Understanding the neuroinflammatory response following concussion to develop treatment strategies
Reviewer: Paul Anderson, NMD
Title: Understanding the neuroinflammatory response following concussion to develop treatment strategies
Reference: Patterson ZR and Holahan MR. Understanding the neuroinflammatory response following concussion to develop treatment strategies. Front.Cell.Neurosci. 6:58.doi: 10.3389/fncel.2012.00058
Design: Literature Review
Neuroinflammation is becoming more and more associated in the literature with a host of downstream comorbidities including depression, anxiety, addictive behavior, dementia and others.
The setting of this widespread issue is described in the abstract:
“Mild traumatic brain injuries (mTBI) have been associated with long-term cognitive deficits relating to trauma-induced neurodegeneration. These long-term deficits include impaired memory and attention, changes in executive function, emotional instability, and sensorimotor deficits. Furthermore, individuals with concussions show a high co-morbidity with a host of psychiatric illnesses (e.g., depression, anxiety, addiction) and dementia. The neurological damage seen in mTBI patients is the result of the impact forces and mechanical injury, followed by a delayed neuroimmune response that can last hours, days, and even months after the injury. As part of the neuroimmune response, a cascade of pro- and anti-inflammatory cytokines are released and can be detected at the site of injury as well as subcortical, and often contralateral, regions. It has been suggested that the delayed neuroinflammatory response to concussions is more damaging then the initial impact itself.”
The authors of this paper are at a loss for pharmaceutical answers to these issues both due to confounding effects of many standard anti-inflammatory strategies as well as lack of data: “In some cases, treatments that reduce the inflammatory response will also hinder the brain’s intrinsic repair mechanisms. At present, there is no evidence-based pharmacological treatment for concussions in humans.” While in the larger peer-reviewed literature a drug therapy may not be evident, much data exists that supports integrative options for mTBI. These include some common integrative therapies, which have been shown to be helpful in mTBI and TBI, and in my clinical experience are effective in such cases. Some of the most effective interventions are summarized below.
Animal research into TBI has shown a correlation to the pathogenic environment of the CNS (“the inflammatory response following mechanical brain injury is characterized by an increase in the cytokine interleukin-1β (IL-1β) followed by a large elevation in the neurotrophin, nerve growth factor (NGF)” as well as improvement in recovery by augmentation of glutathione in the CNS. While direct data in humans on the effects of glutathione supplementation in TBI and mTBI are lacking, the known cytokine triggers of damage as well as pathways involved are largely manipulated by glutathione in the direction of healing. Nerve regeneration has been documented in an intravenous glutathione trial in humans with post-radiation nerve damage. In this study it was shown that the cofactors for glutathione cycling and function, when given with intravenous glutathione, were effective at aiding nerve regeneration, which has similar pathogenesis to radiation damage.
If intravenous glutathione is unavailable, then liposomal glutathione and oral nutrient cofactor use can be supportive.
In this paper, they review multiple cytokine triggers for the neuroinflammatory cascade following mTBI. The ability of curcumin to modulate these cytokines has been elucidated in many studies.,, In addition to this data, there is human clinical data showing that outcomes in CNS inflammatory depression improved with curcumin administration. 
Curcumin is a well-known integrative therapy and in cases of TBI and mTBI is a very appropriate inclusion into a treatment protocol.
In many of the same ways as are known about curcumin, boswelya can modulate the inflammatory cytokines involved in the pathogenesis of mTBI.  As with curcumin, boswelya can be considered in any case of mTBI as a potential therapy.
Neurosteroids are the CNS steroids involved in the anti-inflammatory activity as well as the repair mechanisms of the nervous system., Neurosteroids are also showing promise in the therapy of TBI., Most studies on neurosteroids include pregnenolone, progesterone and more recently DHEA. The effects of the neurosteroids are opposed by estrogens in the CNS.
The optimization of DHEA levels and the use of pregnenolone and progesterone as therapeutic interventions have shown in our clinical experience to be synergistic in the treatment of TBI and mTBI.
Hyperbaric Oxygen Therapy:
Hyperbaric Oxygen Therapy (HBOT) has been used for years in TBI and other non-healing injury states. A recent study showed that HBOT can induce neuroplasticity leading to repair of chronically impaired brain functions and improved quality of life in mTBI patients, even at late chronic stage. In our own clinic, we have likewise seen synergy with HBOT therapy and the others mentioned above in cases of TBI and mTBI. In a recent clinical trial, which is in pre-publication, patients with mild to moderate TBI improved in the following areas after 35 treatments: significant improvements 8/8 ANAM mood, 6/7 ANAM neurocognitive, and 7/10 CNS vital signs cognitive measures. Additionally earlier intervention with HBOT in younger patients and military personnel who had an increased number of HBOTs, correlated with improved outcomes.
While the authors of the Patterson paper do not come to any therapeutic conclusions using pharmaceutical therapies in mTBI, an integrative medical approach can offer many well-researched potential therapies. In my clinical experience, no single therapy equals the synergy of a multifaceted approach. The combinations of the therapies mentioned above, as well as many others known in integrative medicine, are the best approach for the patient with TBI and mTBI.
 Goss J. et.al. The Antioxidant Enzymes Glutathione Peroxidase and Catalase Increase Following Traumatic Brain Injury in the Rat. Experimental Neurology. Volume 146, Issue 1, July 1997, Pages 291–294.
 Reed TT, et.al. Proteomic identification of nitrated brain proteins in traumatic brain-injured rats treated postinjury with gamma-glutamylcysteine ethyl ester: Insights into the role of elevation of glutathione as a potential therapeutic strategy for traumatic brain injury. Journal of Neuroscience Research. Volume 87, Issue 2, pages 408–417, 1 February 2009 DOI: 10.1002/jnr.21872.
 Anderson PS. Et.al. Glutathione therapy in post radiation nerve injury. Presented in multiple scientific meetings 2013-16. https://www.academia.edu/21925456/Glutathione_ Augmentation_in_a_nerve_injury_model
 Bright JJ. Curcumin and autoimmune disease. Adv Exp Med Biol. 2007;595:425-51.
 Wilken et al. Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma. Molecular Cancer 2011, 10:12.
 Chen, C. et. al. An in vitro study of liposomal curcumin: Stability, toxicity and biological activity in human lymphocytes and Epstein-Barr virus-transformed human B-cells. International Journal of Pharmaceutics Vol. 366, No. 1, pages 133-139 (2009) DOI: 10.1016/j.ijpharm.2008.09.009.
 Lopresti AL, Maes M, Maker GL, Hood SD, Drummond PD. Curcumin for the treatment of major depression: a randomised, double blind, placebo controlled study. J Affect Disord. 2014 Oct;167:368-375.
 Ammon HP. Modulation of the immune system by Boswellia serrata extracts and boswellic acids. Phytomedicine. 2010 Sep;17(11):862-7.
 Paul SM, Purdy RH. Neuroactive steroids. FASEB. 1992;6:2311-2322.
 Djebaili M, Guo Q, Pettus EH, Hoffman SW, Stein DG. The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain injury in rats. J Neurotrauma. 2005 Jan;22(1):106-18.
Djebaili M, Guo Q, Pettus EH, Hoffman SW, Stein DG. The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain injury in rats. J Neurotrauma. 2005 Jan;22(1):106-18.
 Marx CE, Naylor JC, Kilts JD, et al. Neurosteroids and Traumatic Brain Injury: Translating Biomarkers to Therapeutics; Overview and Pilot Investigations in Iraq and Afghanistan Era Veterans. In: Laskowitz D, Grant G, editors. Translational Research in Traumatic Brain Injury. Boca Raton (FL): CRC Press/Taylor and Francis Group; 2016. Chapter 7.
 Boussi-Gross R, et al. (2013) Hyperbaric Oxygen Therapy Can Improve Post Concussion Syndrome Years after Mild Traumatic Brain Injury – Randomized Prospective Trial. PLoS ONE 8(11): e79995.
 Multi-center freestanding HBOT clinic study Organized by IHMF: Initiated by Duncan. Mozayeni P.I. with Jim Wright at mid-point, coordinated by Beckman. Supported by Reimers. Template/documents by Harch. Adults, PPC Sx, blast or blunt, mild-moderate TBI, > 3 old. (Submitted for publication – under review).