Spinal cord injury (SCI) is a potentially devastating condition for patients that can be caused by non-traumatic or traumatic events [1]. Patients with SCI may sustain multiple sensorimotor deficits. These can include full or partial paralysis of muscles below the lesion; muscle spasms; spasticity; neuropathic pain; and bowel, bladder, and sexual dysfunctions. Deficits in neurological function have significant impacts on the metabolism and can lead to subsequent metabolic-related disease risk (e.g., type 2 diabetes and cardiovascular disease) in SCI patients. Subjects with high-level injuries have manifested reduced glucose tolerance, greater insulin resistance, impairment of lipid profiles, decreased bone density and muscle mass, and thermoregulatory alteration leading to periods of hypothermia [2].

The worldwide incidence of traumatic SCI is ~26.5 cases per 1,000,000 inhabitants, and most cases are males (68.3%) [3]. SCI can be divided into primary and secondary phases [4]. The latter is characterized by multifaceted pathological events that may last for months and years ^[5][6][5,6] It is well-known that oxidative stress contributes to a harsh post-injury microenvironment, causing further cell death by necrosis and apoptosis. Therefore, counteracting reactive oxygen species (ROS) generation and oxidative stress are essential strategies for SCI treatment. Physical exercise is an indispensable element in ensuring a correct lifestyle, and an inverse dose–response link exists between volume of physical activity and all-cause mortality ^[7][8][7,8]. In accord, regular exercise promotes psychophysical well-being, preventing and managing disorders of the osteomuscular, cardiovascular, endocrine, and immune systems and the onset of potential cancer ^[9][10][11][9,10,11]. In the nervous system, physical exercise induces neurogenesis and brain plasticity, enhancing cognitive and motor functions. It promotes axonal growth, induces phenotypic changes in peripheral structures, and positively affects the levels of neurotrophins such as brain-derived neurotrophic factor (BDNF) ^[12][13][12,13]. Furthermore, exercise has been demonstrated to improve insulin resistance, adipose fuel metabolism, inflammation, and epigenetic factors by preventing and mitigating the impacts of secondary metabolic diseases related to SCI [14].

SCI is highly complex from its pathophysiology to its management, and to date, there is no resolving clinical therapy. A robust portion of the literature has demonstrated that exercise has several beneficial effects after SCI.

Exercise strengthens paralyzed muscles and promotes the recovery of motor functions ^[15][16][57,58]. In an intact spinal cord, exercise dynamically modulates adult neurogenesis mediated by the ACh and GABA neurotransmitters ^[17][59]. In SCI rodent models, endurance exercise has promoted axonal regeneration via hormonal mechanisms, DNA methylation, and BDNF expression ^[18][19][20][60,61,62]. Moreover, exercise has increased myelination and restoration of serotonergic fiber innervation to the lumbar spinal cord, promoting the survival of grafted neural stem cells via IGF-1 ^[21][63]. It has also improved neuroplasticity and restored motor and sensory functions in SCI patients, also affecting the secondary consequences of SCI, such as chronic inflammation and cardiometabolic syndrome ^{[22][23][24][25]}[64,65,66,67].

In able-bodied individuals, physical exercise leads to an immediate increase in oxidative stress levels, followed by high antioxidant enzyme activity ^[26][27][28][68,69,70]. Similarly, in SCI subjects, exercise induces the increase in oxidative stress as the first response, but generally, this increment is balanced by a progressive activation of antioxidative activities such as the production of SOD and GPx glutathione peroxidase (GPx) ^[28][70] or a reduction in oxidized lipid levels. In this way, exercise trains the ability to rebalance the antioxidative to oxidative activity ratio. Indeed, it has been demonstrated that ROS production during exercise, through a feedback mechanism, activates the process of antioxidant enzyme production through cell-signaling processes ^[29][71]. Moreover, people who train have higher glutathione concentrations at rest and lower resting concentrations of glutathione disulfide and malondialdehyde (markers of oxidative stress) ^[30][31][32][72,73,74]. In contrast, a sedentary lifestyle, without the intake of adequate nutrients in quantity and quality, will result in increases in circulating glucose and fatty acids that will induce, through the mitochondrial electron transport chain, excess production of ROSs ^[33][75]. Thus, there is already evidence that, in non-pathologic subjects, fitness level, often assessed as the maximum rate of oxygen employed during exercise, strongly influences antioxidant capacity. SCI subjects generally have lower maximum oxygen consumption (VO2 max) than normal subjects, as it turns out that less muscle mass is activated during exercise. In addition, the atrophy characteristic of SCI leads to progressive loss of lean mass, which also has intrinsic alterations, such as reduced mitochondrial oxidative capacity ^[34][76]. This condition, certainly depending on the type and level of injury, predisposes this population to chronic increases in oxidative stress ^[35][77]. In addition, subjects with SCI and sedentary lifestyles seem to have higher levels of lipid peroxides both at rest and in response to a single exercise test. From this evidence follows the hypothesis that exercise may influence the management of oxidative stress even in SCI subjects. However, to date, the studies in the literature that have examined the effects of training protocols on oxidative stress in humans with SCI are few and heterogeneous in their results, as several open questions exist. First of all, there is one regarding the differential effects of different types, durations, and intensities of exercise: for example, between aerobic, anaerobic, and combined aerobic–anaerobic training. Another open question is that of different metabolic reactions to chronic or acute exercise. When aerobic training is repeated over time and becomes “chronic”, it will result in reduced LDL oxidation, but a single exercise to exhaustion (acute) is associated with a progressive increase in LDL. Thus, regular training could give benefits in managing the oxidative/antioxidative ratio, but intense and prolonged exercise inappropriate to a subject’s characteristics and fitness level could result in excess ROS production in various tissues, increasing oxidative stress ^[36][37][78,79].

Van Duijnhoven et al. ^[38][80] and Goldhardt et al. ^[39][81] have evaluated the chronical and acute effects, respectively, of associating functional electrical stimulation (FES), with aerobic training protocols, with the oxidative stress of subjects with SCI. This research hypothesis is based on the fact that it has already been demonstrated that muscle activation by FES in this population immediately increases oxygen consumption ^[40][82]. Van Duijnhoven et al. hypothesized that a single exercise with FES would immediately alter oxidative stress but improve the antioxidative capacity when the exercise became chronic. Therefore, for 8 weeks, they trained subjects with chronic SCI by applying gradual electrical stimulation during leg cycle ergometer exercise with a constant rpm frequency but did not find a difference in the concentrations of oxidative and antioxidative markers between before and after those 8 weeks. Therefore, the intensity of this training method appears to be ineffective in increasing the antioxidant capacities of subjects with SCI, but subjects should be able to tolerate it without an increase in oxidative stress. However, Van Duijnhoven et al. also showed that the subjects’ starting fitness levels were negatively correlated with oxidative stress, as assessed with the malondialdehyde (MDA) concentration. In contrast, Goldhardt et al. evaluated the effect of associating FES with two different exercises but carried out the FES before the training session and not during it. Goldhardt submitted participants with SCI to two different single training sessions: first, FES followed by treadmill walking with body weight support, and then FES followed by walking with a floor walker. Both acute exercises caused increased concentrations of oxidative stress markers, but only the exercise with the walker also activated an antioxidant response. This means that exercise influences oxidative stress in a protocol-dependent manner. In contrast to the findings of Van et al., Ordonez, F.J., et al. ^[41][83] demonstrated that (chronic) aerobic exercise, with arm-cranking, increased the total antioxidant statuses (TASs) of plasma and GPx (markers of antioxidant processes) and reduced concentrations of MDA and carbonyl groups (markers of oxidative stress) in participants with SCI. However, the number of training sessions was higher in the study by Ordonez et al. (36 sessions) than in Van Duijnhoven’s study (20 sessions), with higher intensity, and the protocol did not provide for the use of FES. However, when a single session of the same exercise at the same moderate intensity but with a longer duration (2 h instead of the 30 min for Ordonez et al.) was considered and evaluated by Mitsui et al. ^[42][84], the concentrations of oxidized low-density lipoprotein (oxLDL), an indicator of oxidation, did not change in subjects with SCI compared to able-bodied (AB) subjects. This seems to be associated with concentrations of adrenaline, which were higher in AB subjects in the study by Mitsui et al. Indeed, the antioxidant role of adrenaline has been already demonstrated ^[43][85]. The results suggest that increases in plasma adrenaline levels during exercise contribute to increases in plasma oxLDL levels but that subjects with SCI do not have the same response. In fact, this type of single-session exercise does not seem to alter the oxidative states of these populations. However, when the same exercise was performed to exhaustion with higher intensity in the study by Wang et al. [5], oxidative markers increased only in the SCI group, but the “antioxidant” defense mechanisms after this type of acute exercise were activated only in the control group (subjects without SCI). Another key issue is the association between a subject’s daily amount of physical activity and their antioxidant capacity. Inglés et al. ^[44][86] monitored the amount of moderate to vigorous physical activity (MVPA) performed by subjects with SCI for one week, dividing them successively into two groups, one active and one sedentary, and then assessing their fitness statuses with an incremental exhaustion test. They noted that both groups had significant increases in MDA and protein carbonylation after the test but only the active subjects also had increases in their concentrations of the antioxidant markers exercise-induced catalase and GPx. However, that study assessed physical activity with only an accelerometer, not giving specific information on the type of physical or sports activity performed. Similar results have been found in tetraplegic rugby players; Hübner-Woźniak et al. ^[45][87] compared subjects with tetraplegia, who had been playing rugby for about 7 years with a biweekly frequency and a duration of two hours per training session, with inactive subjects with the same pathology. Rugby is a sport that combines different exercise intensities, alternating high-intensity phases with low-intensity phases and also aerobic phases with anaerobic phases, also requiring skills such as speed, muscle strength, and endurance. In fact, Hübner-Woźniak et al. found that resting catalase and GPx activity concentrations were higher in tetraplegic rugby player subjects than in sedentary subjects. In contrast to the results of Hübner-Woźniak et al., Garbeloti et al. ^[46][88] analyzed the effects of wheelchair basketball, a discipline categorized among the disciplines with mixed aerobic–anaerobic effort in the same way as rugby, in subjects with SCI, comparing them to sedentary subjects with SCI and sedentary AB subjects. The wheelchair basketball players had been practicing this sport for 7 years, three times a week. However, no statistically significant differences were found in the nitric oxide (NO) concentrations of the two SCI subject groups nor in their thiobarbituric acid-reactive substance (TBARS) concentrations. Garbeloti explained these results by hypothesizing that the disuse of the lower limb muscles did not modify the production of nitric oxide or oxidative stress because it activated a protective metabolic mechanism involving vascular factors, independently from the exercises of the upper limbs. However, this point needs further clarification not specified by the authors. Therefore, wheelchair basketball seemed not to be effective in improving the antioxidative capacities of the subjects but did not alter the TBARS levels accordingly. Basketball is an activity well-tolerated by subjects with SCI because it does not produce excessive oxidative stress; the same can be said for performing a wheelchair half-marathon race. In fact, Mitsui et al. ^[47][89] analyzed the concentrations of derivatives of reactive oxygen metabolites (d-ROMs) and ox-LDL as oxidative stress markers and of biological antioxidant potential (BAP) and adrenaline as antioxidative mechanism markers before and after a wheelchair half-marathon in subjects with cervical SCI and lumbar SCI. By collecting blood samples 10  min and 1 h after the end of the competition, they found that there were no changes in the ox-LDL or d-ROMs in the two groups and that the only statistically significant differences were the increases in adrenaline and BAP, only within 10 min from the end of the race and only in the lumbar SCI group. This also underlines different responses according to the lesion level. However, in Mitsui’s study, the two groups (lumbar and cervical SCI) had different BMIs and ages, which can influence d-ROM concentration.

In conclusion, few studies in the literature have analyzed the effect of physical exercise on the oxidative stress of subjects with SCI (particularly, in considering the Scopus and PubMed databases, eight papers have considered the effect on oxidative stress and one has considered only the antioxidant effect). Of these, five have referred to evaluation of single sessions or single incremental tests, evaluating only the acute effect of exercise, and others have evaluated the effects of long-term training protocols (only two have evaluated sports activity protocols and only two have evaluated physical activity protocols) programmed in order to also train the antioxidant capacity in the SCI condition.

Nevertheless, from these researches, analyzed by us, people can draw the following conclusions:

• FES can be useful in programming the training plans of individuals with SCI when combined with stimuli with appropriate intensities, but the duration, intensity, and timing of administration can affect the effects on oxidative stress management;
• Twelve weeks of aerobic exercise with a three-week frequency and an intensity of about 60% of the maximum heart rate are suitable to train the antioxidant capacities of subjects with SCI;
• Exhaustion exercise seems to be poorly tolerated in subjects with SCI because they fail to have adequate antioxidant responses;
• Active (>180′ per week of MVPA) SCI subjects have greater antioxidative capacities in response to oxidative damage, induced by high-intensity to exhaustive exercise, than inactive subjects with SCI;
• The exercise intensity of wheelchair basketball is adequate and that of a half-marathon race is not excessive for trained SCI subjects because the balance between oxidation and antioxidation is maintained during these two sports activities.