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New Perspectives and Natural Compounds for Traumatic Brain Injury

Traumatic brain injuries (TBI) and concussions are generating greater medical and research interest as public awareness grows, especially in terms of their impact on younger and more vulnerable populations. A recent study found there are approximately 30,000 concussions or head related injuries reported annually among the 12 to 19 year old age group, with over 80% being sports related.1 While these numbers are increasing every year, the majority of concussions are still not being reported so the true numbers are most likely underestimated.An explosion of recent research has uncovered some of the pathophysiological pathways involved in TBI. While one unified theory has yet to be confirmed, there is emerging evidence that brain trauma causes neurotransmitter and calcium release which initiates a cascade of neuroinflammation, excitotoxin production, mitochondrial dysfunction and immune activation.2 People that sustain a TBI undergo a very brief period of increased metabolism as brain cells try to restore balance and deal with the trauma. Following the brief hypermetabolic period, brain tissue rapidly progresses into a hypometabolic state as mitochondria function is impaired. This state can last 7 days or longer (30 days in severe cases) depending on the severity of the TBI. A very prevalent problem is that many athletes underplay or hide their symptoms in order to return to activity earlier. The risk of a concussion appears to increase when the brain has suffered a prior concussive injury.Until recently, little has been known about the long-term effects of TBIs and sub-concussive injuries. The symptoms of most concussions (mild to moderate severity) resolve spontaneously after 1-2 weeks, but a small proportion (less than 10%) progress to more advanced stages with persistent symptoms and cognitive impairment.3 The spectrum of post-concussive conditions includes acute TBI symptoms, post-concussion syndrome (PCS), prolonged post-concussion syndrome (PPCS), mild cognitive impairment (MCI), chronic traumatic encephalopathy (CTE), and dementia pugilistica (DP).3 Incomplete recovery, early return to activity and multiple injuries may contribute to the prolonged duration of symptoms and greatly increase the chance and severity of future concussions.3TBI is a common form of injury, which often goes un-reported and is commonly mismanaged. Researchers are just now beginning to understand the complex pathophysiological cascade after a brain injury. The current treatment and management of TBI and PCS is rest, reduction of sensory inputs, and symptomatic treatment (for conditions such as depression).2 Conventional and pharmaceutical approaches have shown limited benefits due to their singular mechanisms. Currently, no neuroprotective treatment options exist that improve symptoms after a TBI.4 Now many researchers are starting to study a wide range of natural compounds and vitamins that have promising broad-spectrum, neuroprotective and anti-inflammatory activity.

Natural Compounds for Neuroprotection and Recovery

While the evidence is far from conclusive, some simple conclusions can be drawn and applied to clinical practice. Some of the most promising natural compounds in active treatment of TBI are CDP-choline, omega-3 fatty acids, curcumin, green tea extract, vitamin E and resveratrol. From a preventative perspective, a diet high in polyphenols found in colourful fruits and vegetables, and omega-3 fatty acids, along with supplementation of vitamin E, may improve recovery after a TBI. The one definitive point is that very few (if any) side effects and negative results have been found in trials with natural substances, making their use safe. We can remain cautiously optimistic that more evidence will emerge to support natural therapies for TBI. This article will explore a number of the most promising natural treatment options to address the symptoms and pathophysiological pathways found in TBI. CDP-choline and omega-3 fatty acids have the most evidence, while vitamin E, curcumin, green tea and resveratrol are some of the compounds which also offer potential therapeutic benefit in the treatment of TBI.

CDP-Choline as a Beneficial Supplement for TBI

Cytidine diphosphoryl choline (CDP-choline) was found to be beneficial in treating post-concussive symptoms. A double blind placebo-controlled study investigated the effects of CDP-choline on patients with a mild to moderate closed head injury (CHI) with treatment provided for a month following the injury. Fourteen young men admitted to the neurosurgery department after sustaining mild to moderate CHI were randomized to oral CDP-choline (1 g) and placebo control groups which were matched for age, education and severity of impaired consciousness. At baseline (prior to discharge) and at one month, examinations consisted of a structured post-concussive symptom interview and neuropsychological tests. Analysis of the neuropsychological findings revealed a significantly greater improvement in recognition memory for the CDP-choline treated patients, whereas other changes in test performance did not differ for the two groups.6 Although further study is warranted, these findings suggest that CDP-choline may be effective in treating mild to moderate CHI.Another single blind randomized study was conducted in 216 patients with severe or moderate head injury.7The aim of the study was to compare the evolution of the injuries of those that received only conventional treatment with the evolution of those treated with CDP-choline. The results indicate that CDP-choline improves patient outcome. There was a trend towards a greater improvement in motor, cognitive and psychic alterations in the patients treated with CDP-choline, as well as a shortened hospital stay for the patients that initially presented with severe head injuries.7

Essential Fatty Acids

Omega-3 polyunsaturated fatty acids have long been considered essential for brain development and function. Docosahexaenoic acid (DHA) (and to a lesser degree eicosapentaenoic acid (EPA)) is primarily found in nerve membranes and influences fluidity, cell signaling, and inflammatory pathways.8 Since the human body cannot efficiently convert plant based essential fatty acids to EPA and DHA, fish oil supplements are the best source of these active components. It is important to note that while consuming fish that are high in omega-3 fatty acids is desirable, the high amount of heavy metals and polychlorinated biphenyls (PCBs) found in most fish is a concern, especially in regards to brain function.9A number of trials in animal models of TBI have found that that DHA and omega-3 supplementation improves cognitive function, reduces neuronal edema, stabilizes cellular energy homeostasis and increases dendrite growth.10,11 One of these studies also showed that pre-injury dietary supplementation with fish oil also had a neuroprotective effect.10 Mechanistically and functionally, DHA and EPA have promising therapeutic value for neuroprotection, when consumed from plant and fish sources, or from high quality contaminant-free fish oil.

Vitamin E

One of the frequently studied natural compounds for brain health is vitamin E, a family of molecules that have a potent antioxidant effect in fatty tissue. A number of animal studies have found that vitamin E supplementation reduces lipid peroxidation and improves cognitive performance following repetitive, concussive brain injury.12,13 Interestingly, supplementation before the concussions also had a neuroprotective effect.13Unfortunately there have been conflicting studies on the benefits of vitamin E supplementation, calling into question its clinical application.14Some of the conflicting results may be due to a number of flaws that exist in the use of vitamin E as an intervention in research trials. Vitamin E is a family of 8 molecules (four tocopherols and four tocotrienols) that function synergistically in human physiology. Most studies have used only low doses of alpha-tocopherol which has been shown to be the least active form of vitamin E and actually depletes the other forms.14 Gamma-tocopherol is the main anti-inflammatory component and has been found to be more effective than the alpha form in scavenging free radicals that cause inflammation.14 Emerging evidence suggests that the tocotrienol family provides even more benefits than the tocopherols in supporting brain and heart health.14

Curcumin

While results are still preliminary, curcumin (from turmeric) extract is showing positive benefit in neuro-recovery, membrane stabilization and reduction of oxidative stress in TBI models.16,17,18

The impact of oxidative stress on neuronal function and plasticity after (TBI) is becoming increasingly recognized. Animal studies have evaluated the capacity of this powerful antioxidant found in curry spice and found it is able to counteract the oxidative damage encountered in the injured brain as well as interact with molecular mechanisms that maintain synaptic plasticity and cognition. Other animal data suggests that clinically achievable concentrations of curcumin reduce glial activation and cerebral edema following neurotrauma. Supplementation of curcumin in the diet dramatically reduced oxidative damage and normalized levels of Brain Derived Neurotrophic Factor, synapsin I, and cellular transcription factors that had been altered after TBI. Furthermore, curcumin supplementation counteracted the cognitive impairment caused by TBI. Further, another animal study revealed the potential of a curcumin derivative to promote membrane homeostasis following TBI, which may foster a new line of non-invasive therapeutic treatments for TBI patients by up-regulation of molecules important for neural repair and plasticity. For more information on Curcumin, please see the article titled “Ayurveda and Cognition”.


Figure 1. Pathophysiology of traumatic brain injury.(1) In traumatic brain injury, excitotoxic effects (which occur when nerve cells die from being over stimulated), are mediated by an increased concentration of extracellular glutamate resulting from neuronal death and overproduction. Normally glutamate is taken up by astrocytes (cells in the brain), which convert it into glutamine and deliver it back to neurons as an alternative energy source. If glutamate is excessively produced, the astrocytes cannot remove it from the extracellular space. (2) Glutamate binding to neuronal receptors, such as NMDA, causes the influx of Ca2+ and Na+ and the efflux of K+. This ion imbalance causes depolarisation of the cell membrane and an overload of intracellular Ca2+.(3a) Compromised mitochondrial integrity is followed by release of reactive oxygen species and nitric oxide species, which together cause the oxidative stress that damages membrane lipids, proteins, and DNA, eventually leading to death of the nerve cell. (3b) Free Ca2+ also activates several enzymes, such as caspases, which contribute to DNA fragmentation and cell apoptosis. Other calcium-activated enzymes such as calpains impair axonal transport and function. (4) Ischaemia (low oxygen) causes a shift to anaerobic metabolism by astrocytes, producing lactate, which provides an alternative energy source to neurons in a process called coupled lactate metabolism.(5) Neuroinflammation consists of activation of glial cells (line the exterior of the neuron), the astrocytes, and microglia, which undergo several morphological and molecular changes. Glial cells secrete inflammatory cytokines, chemokines (which stimulate the transmigration of activated blood leucocytes into the brain), and reparative factors such as neurotrophins. Together with fibroblasts, these cells form the glial scar, which impairs axonal regrowth. (6) Microglia accumulate in the injured brain region and phagocytose the debris that originate from dying cells. (7) Infiltrated neutrophils and monocytes sustain the immune response to injury, thus impairing the integrity of the blood–brain barrier, which leads to increased extracellular fluid that, combined with cell swelling, leads to brain oedema and increased intracranial pressure.

Green Tea, Resveratrol and Other Polyphenols

EGCG-rich green tea extract has been shown to have antioxidant and anti-inflammatory effects in animal models of brain injury.19,20 There have also been a number of animal trials using polyphenols such as resveratrol, demonstrating anti-inflammatory and neuroprotective effects in TBI, but like green tea there have been no human trials to date.21,22

Endocrine Dysfunction and TBI

There may be other factors to investigate in cases involving traumatic brain injuries. One study investigated the prevalence of anterior pituitary dysfunction in a multi-centre screening program across five German endocrine centres in patients rehabilitating from TBI. A total of 246 patients underwent a series of endocrine tests. In 21% of these TBI patients, some degree of impaired anterior pituitary function was observed. These findings strongly suggest that patients who suffer head trauma should routinely undergo endocrine evaluation and may benefit from supplements that help to balance the endocrine system such as adaptogenic botanicals and nutrients to support the adrenals, thyroid and other glands. Please see the article titled “Stress-Induced Cognitive Dysfuntion: The Hormone-Neurotransmitter Connection” for further information on the endocrine system’s effects on cognitive health.

References

1. Gordon KE, Dooley JM, Wood EP. Descriptive epidemiology of concussion. Pediatr Neurol. 2006 May;34(5):376-8.

2. Maroon JC, Lepere DB, Blaylock RL, et al. Postconcussion syndrome: a review of pathophysiology and potential nonpharmacological approaches to treatment. Phys Sportsmed. 2012 Nov;40(4):73-87.

3. Giza CC and Difiori JP. Pathophysiology of sports-related concussion: an update on basic science and translational research. Sports Health. 2011 Jan;3(1):46-51

4. McConeghy KW, Hatton J, Hughes L, et al. A review of neuroprotection pharmacology and therapies in patients with acute traumatic brain injury. CNS Drugs. 2012 Jul 1;26(7):613-36.

5. Blaylock R and Maroon J. Natural plant products and extracts that reduce immunoexcitotoxicity-associated neurodegeneration and promote repair within the central nervous system. Surg Neurol Int. 2012; 3: 19.

6. Levin HS.Treatment of postconcussional symptoms with CDP-choline. J Neurol Sci. 1991 Jul;103 Suppl:S39-42.

7. Calatayud Maldonado V, Calatayud Pérez JB, Aso Escario J.J Neurol Sci. Effects of CDP-choline on the recovery of patients with head injury. 1991 Jul;103 Suppl:S15-8.

8. Dyall SC and Michael-Titus AT. Neurological benefits of omega-3 fatty acids. Neuromolecular Med. 2008; 10(4):219-35.

9. Mania, Wojciechowska-Mazurek M, Starska K, et al. Fish and seafood as a source of human exposure to methylmercury. Rocz Panstw Zakl Hig. 2012;63(3):257-64.

10. Mills JD, Bailes JE, Sedney CL, et al. Omega-3 fatty acid supplementation and reduction of traumatic axonal injury in a rodent head injury model. J Neurosurg. 2011 Jan; 114(1):77-84.

11. Wu A, Ying Z, Gomez-Pinilla F. Omega-3 fatty acids supplementation restores mechanisms that maintain brain homeostasis in traumatic brain injury. J Neurotrauma. 2007 Oct; 24(10):1587-95

12. Wu A, Zhe Y and Gomez-Pinilla F. Vitamin E protects against oxidative damage and learning disability after mild traumatic brain injury in rats. Neurorehabil Neural Repair. 2010;24:290–8.

13. Conte V, Uryu K, Fujimoto S, et al. Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury. J Neurochem. 2004;90:758–64.

14. Usoro OB and Mousa SA. Vitamin E forms in Alzheimer’s disease: A review of controversial and clinical experiences. Crit Rev Food Sci Nutr. 2010;50:414–9

15. Sen CK, Khanna S, Roy S. Tocotrienols: Vitamin E beyond tocopherols. Life Sci. 2006 Mar 27;78(18):2088-98. Epub 2006 Feb 3.

16. Wu A, Ying Z, Gomez-Pinilla F. Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity, and cognition. Exp Neurol. 2006 Feb;197(2):309-

17. Epub 2005 Dec 20.17. Laird MD, Sukumari-Ramesh S, Swift AE, et al. Curcumin attenuates cerebral edema following traumatic brain injury in mice: a possible role for aquaporin-4? J Neurochem. 2010 May;113(3):637-48.

18. Sharma S, Ying Z, Gomez-Pinilla F. A pyrazole curcumin derivative restores membrane homeostasis disrupted after brain trauma.Exp Neurol. 2010 Nov;226(1):191-9.

19. Wei IH, Tu HC, Huang CC, et al. (-)-Epigallocatechin gallate attenuates NADPH-d/nNOS expression in motor neurons of rats following peripheral nerve injury BMC Neurosci. 2011 Jun 1; 12():52.

20. Itoh T, Imano M, Nishida S, et al. Neuroprotective effect of (-)-epigallocatechin-3-gallate in rats when administered pre- or post-traumatic brain injury. J Neural Transm. 2012 Nov 21.

21. Ates O, Cayli S, Altinoz E, et al. Neuroprotection by resveratrol against traumatic brain injury in rats. Mol Cell Biochem. 2007 Jan; 294(1-2):137-44.

22. Gatson JW, Liu MM, Abdelfattah K, et al. Resveratrol decreases inflammation in the brain of mice with mild traumatic brain injury. J Trauma Acute Care Surg. 2013 Feb;74(2):470-4.Additional ReferencesPetraglia AL, Winkler EA, Bailes JE. Stuck at the bench: Potential natural neuroprotective compounds for concussion. Surg Neurol Int. 2011;2:146. doi: 10.4103/2152-7806.85987. Epub 2011 Oct 12Bengmark S. Curcumin, an atoxic antioxidant and natural NFkappaB, cyclooxygenase-2, lipooxygenase, and inducible nitric oxide synthase inhibitor: a shield against acute and chronic diseases. JPEN J Parenter Enteral Nutr. 2006 Jan-Feb; 30(1):45-51.Baum L, Lam CW, Cheung SK, et al. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J Clin Psychopharmacol. 2008 Feb; 28(1):110-3.Wu A, Ying Z, Schubert D, et al. Brain and spinal cord interaction: a dietary curcumin derivative counteracts locomotor and cognitive deficits after brain trauma. Neurorehabil Neural Repair. 2011 May;25(4):332-42. Park SK, Jung IC, Lee WK, et al. A combination of green tea extract and l-theanine improves memory and attention in subjects with mild cognitive impairment: a double-blind placebo-controlled study. J Med Food. 2011 Apr; 14(4):334-43.Begum AN, Jones MR, Lim GP, et al .Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer’s disease. J Pharmacol Exp Ther. 2008 Jul; 326(1):196-208.DiSilvestro RA, Joseph E, Zhao S, et al. Diverse effects of a low dose supplement of lipidated curcumin in healthy middle aged people. Nutrition Journal 2012, 11:79 Petraglia AL, Winkler EA, Bailes JE. Stuck at the bench: Potential natural neuroprotective compounds for concussion. Surg Neurol Int. 2011;2:146. doi: 10.4103/2152-7806.85987. Epub 2011 Oct 12.Kakuda T. Neuroprotective effects of theanine and its preventive effects on cognitive dysfunction. Pharmacol Res. 2011 Aug;64(2):162-8.

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