High-Intensity Interval Training Is Associated With Alterations in Blood Biomarkers Related to Brain Injury

The brain and the immune system are the two major adaptive systems of the body. During an immune response the brain and the immune system "talk to each other" and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs. Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation. Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenoreceptors. Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells. Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest. In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta(2)-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta. Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity. On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8 production. Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages. The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth. Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome.

1. The present study investigates to what extent and by which time course prolonged strenuous exercise influences the plasma concentration of pro-inflammatory and inflammation responsive cytokines as well as cytokine inhibitors and anti-inflammatory cytokines. 2. Ten male subjects (median age 27.5 years, range 24-37) completed the Copenhagen Marathon 1997 (median running time 3 : 26 (h : min), range 2 : 40-4 : 20). Blood samples were obtained before, immediately after and then every 30 min in a 4 h post-exercise recovery period. 3. The plasma concentrations of tumour necrosis factor (TNF)alpha, interleukin (IL)-1beta, IL-6, IL-1ra, sTNF-r1, sTNF-r2 and IL-10 were measured by enzyme-linked immunosorbent assay (ELISA). The highest concentration of IL-6 was found immediately after the race, whereas IL-1ra peaked 1 h post exercise (128-fold and 39-fold increase, respectively, as compared with the pre-exercise values). The plasma level of IL-1beta, TNFalpha, sTNF-r1 and sTNF-r2 peaked in the first hour after the exercise (2. 1-, 2.3-, 2.7- and 1.6-fold, respectively). The plasma level of IL-10 showed a 27-fold increase immediately post exercise. 4. In conclusion, strenuous exercise induces an increase in the pro-inflammatory cytokines TNFalpha and IL-1beta and a dramatic increase in the inflammation responsive cytokine IL-6. This is balanced by the release of cytokine inhibitors (IL-1ra, sTNF-r1 and sTNF-r2) and the anti-inflammatory cytokine IL-10. The study suggests that cytokine inhibitors and anti-inflammatory cytokines restrict the magnitude and duration of the inflammatory response to exercise.

Traumatic brain injury (TBI) is a major worldwide neurological disorder of epidemic proportions. To date, there are still no FDA-approved therapies to treat any forms of TBI. Encouragingly, there are emerging data showing that biofluid-based TBI biomarker tests have the potential to diagnose the presence of TBI of different severities including concussion, and to predict outcome. Areas covered: The authors provide an update on the current knowledge of TBI biomarkers, including protein biomarkers for neuronal cell body injury (UCH-L1, NSE), astroglial injury (GFAP, S100B), neuronal cell death (αII-spectrin breakdown products), axonal injury (NF proteins), white matter injury (MBP), post-injury neurodegeneration (total Tau and phospho-Tau), post-injury autoimmune response (brain antigen-targeting autoantibodies), and other emerging non-protein biomarkers. The authors discuss biomarker evidence in TBI diagnosis, outcome prognosis and possible identification of post-TBI neurodegernative diseases (e.g. chronic traumatic encephalopathy and Alzheimer's disease), and as theranostic tools in pre-clinical and clinical settings. Expert commentary: A spectrum of biomarkers is now at or near the stage of formal clinical validation of their diagnostic and prognostic utilities in the management of TBI of varied severities including concussions. TBI biomarkers could serve as a theranostic tool in facilitating drug development and treatment monitoring.