Services on Demand
- Cited by SciELO
- Access statistics
Print version ISSN 1517-8692On-line version ISSN 1806-9940
Rev Bras Med Esporte vol.13 no.5 Niterói Sept./Oct. 2007
Aderbal S. Aguiar Jr.; Ricardo A. Pinho
Laboratório de Fisiologia e Bioquímica do Exercício, Programa de PósGraduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brasil
Physical activity is known for promoting health and wellbeing. Exercise is also responsible for increasing the production of Oxygen Reactive Species (ORS) by increasing mitochondrial oxygen consumption causing tissue oxidative stress. The imbalance between ORS production and tissue antioxidant defenses can cause oxidative damage to proteins, lipids and DNA. Brain oxidative damage is a common etiopathology mechanism of apoptosis and neurodegeneration. The brainderived neurotrophic factor plays an important role in this context. In this review, we showed the results of different models and configurations of physical exercise in oxidative and neurotrophic metabolism of the Central Nervous System (CNS). We also reviewed studies that utilized antioxidant supplementation to prevent exerciseinduced oxidative damage to CNS. The commonest physical exercise models were running wheels, swimming and treadmill with very different configurations of physical training such as duration and intensity. The results of physical training on brain tissues are very controversial, but generally show improvement in synaptic plasticity and cognition function with low and moderate intensity exercises.
Keywords: Physical activity. Oxidative stress. Antioxidants. Neurotrophins. Brain.
Neurosciences have introduced a variety of new neurological concepts as well as scientific methods of investigation of the nervous system associating the discussion of factors of physical and environmental stress, such as physical exercise(1). Despite the evidence of general health benefits caused by regular physical exercise to healthy individuals and to the ones with diabetes mellitus, asthma, obesity, hypertension, arthrosis and arthritis(24); the effects of the exercise on the brain still present controversial results.
It is believed that moderate exercises increase cognition; moreover, it has been demonstrated that the brain is responsive to physical activity(58). It means that physical activity presents potential in the prevention and treatment of cerebral traumatic damage(9) as well as in neurodegenerative diseases such as Parkinson disease(1011) and Alzheimer's disease(1213). Studies support that many of these alterations occur in specific areas of important brain functions such as longrun memory(1415) and prevention of cognitive decline during the aging process(16). Some studies also demonstrate evidence on neurogenesis and brain plasticity(1719) specifically induced by families of neurothrophic molecules(2021); however, the mechanisms of these alterations are still unknown.
The majority of the research with the aim to study the neurological adaptation mechanisms to exercise develops research with animal models due to the possibility to evaluate the nervous tissue in vivo(2225). Studies involving humans indirectly evaluate the brain function mainly by nuclear magnetic resonance(2627) , electrophysiology(28), neuroendocrinology(29) and brain function scales(30). The aim of this investigation is to review and discuss some of the brain mechanisms under physical exercise influence, as well as the adaptations of the brain tissue and the consequences in the neurological functions.
PHYSICAL EXERCISE MODEL FOR STUDY OF THE CNS
Rodents are the main study animal models for the physical exercise paradigms in the brain functions and their mechanisms, where the two main physical activity models are: (1) voluntary activities such as activities in running wheels(3134) and enriched environments(3538), and (2) forced exercises such as swimming(3942) and treadmill(4347). These models usually aim to stimulate the responses to training with predominance of aerobic metabolism, once this kind of exercise is associated with general health benefits.
Enriched environment is a reference to the standardized kind of cage, where a set of different stimuli are given to the animals, namely: access to running wheels, group interaction, and complex environments containing toys, tunnels and frequent changes in the food placement, which is usually followed by gains in the brain function, especially the ones associated with learning and memory(48). The running wheel is a circadian intermittent(5), voluntary and of free access physical activity(1) which allows running at a selfdetermined velocity. The velocity spontaneously chosen corresponds to the level of optimum bioenergetic efficiency leveling the oxidative metabolism level(49).
Forced activities make the animals perform physical exercise at higher intensities, that is, higher energetic demands. Forced swimming allows selecting exercise overloads through the variation from 3% to 6% of body mass of the animal's body and imposes lower mechanical stress due to the water thrust, recruiting different muscle groups and reducing the gravity effects(50).
Running on treadmill activates the stress neuroendocrin responses and makes the animal run at a steady velocity, according to the experiment's configurations of the physical training: time, duration, velocity(5) and inclination(5152). Running on treadmill is usually selected due to aerobic metabolism responses higher than swimming(53), since it is characterized by relative inactivity of the hinder legs(54). Treadmill training with controlled intensity induces to some of the highest and most consistent effects of physical training(5556).
PHYSICAL EXERCISE AND NEUROTHROPHINS
Neurothrophins are a family of essential cytokines for the differentiation, growth and survival of the CNS dopaminergic, cholinergic and noradrenergic hormones and of sympathetic and sensory hormones of the Peripheral Nervous System (PNS) during adulthood(5759). Up to the present time, they are represented by five proteins of related structure which constitute the neurothrophins family, including the nerve growth factor (NGF), and the Brain Derived Neurothrophic Factor (BDNF), and the neurothrophins 3, 4/5 and 6 (NT 3, NT 4/5 and NT 6 Neurothrophic Factor)(6061).
Evidence has shown the BDNF role as critical modulator in the synaptic plasticity in the hypofield(62). The deletion or inhibition of the BDNF gene(63) produces a deficiency in the longrun memory (LTP). This deficiency in the synaptic function may be corrected by exogenous applications(64) or overexpression(65) of the BDNF. Many genes associated to the BDNF action in the synapses increase their expression as an exercise result and may support the synaptic function or neuroplasticity(66).
The exercise increases the expression of many genes associated with the synaptic function(66). Additionally to the synapsin I, exercise increases the mRNA levels for syntaxin and synaptogamin. Synapsin I is predominantly increased at short periods of exercise (3 and 7 days), being hence consistent to its role in the release of synaptic vesicles(67). Synaptogamin progressively increases after long periods of exercise, being consistent to its role of synaptic vesicles(68). The deletion of the BDNF gene in mice results in reduction of the synaptic proteins as well as their vesicles resulting in damage in the neurotransmissors release(69). The BDNF promotes the phosphorylation of the synapsin I via activation of the TrkB receptors in the presynaptic terminal, resulting in release of neurotransmissors(70). The exercise increases the mRNA levels and TrkB protein and synapsin I in the synapses via BDNF(7174). It is possible that high levels of inducedexercise BDNF facilitate the formation and mobilization of synaptic vesicles, and the extension of these events may be translated in long alterations in the synaptic plasticity(66).
These increases in the gene concentration and expression of the neurothrophins as well as their receptors present a distinct behavior to the different physical training studied. After two weeks of free access to the running wheel, the rats developed higher concentrations of BDNF in the hypofield, persisting up to a week after the exercise interruption(71). The hypofield BDNF, TrkB, NT3 mRNA levels returned to the normal concentrations with the total interruption of the exercise, meaning that these increases are dependent on the continuity of the exercise and reversible(74). The higher the exercise volume, both swimming and running, the higher the BDNF levels were in the brains of the mice(7577). There is strong evidence that the exercise develops neurological alterations via BDNF, since the increase in the neurothrophins levels and their gene expression in running wheels was cancelled in the CA3 area and dented spin in the hypofield of rats, when blockers of the neuronal receptors of neurothrophins such as the K252a are administered, which inhibits the Trk receptor of the BDNF(78). Similar effects have been found with the use of the KN62 antagonists, an inhibitor of the nicotinodiamide (NMDA) or PD98059 channels which inhibits the MAPK(78).
The exercise increases the gene expression of many complements of the MAPK cascade such as the MAPKI and MAPKII. The MAPK way is the largest signaling cascade of the Trk receptors(79). The MAPK is involved in the synaptic plasticity, memory formation and integration of multiple extra cellular signals(8081). It seems that the MAPK ways coordinate many synaptic events in conjunction with the CaMK ways. For instance, the synapsin I is phosphorylated by the MAPK and CaMKII systems(82). The CaMKII affects the Ca+2 postsynaptic important for the synaptic function(83), and is involved in the formation of hypofielddependent memory(84). The PKCd expression increased after 7 days of exercise(66). PKCd is necessary for the activation of the MAPK cascade and for nerves growth(85). Members of the CaMK family increased their activity after short periods of exercise while members of the MAPK way increased their activity according to the exercise tie, especially after 7 days(66).
Exercising increases the expression of the CREB transcription factor(66). The CREB may regulate the BDNF gene transcription in the calciumdependent mechanism(8687). Thus, through the MAPK cascade, the BDNF causes the CREB phosphorylation resulting in its activation and gene transcription(88). CREB is necessary for many kinds of memory(8990), and seem to play an important role in the neuronal resistance to insults(91). The hypofield of mice with CREB low levels presented harm in the maintenance of LTP(90). The highest increases in the mRNA levels of the CREB were observed after 7 days of consistent exercise, with induction of the MAPK members(66).
Plenty of evidence has shown increase of the neurothrophic proteins concentrations and their transcription associated with regular physical activity practice(9293). Treadmill running and running wheels increased the protein levels and mRNA of BDNF(14,93) as well as NT3(77) in the hypofield of rats, in cortex and cerebellum(59). The same fact was observed in swimming as well(94). Additionally, exercising protects the neurons from many kinds of insults(95), since the BDNF promotes neurogenesis in adults(96) and increases the synaptic efficiency(62). Twelve weeks of running on treadmill decreased the brain ischemic volume induced by occlusion of the medium brain artery of rats, being followed by increase of the mRNA concentration of NGF and its p75 GAPDH receptor, that is, the induced exercise increased the gene expression of neurothrophins causing neuroprotection to neuronal ischemia(97).
There are studies showing that exercising increases memory and spatial learning. Increase of the LTP occurs with increase of the neurothrophic factors endogenous to exercise(19). The LTP can also be moderated by alterations in endogenous cytokines such as TNFa (necrosis a transcription factor) and the IL1b (Interleukin 1b)(9899) as a straight consequence from exercise(100).
EXERCISE AND OXIDATIVE STRESS
The molecular oxygen in its diatomic state (3ågO2) is a highly oxidant species essential to the energy production during the oxidative mitochondrial phosphorylation(101). The extra reactive oxygen has a strong oxidative potential: according to the exclusion principle by Pauli, the O2 oxidizes the other molecule by accepting an electronic pair, only if both electrons from the pair have a pair of spins anti parallel to their own nonpaired electrons(101). Due to this criterion rarely found, the O2 slowly reacts in the lack of catalyzers and tends to accept a single electron during its redox chemistry(102103).
In vivo, enzymes usually use an electron in the period in which they perform O2 multi electronic reductions. If a single electron is accepted, it must enter an orbital and produce O2(104).
The reduction of the two electrons of the O2 plus the addition of 2 protons (H+) generates H2O2.
Many oxidases use this mechanism to reduce O2 directly to H2O2. The O2 spontaneous or catalyzed dismutation by the peroxide dismutase also produces H2O2(104).
Peroxide is a nonradical intermediary which oxidizes a wide range of biological media, despite being a nonreactive species.
In the HaberWeiss reaction (also known as Fenton superoxideguided chemistry), chelatings of transition free or of low molecular weight metals, such as the Fe3+ are reduced by the O2 to Fe2+. The metallic reduced ion which reacts with the H2O2 generates the extremely reactive HO(101).
This species has been widely postulated as being the most important cause of damage to proteins, lipids, carbohydrates and DNA; however, there is slight straight evidence that the HO is generated in biological systems(104). The biggest unsolved issue concerning the biological relevance of the HaberWeiss reaction is the need of free Fe3+ or Cu2+ due to the great variety of metaltransporter and metalligant proteins keeping the concentration of free activeredox metallic ions at low levels in the normal tissues. Nevertheless, this destruction may release activeredox metallic ions(101,105).
Massive attention has been directed to the production of oxidative species by the O2. However, it is important highlighting that O2 is a strong reducing agent. Its properties are added to its easy ability to rapidly react with the metallic ions (Mn+)(104).
This reaction has been proposed to generate the reduced metals needed for the HO production by the HaberWeiss reaction (equation 4)(104). Recent studies suggest that proteins containing transition metals, such as the aconitase, an enzyme of the tricarboxilic acid cycle, are vulnerable to reduction by O2 damage, which can be a contributing factor to muscular fatigue during exercise(101,105).
The oxidative phosphorylation generates the greatest part of the cellular ATP, and mitochondrial dysfunctions do harm to the energetic metabolism, where 1% of the mitochondrial electronic flow generates superoxide anions (O2), the first mitochondrial oxygen reactive species (ORS), demonstrating the importance of an efficient antioxidant system for preservation of the transporter chain of mitochondrial electrons(106). Thus, there is a critical balance between the blood continuous supply of nutrients and oxidative energetic metabolism of the cerebral mitochondria(107), also regulated by additional mechanisms such as the mitochondrial calcium, membrane potential, and couplingmembrane proteins(106). A dysfunction in the mitochondrial chain of electrons transport may be the highest source of toxic oxidants, including mitochondrial DNA, proteins and lipids oxidation, and opening of mitochondrial permeability pores, an event associated with neurodegeneration and death(101,107).
The brain represents approximately 2% of the body mass, but its O2 (CMRO2: 5 ml/min/100g) and glucose (CMRglu: 31 µMol/min/100g) consumption represents respectively 20 and 25% of the total consumption of the body at rest. The cerebral blood debt is consequently high: 1420% of the rest blood debt. This energetic metabolism is wellevidenced by the continuous activity of neuronal intercellular communication(108), kept by the high glycemic metabolism through small supplies of high energy carbohydrates and phosphates, with no oxygen supplies(107).
The CNS is more susceptible to oxidative damage, since it represents great oxygendependant mitochondrial activity, associated with high free iron and polyunsaturated lipids and low levels of antioxidant enzymes(108). The brain has 3% of the peroxides glutathione and 1% of the liver catalase. The glutathione is precursor of the antioxidant enzyme glutathione peroxidase(109). The basis glands have high iron concentration and altered iron metabolism has high oxidant potential by the HaberWeiss reaction.
When polynsaturated fatty acids in the biomembranes are attacked by free radicals in the presence of molecular oxygen, a chain of peroxidation reactions occurs, occasionally leading to formation of hydrocarbon gases (e.g. methane, ethane and pentane) and aldeids (e.g. malonaldehyde, MDA). Bioproducts of the lipid peroxidation are the most studies markers of oxidative tissue injury during exercise, as well as the oxidative alterations caused to the proteins (including enzymes) and nucleic acids(101,105).
Young and old rats have improved learning and memory after swimming training(110) as well as decreased proteins carbonilyzation(50,111112) and lypoperoxidation in the cerebellum(94), hypofield and cerebral cortex(50). These adaptations have persisted even after the same period of lack of exercise(94). These swimming outcomes were wellevidenced with a high intensity exercise(111).
After 8 weeks of treadmill running, diabetic rats presented higher concentrations of cerebral lypoperoxidation(113). In normal rats, the lypoperoxidation in the brain occurred with vitamin C supplementation(114). The lipids oxidation in the CNS usually demonstrates different concentrations at different regions of the brain, and it can be attributed to regional differences in the O2 consumption(115116).
An acute exercise bout may increase the activity of some antioxidant enzymes with no new protein synthesis. This protection activity is limited to individual enzymatic characteristics and the involved tissue. As longrun strategy, the cells may increase the protein synthesis of antioxidant proteins in order to control the oxidative stress.
It has been demonstrated that intense exercise does not alter the SOD and GPx enzymes activities in the hypofield, striated and prefrontal cortex 24 hours after the exercise(3).
The acute effects of the exercise over the brain antioxidant enzymes did not show differences in the SOD activity in the spinal cord and hypothalamus(117), cerebellum(118), cerebral cortex and hypofield either(50). The increase in antioxidant enzymes activity in the brain as response to regular physical exercise is more probable linked to excess of free radicals formation(118120).
The oxygen reactive species and associated damage are some of the possible associated factors in the cerebral function regulation(118121). The activity of the superoxide dismutase enzyme increased in the cerebral and striated trunk of rats after treadmill running training, followed by increase in the glutathione concentration in the cerebral cortex and trunk(111).
The general health benefits as well as diseases prevention by the exercise are widely known. However, chronic exercise also represents a kind of oxidative stress for the organism and may alter the balance between oxidants and antioxidants. The biological antioxidants play an important role in the cellular protection of the oxidative stress induced by exercising. Both a great production of free radicals and the deficiency or depletion of many antioxidant systems may reveal exacerbation of the oxidative cellular injury, while the supplementation of many antioxidants generates diverse outcomes(101,105).
Vitamin E (atocopherol) is an important soluble lipid, screening openchain free radicals. Its unique location in the cellular membrane decreases its efficiency in acting in the free radicals originated from the internal mitochondrial membrane and other biomembranes(101,105). Moderate physical exercise increased the mitochondrial oxidative damage in the brain of old rats(122). Integration between physical training and vitamin E supplementation has been demonstrated, which caused neuroprotection against the decrease concerning age in the antioxidant enzymes and in the increase of the lipid peroxidation in the brain(50,123).
The antioxidant role of the vitamin C is well established; however, its importance in the protection against exerciseinduced stress is not clear. It is suggested that vitamin C plays its function recycling vitamin E radical again to vitamin E(105). Vitamin C isolated supplementation was not beneficial to the nervous tissue, once it increased the oxidation of lipids of the brain of trained rats(114).
We presented massive evidence of the exercise effects in the cognitive function and synaptic plasticity in the neurothrophic and cerebral oxidative mechanisms. The brain responses follow the model and configuration of the exercise, and may be influenced by the administration of antioxidants. Another factor is the differentiated responsitivity of the brain regions to acute and chronic exercise. Since studies concerning exercise and brain are scant, they widely vary from the model and exercise configuration, to the variables and adopted methodologies, a fact which decreases the capacity of results comparison. Thus, the effects and action mechanisms of physical exercise in the central nervous system still need further understanding.
1. Cotman CW, Berchtold NC, Adlard PA, Perreau VM. Exercise and the brain. In: Mooren FC, Völker K, editors. Molecular and cellular exercise physiology. Champaign, IL, USA; 2005. p. 331-41. [ Links ]
2. Warburton DER, Nicol CW, Bredin SSD. Health benefits of physical activity: the evidence. CMAJ. 2006;6:801-9. [ Links ]
3. Acikgoz 0, Aksu I, Topcu A, Kayatekin BM. Acute exhaustive exercise does not alter lipid peroxidation levels and antioxidant enzyme activities in rat hippocampus, prefrontal cortex and striatum. Neuroscience Letters. 2006;406:148-51. [ Links ]
4. Monzillo Lu, Hamdy O, Horton ES, Ledbury S, Mullooly C, Jarema C. Effect of lifestyle modification on adipokine levels in obese subjects with insulin resistance. Obes Res. 2003;11:1048-54. [ Links ]
5. Arida RM, Scorza CA, Silva AV, Scorza FA, Cavalheiro EP. Differential effects of spontaneous versus forced exercise in rats on the staining of parvalbumin-positive neurons in the hippocampal formation. Neurosci Lett. 2004;364:135-8. [ Links ]
6. Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 2002;25:295-301. [ Links ]
7. Kramer AF, Hahn S, Cohen NJ, Banich MT, McAuley E, Harrison CR. Ageing, Fitness and neurocognitive function. Nature. 1999;400:418-9. [ Links ]
8. Fordyce DE, Farrar RP. Enhancement of spatial learning in F344 rats by physical activity and related learning-associated alterations in hippocampal and cortical cholinergic functioning. Behav Brain Res. 1991;46:123-33. [ Links ]
9. Mattson MP. Neuroprotective signaling and the aging brain: take away my food and let me run. Brain Res. 2000;886:47-53. [ Links ]
10. Scandalis TA, Bosak A, Berliner JC, Helman LL, Wells MR. Resistance training and gait function in patients with Parkinson's disease. Am J Phys Med Rehabil. 2001;80:38-43. [ Links ]
11. Reuter I, Engelhardt M, Stecker K, Baas H. Therapeutic value of exercise training in Parkinson's disease. Med Sci Sports Exerc. 1999;31:1544-9. [ Links ]
12. Wolf SA, Kronenberg G, Lehmann K, Blankenship A, Overall R, Staufenbiel M. Cognitive and physical activity differently modulate disease progression in the amyloid precursor protein (APP) 23 model of Alzheimer's disease. Biol Psychiatry. 2006 "in press". [ Links ]
13. Adlard PA, Perreau VM, Pop V, Cotman CW. Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer's disease. J Neurosci. 2005;17: 4217-21. [ Links ]
14. Huang AM, Jen CJ, Chen HF, Yu L, Kuo YM, Chen HI. Compulsive exercise acutely upregulates rat hippocampal brain derived neurotrophic factor. J Neural Transm. 2006;113:803-11. [ Links ]
15. Van Praag H, Kempermann G, Gage FH. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci. 1999;2:266-70. [ Links ]
16. Laurin D, Verreault R, Lindsay J, MacPherson K, Rockwood K. Physical activity and risk of cognitive impairment and dementia in elderly persons. Arch Neurol. 2001;58:498-504. [ Links ]
17. Lee H, Kim H, Lee J, Kim Y, Yang H, Chang H. Maternal swimming during pregnancy enhances short-term memory and neurogenesis in the hippocampus of rat pups. Brain & Development. 2006;28:147-54. [ Links ]
18. Yu BK, Yoon BC, Kim SS, Chun SL. Treadmill exercise increases cell proliferation in hippocampal dentate gyrus in alcohol intoxicated rats. J Sports Med Phys Fitness. 2003;43:393-7. [ Links ]
19. Van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Nat Ac Sci USA. 1999;96: 13427-31. [ Links ]
20. Briones TL. Environment, physical activity, and neurogenesis: implications for prevention and treatment of Alzheimer's disease. Curr Alzheimer Res. 2006;1:49-54. [ Links ]
21. Redila VA, Christie BR. Exercise-induced changes in dendritic structure and complexity in the adult hippocampal dentate gyrus. Neuroscience. 2006;137(4):1299-307. [ Links ]
22. Dietrich MO, Mantese CE, Porciuncula LO, Ghisleni G, Vinade L, Souza DO. Exercise affects glutamate receptors in postsynaptic densities from cortical mice brain. Brain Res. 2005;1-2:20-5. [ Links ]
23. Carmichael MD, Davis JM, Murphy EA, Brown AS, Carson JA, Mayer E. Recovery of running performance following muscle damaging exercise: relationship to brain IL-1beta. Brain Behav Immun. 2005;5:445-52. [ Links ]
24. Kaspar BK, Frost LM, Christian L, Umapathi P, Gage FH. Synergy of insulin-like growth factor-1 and exercise in amyotrophic lateral sclerosis. Ann Neurol. 2005; 5:649-55. [ Links ]
25. Che FY, Yuan Q, Kalinina E, Fricker LD. Peptidomics of Cpe fat/fat mouse hypothalamus: effect of food deprivation and exercise on peptide levels. J Biol Chem. 2005;6:4451-61. [ Links ]
26. Caglar E, Sabuncuoglu H, Keskin T, Isikli S, Keskil S, Korkusuz F. In vivo human brain biochemistry after aerobic exercise: preliminary report on functional magnetic resonance spectroscopy. Surg Neurol. 2005;64 S53-6. [ Links ]
27. Ito H, Shidahara M, Inoue K, Goto R, Kinomura S, Taki Y. Effects of tissue heterogeneity on cerebral vascular response to acetazolamide stress measured by an I-123-IMP autoradiographic method with single-photon emission computed tomography. Ann Nucl Med. 2005;4:251-60. [ Links ]
28. Crabbe JB, Dishman RK. Brain electrocortical activity during and after exercise: a quantitative synthesis. Psychophysiology. 2004;4:563-74. [ Links ]
29. Lanfranco F, Gianotti L, Giordano R, Pellegrino M, Maccario M, Arvat E. Ageing, growth hormone and physical performance. J Endocrinol Invest. 2003;9:861-72. [ Links ]
30. Hatta A, Nishihira Y, Kim SR, Kaneda T, Kida T, Kamijo K. Effects of habitual moderate exercise on response processing and cognitive processing in older adults. Jap J Physiol. 2005;1:29-36. [ Links ]
31. Pang TYC, Stam NC, Nithianantharajah J, Howard ML, Hannan AJ. Differential effects of voluntary physical exercise on behavioral and brainderived neurotrophic factor expression deficits in Huntington's disease transgenic mice. Neurosci. 2006; 141:569-84. [ Links ]
32. Zheng H, Liu Y, Li W, Yang B, Chen D, Wang X. Beneficial effects of exercise and its molecular mechanisms on depression in rats. Behav Brain Res. 2006;168:47-55. [ Links ]
33. Tong L, Shen H, Perreau VM, Balazs R, Cotman CW. Effects of exercise on gene Expression profile in the rat hippocampus. Neurobiol Dis. 2001;8:1046-56. [ Links ]
34. Brown BS, Van Huss W. Exercise and rat brain catecholamines. J Appl Physiol. 1973;34:665-9. [ Links ]
35. Lewis MH. Environmental complexity and central nervous system development and function. Ment Retard Dev Disabil Res Ver. 2004;2:91-5. [ Links ]
36. Burghardt PR, Fulk LJ, Hand GA, Wilson MA. The effects of chronic treadmill and wheel running on behavior in rats. Brain Res. 2004;1019:84-96. [ Links ]
37. Kleim JA, Jones TA, Schallert T. Motor enrichment and the induction of plasticity before or after brain injury. Neuroch Res. 2002;28:1757-69. [ Links ]
38. Kempermann G, Kuhn HG, Gage FH. More hippocampal neurons in adult mice living in an enriched environment. Nature. 1997;386:493-5. [ Links ]
39. Ding Q, Vaynman S, Akhavan M, Ying Z, Gomez-Pinilla F. Insulin-like growth factor I interfaces with brain-derived neurotrophic factor-mediated synaptic plasticity to modulate aspects of exercise-induced cognitive function. Neuroscience. 2006;140:823-33. [ Links ]
40. Albeck DS, Sano K, Prewitt GE, Dalton L. Mild forced treadmill exercise enhances spatial learning in the aged rat. Behavioural Brain Research. 2006;168:345-8. [ Links ]
41. Inal M, Akyüz F, Turgut A, Getsfrid WM. Effect of aerobic and anaerobic metabolism on free radical generation swimmers. Med Sci Sports Exerc. 2001;33:564-7. [ Links ]
42. Ostman HN. Adaptive changes in central and peripheral no-adrenergic neurons in rats following chronic exercise. Neurosci. 1976;1:41-7. [ Links ]
43. Ploughman M, Granter-Button S, Chernenko G, Tucker BA, Mearow KM, Corbett D. Endurance exercise regimens induce differential effects on brain-derived neurotrophic factor, synapsin-I and insulin-like growth factor I after focal ischemia. Neuroscience. 2005;136:991-1001. [ Links ]
44. Carro E, Trejo JL, Busiguina S, Torres-Aleman I. Circulating insulin-like growth factor I mediates the protective effects of physical exercise against brain insults of different etiology and anatomy. J Neurosci. 2001;21(15):5678-84. [ Links ]
45. Kishorchandra G, Rothfuss L, Lang J, Packer L. Effect of exercise training on tissue vitamin E and ubiquinone content. J Appl Physiol. 1987;4:1638-41. [ Links ]
46. MacRae PG, Spirduso WW, Cartee GD, Farrar RP, Wilcox RE. Endurance training effects on striatal D2 dopamine receptor binding and striatal dopamine metabolite levels. Neurosci Lett. 1987;79:138-44. [ Links ]
47. Brown BS, Payne T, Kim C, Moore G, Krebs P, Martin W. Chronic response of rat brain norepinephrine and serotonin levels to endurance training. J Appl Physiol. 1979;46:19-23. [ Links ]
48. Will B, Galani R, Kelche C, Rosenzweig MR. Recovery from brain injury in animals: relative efficacy of environmental enrichment, physical exercise or formal training (1990-2002). Progress Neurobiol. 2004;72:167-82. [ Links ]
49. Casillas J. Custo energético da marcha. In: Viel E, editor. A marcha humana, a corrida e o salto. São Paulo: Manole; 2001. p. 141-55. [ Links ]
50. Jolitha AB, Subramanyam MVV, Devi S. Asha. Modification by vitamin E and exercise of oxidative stress in regions of aging rat brain: studies on superoxide dismutase isoenzymes and protein oxidation status. Experimental Gerontology. 2006 "in press". [ Links ]
51. Dohm MR, Hayes JP, Garland T Jr. The quantitative genetics of maximal and basal rates of oxygen consumption in mice. Genetics. 2001;159:267-77. [ Links ]
52. Lighfoot JT, Turner MJ, Debate KA, Kleeberger SR. Interstrain variation in murine aerobic capacity. Med Sci Sports Exerc. 2001;33:2053-7. [ Links ]
53. Liu J, Yeo HC, Övervik-Douk E, Hagen T, Doniger SJ, Chu DW. Chronically and acutely exercised rats: biomarkers of oxidative stress and endogenous antioxidants. J Appl Phsiol. 2000;89:21-8. [ Links ]
54. Kaplan ML, Cheslow Y, Vikstrom K, Malhotra A, Geenen DL, Nakouzi A. Cardiac adaptations to chronic exercise in mice. Am J Physiol Heart Circ Physiol. 1994; 273:H1167-73. [ Links ]
55. Kemi OJ, Loennechen JP, Wisløff, Ellisngsen O. Intensity-controlled treadmill running in mice: cardiac and muscle hypertrophy. J Appl Physiol. 2002;93:1301-9. [ Links ]
56. Wisløff U, Helgerud J, Kemi OJ, Ellingsen Ø. Intensity controlled treadmill in rats: VO2max and cardiac hypertrophy. Am J Physiol Heart Circ Physiol. 2001;280: H1301-10. [ Links ]
57. Mattson MP, Maudsley S, Martin B. BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci. 2004; 27:589-94. [ Links ]
58. Schuman EM. Neurotrophin regulation of synaptic transmission. Curr Opin Neurobiol. 1999;1:105-9. [ Links ]
59. Neeper SA, Gomez-Pinilla F, Cotman C. Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain. Brain Res. 1996; 726:49-56. [ Links ]
60. Lorigados-Pedre L, Bergado-Rosado J. El factor de crecimiento nervioso en la neurodegeneración y el tratamiento neurorrestaurador. Rev Neurol. 2004;10:957-71. [ Links ]
61. Serrano-Sánchez T, Díaz-Armesto I. Factor de crecimiento derivado del cerebro: aspectos de actualidad. Rev Neurol. 1998;154:1027-32. [ Links ]
62. Poo M. Neurotrophins as synaptic modulators. Nature Rev Neurosci. 2001;2:24-32. [ Links ]
63. Figurov A, Pozzo-Miller LD, Olafsson P, Wang T, Lu B. Regulation of synaptic responses to high frequency stimulation and LTP by neurotrophins in the hippocampus. Nature. 1996;381:706-9. [ Links ]
64. Patterson SL, Abel T, Deuel TAS, Martin KC, Rose JC, Kandel ER. Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knock out mice. Neuron. 1996;16:1137-45. [ Links ]
65. Korte M, Carroll P, Wolf E, Brem G, Thoenen H, Bonhoeffer T. Hippocampal long-term potentiation is impaired in mice lacking brain derived neurotrophic factor. Proc Natl Acad Sci USA. 1995;92:8856-60. [ Links ]
66. Molteni R, Ying Z, Gomez-Pinilla F. Differential effects of acute and chronic exercise on plasticity related genes in the rat hippocampus revealed by microarray. European Journal of Neuroscience. 2002;16:1107-16. [ Links ]
67. Vaynman S, Ying Z, Gómez-Pinilla F. Exercise Induces BDNF and synapsin I to specific hippocampal subfields. J Neurosci Res. 2004;76:356-62. [ Links ]
68. Augustine GJ. How does calcium trigger neurotransmitter release? Curr Opin Neurobiol. 2001;11:320-6. [ Links ]
69. Pozzo-Miller LD, Gottschalk W, Zhang L, Du McDermott KJ, Gopalakrishnan R, Oho C. Impairments in high frequency transmission, synaptic vesicle docking, and synaptic protein distribution in the hippocampus of BDNF knockout mice. J Neurosci. 1999;19:4972-83. [ Links ]
70. Jovanovic JN, Czernik AJ, Fienberg AA, Greengard P, Sihra TS. Synapsins as mediators of BDNF enhanced neurotransmitter release. Nature Neurosci. 2000; 3:323-9. [ Links ]
71. Bertchold NC, Chinn G, Chou M, Kesslak JP, Cotman CW. Exercise primes a molecular memory for brain-derived neurotrophic factor protein induction in the rat hippocampus. Neurosci. 2005;133:853-61. [ Links ]
72. Klintsova AY, Dickson E, Yoshida R, Greenough WT. Altered expression of BDNF and its high-affinity receptor TrkB in response to complex motor learning and moderate exercise. Brain Res. 2004;1028:92-104. [ Links ]
73. Kim M, Bang M, Han T, Ko Y, Yoon B, Kim J. Exercise increased BDNF and TrkB in the contralateral hemisphere of the ischemic rat brain. Brain Res. 2005;1052:16-21. [ Links ]
74. Widenfalk J, Olson L, Thorén P. Deprived of habitual running, rats downregulate BDNF and TrkB messages in the brain. Neurosci Res. 1999;34:125-32. [ Links ]
75. Russo-Neustadt A, Ha T, Ramirez R, Kesslak JP. Physical activity antidepressant treatment combination: impact on brain-derived neurotrophic factor and behavior in an animal model. Behav Brain Res. 2001;120:87-95. [ Links ]
76. Johnson RA, Rhodes JS, Jeffrey SL, Garland T, Mitchel GS. Hippocampal brain-derived neurotrophic factor but not neurotrophin-3 increases more in mice selected for increased voluntary wheel running. Neuroscience. 2003;121:1-7. [ Links ]
77. Johnson RA, Mitchell GS. Exercise induced changes in hippocampal brain derived neurotrophic factor and neurotrophin-3: effects of rat strain. Brain Res. 2003;983:108-14. [ Links ]
78. Vaynman S, Ying Z, Gomez-Pinilla F. Interplay between brain-derived neurotrophic factor and signal transduction modulators in the regulation of the effects of exercise on synaptic-plasticity. Neuroscience. 2003;122:647-57. [ Links ]
79. Segal RA, Greenberg ME. Intracellular signaling pathways activated by neurotrophic factors. Annu Rev Neurosci. 1996;19;463-89. [ Links ]
80. Selcher JC, Nekrasova T, Paylor R, Landreth GE, Sweatt J. Mice lacking the ERK1 isoform of MAP kinase are unimpaired in emotional learning. Learn Mem. 2001; 8:11-9. [ Links ]
81. Sweatt JD. The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory. J Neurochem. 2001;76:1-10. [ Links ]
82. Matsubara M, Kusubata M, Ishiguro K, Uchida T, Titani K, Taniguchi H. Site-speciffic phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions. J Biol Chem. 1996;271:21108-13. [ Links ]
83. Soderling TR. CaM-kinases: modulators of synaptic plasticity. Curr Opin Neurobiol. 2000;10:375-80. [ Links ]
84. Fukunaga K, Miyamoto E. A working model of CaM kinase II activity in hippocampal long-term potentiation and memory. Neurosci Res. 2000;38:3-17. [ Links ]
85. Corbit KC, Foster DA, Rosner MR. Protein kinase C-d mediates neurogenic but not mitogenic activation of mitogen-activated protein kinase in neuronal cells. Mol Cell Biol. 1999;19:4209-18. [ Links ]
86. Finkbeiner S. Calcium regulation of the brain-derived neurotrophic factor gene. Cell Mol Life Sci. 2000;57:394-401. [ Links ]
87. Finkbeiner S. CREB couples neurotrophin signals to survival messages. Neuron. 2000;25:11-4. [ Links ]
88. Finkbeiner S, Tavazoie SF, Maloratsky A, Jacobs KM, Harris KM, Greenberg ME. CREB: a major mediator of neuronal neurotrophin responses. Neuron. 1997;19: 1031-47. [ Links ]
89. Silva AJ, Kogan JH, Frankland PW, Kida S. CREB and memory. Annu Rev Neurosci. 1998;21:127-48. [ Links ]
90. Bourtchuladze R, Frenguelli B, Blendy J, Ciof D, Schutz G, Silva AJ. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell. 1994;79:59-68. [ Links ]
91. Walton M, Connor B, Lawlor P, Young D, Sirimanne E, Gluckman. Neuronal death and survival in two models of hypoxic-ischemic brain damage. Brain Res Rev. 1999;29:137-68. [ Links ]
92. Zhua SW, Phamb TM, Aberg E, Brené S, Winblad B, Mohammeda AW. Neurotrophin levels and behaviour in BALB/c mice: Impact of intermittent exposure to individual housing and wheel running. Behav Brain Res. 2006:167:1-8. [ Links ]
93. Oliff HS, Berchtold NC, Isackson P, Cotman CW. Exercise-induced regulation of brain-derived neurotrophic factor BDNF transcripts in the rat hippocampus. Mol Brain Res. 1998;61:147-53. [ Links ]
94. Radak Z, Toldy A, Szabo Z, Siamilis S, Nyakas C, Silye G. The effects of training and detraining on memory, neurotrophins and oxidative stress markers in rat brain. Neuroch Int. 2006 "in press". [ Links ]
95. Larsson E, Nanobashvili A, Kokaia Z, Lindvall O. Evidence for neuroprotective effects of endogenous brain-derived neurotrophic factor after global forebrain ischemia in rats. J Cereb Blood Flow Metab. 1999;11:1220-8. [ Links ]
96. Pencea V, Bingaman KD, Wiegand SJ, Luskin MB. Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus. J Neurosci. 2001;21:6706-17. [ Links ]
97. Ang ET, Wong PTH, Moochhala S, Ng YK. Neuroprotection associated with running: is it a result of increased endogenous neurotrophic factors? Neuroscience. 2003;118:335-45. [ Links ]
98. Cunningham AJ, Murray CA, O'Neill LA, Lynch MA, O'Connor JJ. Interleukin-1 beta (IL-1 beta) and tumor necrosis factor (TNF) inhibit long-term potentiation in the rat dentate gyrus in vitro. Neurosci Lett. 1996;203:17-20. [ Links ]
99. Butler MP, O'Connor JJ, Moynagh PN. Dissection of tumor-necrosis factor-alpha inhibition of long-term potentiation (LTP) reveals a p38 mitogen-activated protein kinase-dependent mechanism which maps to early-but not late-phase LTP. Neuroscience. 2004;124:319-26. [ Links ]
100. Ang ET, Wong PTH, Moochhala S, Ng YK. Cytokine changes in the horizontal diagonal band of Broca in the septum after running and stroke: a correlation to glial activation. Neuroscience. 2004;129:337-47. [ Links ]
101. Leeuwenburg C, Heinecke JW. Oxidative stress and antioxidants in exercise. Curr Med Chem. 2001;8:829-38. [ Links ]
102. Bowling AC, Beal MF. Bioenergetics and oxidative stress in neurodegenerative diseases. Life Sci. 1995;56:1151-71. [ Links ]
103. Choi BH. Oxygen, antioxidants and brain function. Yonsei Medical J. 1993;34; 1-10. [ Links ]
104. Bayir H. Reactive oxygen species. Crit Care Med. 2005;33:498-501. [ Links ]
105. Banerjee AK, Mandal A, Chanda D, Chakraborti S. Oxidant, antioxidant and physical exercise. Mol Cell Biochem. 2003;253:307-12. [ Links ]
106. Mattson MP, Liu D. Energetics and oxidative stress in synaptic plasticity and neurodegenerative disorders. Neuromolecular Med. 2002;2:215-31. [ Links ]
107. Calabrese V, Lodi TR, Tonon C, D'Agata V, Sapienza M, Scapagnini G. Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia. J Neurol Sci. 2005;233:145-62. [ Links ]
108. Ter-Minassian A. Cerebral metabolism and brain injury. Ann Fr Anesth Reanim. 2006;7:714-21. [ Links ]
109. Jain SK, McVie R, Smith T. Vitamin E supplementation restores glutathione and malondialdehyde to normal concentrations in erythrocytes of type 1 diabetic children. Diabetes Care. 2000;9:1389-94. [ Links ]
110. Radak Z, Kaneko T, Tahara S, Nakamoto H, Pucsok J, Sasvari M. Regular exercise improves cognitive function and decreases oxidative damage in rat brain. Neurochem Int. 2001;38:17-23. [ Links ]
111. Ogonovszky H, Berkes I, Kumagai S, Kaneko T, Tahara S, Goto S, et al. The effects of moderate-, strenuous- and over-training on oxidative stress markers, DNA repair, and memory, in rat brain. Neurochem Int. 2005;46:635-40. [ Links ]
112. Radak Z, Taylor AW, Ohno H, Goto S. Adaptation to exercise induced oxidative stress: from muscle to brain. Exerc Immunol Rev. 2001;7:90-107. [ Links ]
113. Özkaya YG, Agar A, Yargicoglu P, Hacioglu G, Bilmen-Sarikcioglu S, Özen I, et al. The effect of exercise on brain antioxidant status of diabetic rats. Diabetes Metab. 2002;5:377-84. [ Links ]
114. Cosíun S, Gonul B, Guzel NA, Balabanli B. The effects of vitamin C supplementation on oxidative stress and antioxidant content in the brains of chronically exercised rats. Mol Cell Biochem. 2005;280(1-2):135-8. [ Links ]
115. Floyd KA, Carney JM. Age influence on oxidative events during brain ischemia/reperfusion. Arch Gerontol Geriatr. 1991;12:155-77. [ Links ]
116. Zhang JR, Andrus PK, Hall ED. Age-related regional changes in hydroxyl radical stress and antioxidants in gerbil brain. J Neurochem. 1993;61:1640-7. [ Links ]
117. Somani SM, Husain K, Diaz-Phillips L, Lanzotti DJ, Kareti KR, Trammell GL. Interaction of exercise and ethanol on antioxidant enzymes in brain regions of the rat. Alcohol. 1996;13:603-10. [ Links ]
118. Radak Z, Asano K, Inoue M, Kizaki T, Oh-Ishi S, Suzuki K. Acute bout of exercise does not alter the antioxidant enzyme status and lipid peroxidation of rat hippocampus and cerebellum. Pathophysiology. 1995;2:243-5. [ Links ]
119. Radak Z, Asano K, Inoue M, Kizaki T, Oh-Ishi S, Suzuki K. Superoxide dismutase derivative reduces oxidative damage in skeletal muscle of rats during exhaustive exercise. J Appl Physiol. 1995;79:129-35. [ Links ]
120. Somani SM, Ravi R, Rybak LP. Effect of exercise training on antioxidant system in brain regions of rat. Pharmacol Biochem Behav. 1995;50:635-9. [ Links ]
121. Carney JM. Oxidative stress leading to loss of critical proteases in Alzheimer's disease. An alternative view of the etiology of AD. Ann N Y Acad Sci. 2000; 924:160-3. [ Links ]
122. Navarro A, Gomez C, Lopez-Cepero JM, Boveris A. Beneficial effects of moderate exercise on mice aging: survival, behavior, oxidative stress and mitochondrial electron transfer. Am J Physiol Regul Integr Comp Physiol. 2003;286:R505-11. [ Links ]
123. Devi SA, Kiran TR. Regional responses in antioxidant system to exercise training and dietary vitamin E in aging rat brain. Neurobiol Aging. 2001;25:501-8. [ Links ]
Correspondence to: Approved in 31/1/07. All the authors
declared there is not any potential conflict of interests regarding this article.
Prof. Ricardo A. Pinho
Laboratório de Fisiologia do Exercício, PPGCS
Universidade do Extremo Sul Catarinense
88806000 Criciúma, SC, Brazil
Fax: (55 48) 34312644
Email: pinho @unesc.net
Approved in 31/1/07.
All the authors declared there is not any potential conflict of interests regarding this article.