New trends in biological aids to recovery after exercise: Immunomodulators

Alfredo Córdova Martínez, Diego Fernández-Lázaro


The professional sport increases the physical and biochemical demands of muscle that is accompanied by important metabolic changes, such as the accumulation of toxic compounds, increased consumption of nutrients, and alterations in the physical, thermal and mechanical conditions of the cells. Neuroendocrine adaptations to the demands of elite athletic activity also modify local and systemic immune function, which contributes to the development and continuation of the inflammatory response. During intensive training and competition days, the recovery needs are also impressive. In such circumstances, athletes need to ingest often supplements as protein, micronutrients, minerals or substances to improve the muscular recovery In our experience, many specific products as the immunomodulators are directly linked to benefits, such as improved performance and concentration, reduced fatigue, better recovery and improved health or resistance against minor infections, which seem to occur more often when athletes are undergoing very intensive training. The purpose of this review is to provide an update on published research focusing primarily on the efficacy of immunomodulation substances in the recovery of athletes with respect to physical performance.




Agostini, F. & Biolo, G. (2010). Effect of physical activity on glutamine metabolism. Curr Opin Clin Nutr Metab Care, 13, 58-64.

Akerstrom, T. C. & Pedersen, B. K. (2007). Strategies to enhance immune function for marathon runners: what can be done? Sports Med, 37, 416–419.

Bernd, A., Ramirez-Bosca, A., Huber, H., Diaz Alperi, J., Thaci, D., Sewell, A. et al. (1995). In vitro studies on the immunomodulating effects of Polypodium leucotomos extract on human leucocyte fractions. Arzneimittelforschung, 45, 901–904.

Bousquet, J., Chanez, P., Mercier, J. & Prefaut, C. (1996). Monocytes, exercise, and the inflammatory response. Exerc Immunol Rev, 2, 35-44.

Bowtell, J. L., Gelly, K., Jackman, M. L., Patel, A., Simeoni, M., & Rennie, M. J. (1999). Effect of oral glutamine on whole body carbohydrate storage during recovery from exhaustive exercise. Journal of Applied Physiology (Bethesda, Md. : 1985), 86(6), 1770–1777.

Brieva, A., Guerrero, A. & Pivel, J. P. (2002). Inmunoferon, a glycoconjugate of natural origin, regulates the liver response to inflammation and inhibits TNF-alpha production by an HPA axis-dependent mecha¬nism. Int Immunopharmacol, 2, 807-813.

Brieva, A., Guerrero, A. & Pivel, J. P. (2003). Inmunoferon, an immunomodulator of natural origin, does not affect the rat liver cytochrome P-450 and phase II conjugation enzymes. Methods Find Exp Clin Pharmacol, 25, 187-191.

Burke, L. M., Millet, G. & Tarnopolsky, M.A. (2007). International Association of Athletics Federations. Nutrition for distance events. J Sports Sci, 25, S29-38.

Burke, L.M. & Mujika, I. (2014). Nutrition for recovery in aquatic sports. Int J Sport Nutr Exerc Metab, 24, 425-436.

Canonico, M. (1981). The physiologic and metabolic response of the host. Amsterdan, Holland: Ed. Elsevier/Holland.

Castell, L. (2003). Glutamine supplementation in vitro and in vivo, in exercise and in immunodepression. Sports Med, 33, 323–345.

Córdova, A. & Alvárez-Mon, M. (1995). Behaviour of zinc in physical exercise: a special reference to immunity and fatigue. Neurosci Biobehav Rev, 19, 439-445.

Córdova, A. & Alvarez-Mon, M. (2001). (Immunity in Sports) Inmunidad en el deporte. Madrid, España: Ed. Gymnos.

Córdova, A. (2010). Los inmunomoduladores frente a la inflamación y daño muscular originados por el ejercicio. Apunts Med Esport, 45, 265–270.

Cordova, A., Martin, J.F., Reyes, E. & Alvarez-Mon, M. (2004). Protection against muscle damage in competitive sports players: the effect of the im¬munomodulator AM3. J Sports Sci, 22, 827-833.

Córdova, A., Monserrat, J., Villa, G., Reyes, E & Soto, M.A. (2006). Effects of AM3 (Inmunoferon) on increased serum concentrations of inter¬leukin-6 and tumor necrosis factor receptors I and II in cyclists. J Sports Sci, 24, 565-573.

Córdova, A., Sureda, A., Pons, A. & Alvarez-Mon, M. (2015). Modulation of TNF-alpha, TNF-alpha receptors and IL-6 after treatment with AM3 in professional cyclists. J Sports Med Phys Fitness, 55, 345-351.

Crawford, J. & Cohen, H.J. (1995). The essential role of glutamine in lymphocyte differentiation in vitro. J. Cell. Physiol, 124, 275–282.

Dinarello, C.A. (2003). Anti-cytokine therapeutics and infections. Vaccine, 21, S24-34.

El-Haj, N. & Goldstein, N. (2015). Sun protection in a pill: the photoprotective properties of Polypodium leucotomos extract. Int J Dermatol, 54, 362-366.

Fiel, C.J., Johnson, I. & Pratt, V. C. (2000). Glutamine and arginine: immunonutrients for improved health. Med Sci Sports Exerc, 32, S377-S388.

Fuentes, E. & Córdova, A. (1999). (Pharmacological aspects in physical exercise and sport) Aspectos farmacológicos del ejercicio físico y del deporte. Medicine (Spain), 127, 5981-88.

Gleeson M., Nieman D.C. & Pedersen B.K. (2004). Exercise, nutrition and immune function. J. Sports Sci, 22, 115–125.

Gleeson, M. J. (2008). Dosing and efficacy of glutamine supplementation in human exercise and sport training. Nutr, 138, 2045S-2049S.

González, S. & Pathak, M. A. (1996). Inhibition of ultraviolet-induced formation of reactive oxygen species, lipid peroxidation, erythema and skin photosensitization by polypodium leucotomos. Photodermatol Photoimmunol Photomed, 12, 45-56.

Hackney, A. C. (2013). Clinical management of immuno-suppression in athletes associated with exercise training: sports medicine considerations. Acta Med Iran, 51, 751-756.

Horvarth, A., Alvarado, F., Szöcs, J., de Alvarado Z. N. & Padilla, G. (1967). Metabolic effects of calagualinem, an antitumoral saponine of polypodium leucotomos. Nature, 214, 1256-1258.

Hyeyoung, K. (2011). Glutamine as an Immunonutrient. Yonsei Med J. 2011, 52, 892–897.

Jeukendrup, A.E. & Gleeson, M. (2010). Sport Nutrition: An Introduction to Energy Production and Performance. Champaign, IL, USA: Editorial Human Kinetics.

Juhn, M.S. (2002). Ergogenic aids in aerobic activity. Curr Sports Med Rep, 1, 233-238.

Juretic, A., Spagnoli, G. C. & Horig, H. (1994). Glutamine requirements in the generation of lymphokine-activated killer cells. Clin Nutr, 13, 24.

Jurimae, J., Maestu, J., Jurimae, T., Mangus, B. & von Duvillard, S. P. (2001). Pe-ripheral signals of energy homeostasis as possible markers of train¬ing stress in athletes: a review. Metabolism, 60, 335-350.

Kargotich, S., Keast, D., Goodman, C., Bhagat, C. I., Joske, D. J., Dawson, B. et al. (2007). Monitoring 6 weeks of progressive endurance training with plasma glutamine. Int J Sports Med. 2007, 28, 211-216.

Kent, T.H. & Hart, M.N. (1993). Injury, inflammation and repair. Norwalk, Conneticut, USA: Ed. Appleton and Lange.

Koning, D., Wagner, K. H., Elmadla, I. & Berg, A. (2001). Exercise on oxidative stress: Significance of antioxidants with reference to inflammatory muscular and systemic stress. Exerc Immunol Rev, 7, 108-133.

Kreider, R. B., Miriel, V. & Bertun, E. (1993). Amino acid supplementation and exercise performance: proposed ergogenic value. Sports Med 1993, 16, 190-209.

Lagranha, C. J., Levada-Pires, A. C., Sellitti, D. F., Procopio, J., Curi, R. & Pithon-Curi, T. C. (2008). The effect of glutamine supplementation and physical exercise on neutrophil function. Amino Acids, 34, 337-346.

Lemon, P. W. R. (1995). Do athletes need more dietary protein and amino acids? In J Sport Nutr 1995, 5, S39-S61.

Martin-Vilchez, S., Molina-Jimenez, F., Alonso-Lebrero, J. L., Sanz-Ca¬meno, P., Rodriguez-Munoz, Y., Benedicto, I. et al. (2008). AM3, a natural gly¬coconjugate, induces the functional maturation of human dendritic cells. Br J Pharmacol, 154, 698-708.

Maughan, R. J. (1999). Nutritional ergogenic aids and exercise performance. Nutr Res Rev, 12, 255-280.

Maughan, R.J. & Gleeson, M. (2010). The Biochemical Basis of Sports Performance. Oxford, UK: Ed. Oxford University Press.

Moreira, A., Delgado, L., Moreira, P. & Haahtela, T. (2009). Does exercise increase the risk of upper respiratory tract infections? Br Med Bull, 90, 111–131.

Moura, C. S., Lollo, P. C. B., Morato, P. N., Risso, E. M. & Amaya-Farfan, J. (2017). Modulatory effects of arginine, glutamine and branched-chain amino acids on heat shock proteins, immunity and antioxidant response in exercised rats. Food Funct, 8, 3228-3238.

Nestor, M. S., Berman, B. & Swenson, N. (2015). Safety and Efficacy of Oral Polypodium leucotomos Extract in Healthy Adult Subjects. J Clin Aesthet Dermatol, 8, 19-23.

Newsholme, E. A. & Parry-Billings, M. (1990). Properties of glutamine release from muscle and its importance for the immune system. J Parenteral Enteral Nutr, 14, 63S–67S.

Newsholme, E.A. (1994). Biochemical mechanisms to explain immunosuppression in well-trained and overtrained athletes. Int J Sports Med. 1994, 15, S142-147.

Newsholme, P. J. (2001). Why is L-glutamine metabolism important to cells of the immune system in health, postinjury, surgery or infection? Nutr, 131, 2515S-2522S.

Nielsen, H. G. & Lyberg, T. (2004). Long-distance running modulates the expression of leucocyte and endothelial adhesion molecules. Scand J Immunol, 60, 356–362.

Nieman, D. C. (2003). Current perspective on exercise immunology. Curr Sports Med Rep, 2, 239–242.

Nieman, D. C. (2008). Immunonutrition support for athletes. Nutr Rev, 66, 310–320.

Nieman, D.C. & Pedersen, B.K. (1999). Exercise and immune function. Recent developments. Sports Med, 27, 73-80.

Nieman, D.C. (1999). Nutrition, exercise, and immune system function. Clin Sports Med, 18, 537-548.

Nieman, D.C. (2007). Marathon training and immune function. Sports Med, 37, 412-415.

Northoff, H., Enkel, S. & Weinstock, C. (1995). Exercise, injury and immune function. Exerc Immunol Rev, 1, 1-25.

Parry-Billings, M., Budgett, R., Koutedakis, Y., Blomstrand, E., Brooks, S., Williams, C. et al. (1992). Plasma amino acid concentrations in the overtraining syndrome: possible eVects on the immune system. Med Sci Sports Exerc, 24,1353–1358.

Pedersen, B. K. & Febbraio, M. A. (2008). Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev, 88, 1379-406.

Pedersen, B. K., & Hoffman-Goetz, L. (2000). Exercise and the immune system: regulation, integration, and adaptation. Physiological Reviews, 80(3), 1055–1081.

Pedersen, B. K., Bruunsgaard, H., Klokker M., Kappel, M., MacLean, D. A., Mielsen, H.B. et al. (1997). Exercise-induced immunomodulation—possible roles of neuroendocrine and metabolic factors. Int J Sports Med. 1997, 18, S2–S7.

Pedersen, B.K., Steensberg, A., Fischer, C., Keller, C., Ostrowski, K. & Schjerling, P. (2001). Exercise and cytokines with particular focus on muscle derived IL-6. Exerc Immunol Rev, 7, 18-31.

Powers S.K., Duarte, J., Kavazis, A.N. & Talbert, E. E. (2010). Reactive oxygen species are signalling molecules for skeletal muscle adaptation. Exp Physiol, 95, 1-9.

Rayward, J., Villarrubia, V. G., Guillen, C., Prieto, A., Rodríguez-Zapata, M., Sada G. et al. (1997). An extract of the fern polypodium leucotomos inhibits human peripheral blood mononuclear cells proliferation in vitro. In J Immunopharmacol 1997, 19, 9-14.

Saito, H., Furukawa, S. & Matsuda, T. (1999). Glutamine as an immunoenhancing nutrient. JPEN J Parenter Enteral Nutr, 23, S59-61.

Santos, R. V., Caperuto, E. C., de Mello, M. T & Costa Rosa, L. F. (2009). Effect of exercise on glutamine metabolism in macrophages of trained rats. Eur J Appl Physiol, 107, 309-315.

Schuber, M. M. & Astorino, T.A. (2013). A systematic review of the efficacy of ergogenic aids for improving running performance. J Strength Cond Res, 27, 1699-1707.

Sempere JM, Rodrigo C, Campos A, Villalba JF, Diaz J. Effects of anapsos (Polypodium leucotomos extract) on in vitro production of cytokines. Br J Clin Pharmacol. 1997; 43: 85–89.

Smith, D. J. & Norris, S. R. (2000). Changes in glutamine and glutamate concentrations for tracking training tolerance. Med Sci Sports Exerc, 32, 684–689.

Solivellas, B. M., & Martin, T. C. (2012). Polypodium leucotomos Extract use to prevent and reduce the risk of infectious diseases in high performance athletes. Infection and Drug Resistance, 5, 149–153.

Sorichter, S., Puschendorf, B. & Mair, J. (1999). Skeletal muscle injury induced by eccentric muscle action: muscle proteins as markers of muscle fiber injury. Exerc Immunol Rev, 5, 5-21.

Thein, L. A., Thein, J.M. & Landry, G.L. (1995). Ergogenic aids. Phys Ther, 75, 426-439.

Tsai, P. H., Yeh, C. L., Liu, J.J., Chiu, W.C. & Yeh, S.L. (2012). Effects of dietary glutamine on inflammatory mediator gene expressions in rats with streptozotocin-induced diabetes. Nutrition, 28, 288-293.

Vargas, J., Muñoz, C., Osoro, C. & García-Olivares. E. (1983). Anapsos, an antipsoriatic drug which increases the proportion of suppresor cells in human peripheral blood. Ann Immunol (Inst Pasteur), 134C, 393-400.

Wallberg. L., Mikael Mattsson, C., Enqvist, J. K & Ekblom, B. (2011). Plasma IL-6 concentration during ultra-endurance exercise. Eur J Appl Physiol, 111, 1081-1088.

Walsh, N. P. & Blannin, A. K. (19989. Robson PJ, Gleeson M. Glutamine, exercise and immune function. Links and possible mechanisms. Sports Med, 26, 177–191.

Wasinski, F., Gregnani, M. F., Ornellas, F. H., Bacurau, A.V., Câmara, N.O., Araujo, R. C. et al. (2014). Lymphocyte Glucose and Glutamine Metabolism as Targets of the Anti-Inflammatory and Immunomodulatory Effects of Exercise. Mediators Inflamm, 326803.

Welbourne, T. C. (1995). Increased plasma bicarbonate and growth hormone after an oral Glutamine load. Am J Clin Nutr 1995, 61, 1058-1061.

Wilmore, D. W. & Shabert, J.K. (1998). The role of glutamine in immunologic responses. Nutrition, 14, 618–626.

Wilmore, D.W. (2001). The effect of glutamine supplementation in patients following elective surgery and accidental injury. J Nutr, 131, 2543S–2549S.


License URL: