disappears completely overtime.

“Consistent with previous reports of the prolong, cognitive and memory impairment, following TBI compared to sensory/motor dysfunction, we find that performance is poor. This effect of TBI is significantly ameliorated in TNF treatment.”

Sham and performance-behavioral studies together demonstrate the TNF supplementation prior to during recovery phase illicits, brings a pronounced improvement in both the early and long lasting symptoms of TBI that involve the vestibulomotor and cognitive functions, respectively. These findings suggest that TNF nuclear fraction of bovine thymus, which may have a unique composition compared to other thymus extracts we examined contains bioactive components that may be beneficial for faster recovery from TBI.”

Multiple studies have reported dramatic changes in hippocampal gene expression levels following moderate to severe TBI at both early, acute time points after the injury and throughout the recovery. While not many changes in gene expression were reported between days 14 and 30 after TBI, large numbers of genes appear to remain either up or down regulated, long-term. In our study, we find that TNF induces persistent changes in gene expression patterns with the majority of differentially expressed genes involved in inflammation and tissue repair. Conversely, we find the thymus extract supplementation, and TNF supplementation, in particular, induced, notably, larger changes in HIPAA gene expression patterns . These data suggest that beyond the expected normalization of hippocampal gene expression pattern that may accompany recovery from TBI, TNF affects the expression of many additional genes, which are likely to collectively influence the efficiency and the time course of functional recovery from brain injury. This finding is consistent with a known capacity of dietary components to change gene expression in various tissues through a variety of mechanisms. Notably the patterns of activation, versus suppression of the signaling pathways, most affected by thymus gland extract supplementation appear similar between supplemented Groups, Suggesting that the material contained in the nuclear fraction of bovine thymus is similar and composition between these two materials though differentially concentrated, which can explain the observed overlap, and affecting signaling pathways within the hippocampus.

Signaling pathways involved in the immune system response and neuro inflammation as well as in brain tissue, repair, and remodeling, are known to be modulated by TBI. Notably phagosome formation and autophagy, Specifically, are among the most significantly affected signaling pathways in the thymus extract supplementation. Autophagy is vital for both the pathogenesis and the recovery from TBI, and can also be triggered by nutrient, deprivation and attenuated by nutrient supplementation. On the one hand, increased autophagy following TBI can be beneficial for converting damaged or dysfunctional molecules and cellular organelles into the recyclable components. On the other hand, prolonged Autophagy can also eliminate functional proteins, lipids, nuclear acids, and cellular organelles. These results demonstrate that down regulation of key players in auto phagosome formation, coincides, with better recovery from TBI, suggesting one of three possible explanations: (1) the process of Autophagy is no longer highly necessary, and tissue repair has been largely completed in TNF supplementation; (2) prolonged, damaging Autophagy has been attenuated by TNF supplementation leading to fast tissue recovery (3), TNF, and other thymus extract supplementation may have a direct impact.

Among the most promising bio markers of TBI are antigens derived from the proteins residing within the nervous system, which can be detected in blood or cerebral, spinal fluid, potentially due to BBB disruption and cellular damage. Increase levels of circulating auto antibodies against antigens of neuronal and glial origin are found in many neurologic diseases, and may be an important, contributing factor toward disease, pathogenesis and progression. in fact, a proposed mechanism for the development of CT following repeated head trauma, involves repeated BBB permeation events and release of neural and glial proteins from the injured tissue into the blood, resulting in induction of the immune response to these proteins, evidence by higher tiers of auto antibodies against antigens of neuronal and glial origin. Together, these events lead to persistent Neuro inflammation and autoimmune processes, including loss of self tolerance, often observed in athletes and military personnel, who experience mild, repetitive concussions. Harnessing the immune system function. On the other hand, it’s one of the most promising approaches to the treatment of many pathological conditions, including TBI. Here, we demonstrate that bovine tissue extracts are capable of a listening production of IgG antibodies against the antigens specific to the tissues of origin. Notably, the nature of the extract determines what antigens are concentrated, bioavailability, and antigenicity. Consistent with this, we find that supplementation with heart – nuclear fraction elicits production of IgG‘s against myoglobin and troponin , but not some others. This may be due to low concentration of the others in the nuclear fraction of bovine heart tissue or to its low by availability among other possibilities. Yes, heart tissue extract is potent at inducing IgG antibodies against neuronal and glial antigens, in particular, that which also serves as predictive biomarker for patient outcomes, following cardiac arrest. Similarly, we find the thymus extracts increase serum levels of IgG against proteins present in the heart tissues, consistent with the expression of cardiac markers, such as myoglobin and thymus tissues.

Our results also demonstrate the serum levels of circulating IgG auto antibodies against nervous system antigens are elevated in TNF supplemention on day 21 post injury, and that the increased level of IgG antibodies coincide with better behavioral recovery from TBI; The vestibular motor function and spatial memory are both improved with TNF supplementation. The variation in the extent of IgG induction observed with groups of those supplemented, who were healthy compared to those undergoing supplementation prior to TBI, can be explained by the similarities of the supplementation duration time necessary for the switch between the production of IGN versus IgG class antibodies, which is a key feature in the primary immune response, was different. While IGA antibody levels generally peak between 10 and 15 days, following initial antigen exposure, and then rapidly decline, IgG levels toward the same antigen are detected later in the course of the immune response, and peak between 15 and 30 days, following antigen introduction, and display a wide time window of expression, depending on antigen exposure, continuity. In addition different environments, and diets combined with various daily regimens, which included behavioral could contribute to the discrepancy in the observed increase in IgG antibodies against nervous system antigens. The rise in serum levels of IgG antibodies against nervous system antigens in those supplemented with TNF is likely a part of the immune tolerance mechanism, wear by the inflammatory response of the immune system against the antigens delivered orally, is suppressed through expansion and activation of other cells, whereas, for other groups increased in IgG levels, could signify neural inflammation, caused by the stress. Neuro, inflammation, neuronal, silencing, and even ablation of cells within the nervous system or major contributions to the clinical presentation of TBI , and elated by the circulating antigens from the injured brain tissues. therefore I am finding that Tina supplementation can induced oral tolerance towards self antigens could be directly translated into therapies for human patient suffering from TBI related pathologies into individuals who are at risk of sustaining TBI studies are necessary to determine whether the induction of IgG antibodies through oral supplementation with bovine tissue extracts suppresses the immune system response to the antigens presence in those extracts, and whether the progression of diseases that stem from the elevated auto immune response could be delayed via nutrient supplementation and oral tolerance mechanism.

In this study, we demonstrate that a dietary supplement arrived from animal glandular material, is potent in improving the recovery from TBI when administration prior to, and following the injury. This finding is comparable to other studies that found dietary supplementation, including Resveratrol and DHA, among others, being neuroprotective, alleviating the symptoms and enhancing the recovery from brain injury. Compared to individual, dietary compounds and nutrients, however, thymus extracts are derived from the complex matrices of thymus tissue, and are likely to contain of variety of bioactive molecules, including peptides, lipids, and nucleic acids, which together can influence that array of cellular and molecular processes, in the context of brain injury, where ideology is complex, and involves many distinct processes And pathways, nutritional supplementation that offers multiple beneficial, bioactive compounds with a naturally occurring matrix, can possibly deliver a multifaceted neuroprotective effect that is required to effectively support TBI patients.

While meat consumption worldwide remains high, and is still rising, consumption organ meets, especially glandular tissues is low, particularly in countries, where western diets are common, such as the United States. Meanwhile, several nutrients and vitamins that are known to be neuroprotective and facilitate better recovery, following brain trauma, such as vitamin B12 and creatine can be found at higher levels in organ meats compared to muscle meats, and are low in plants if present at all, these observations suggested diet, especially Skeletal muscle, may not deliver the optimal amounts of nutrients that facilitate Neuro protection, support, cognitive function, or facilitate recovery from injuries. Nutritional supplements, derived from animal glandular tissue should be considered in the design of dietary plans for patients suffering from medical conditions and healthy individuals alike.