Perspective Chapter: Pathophysiology of Spinal Cord Injury and Effect of Neutraceuticals in Providing Potential Health Benefits

Abstract

Spinal cord injury (SCI) is extremely debilitating disorder. The increasing incidences and persisting poor prognosis in neurological recovery and QoL (SCIM) have severely exposed the limitations of all known management strategies. Recently simple measures like nutritional supplementation in SCI cases have shown promising results. Efforts in augmenting neurological recovery and QoL (SCIM) following SCI are being studied world over. Unfortunately, little success has been achieved and the most promising ones such as corticosteroids, newer pharmaceutical agents, and cellular therapies have conflicting results. Several studies have found significant improvement in recovery following nutritional intervention in acute trauma and critically ill subjects. These were reported to be cost effective and easy to administer. Since most of these studies were on a specific nutritional supplement, the full potential of a set of nutritional supplementation facilitating neurological recovery needs to be explored. In ASCI, the improvement in neurological status and QOL (SCIM) is unpredictable and remains poor with known therapy. It has been reported that injuries heal better with nutritional supplementation. Taurine, vitamins C and E, omega-3 fatty acid, etc. have specifically found to be effective in facilitating recovery in acute trauma.

1. Introduction

Spinal cord injury (SCI) is a devastating condition, with sudden loss of sensory, motor, and autonomic function distal to the level of trauma. Despite major advances in the medical and surgical care of SCI patients, no effective treatment exists for the neurological deficits of major SCI [1]. The annual incidence of SCI is 15–40 cases per million people [2] and in the United States, the Christopher and Dana Reeve Foundation estimates a prevalence of over 1 million patients with SCI and more than 12,000 new cases each year. In one of the report from Patna by Sinha DK et al., approximately 20,000 new cases of SCI are added every year. In India, the primary causes of traumatic SCI are fall from height, fall of weight, motor vehicle crashes [3]. In young adults, males are four times more likely than females to sustain an SCI [4]. Injury incidence shows a bimodal distribution, with the highest incidence in adolescents and young adults, with more than half aged 16–30 years old [5]. Even after considerable improvements in field of diagnostics and treatment, SCI remains a disease of high morbidity and mortality. In one of the recent study, Gyani zail singh [6] demonstrates that SCI epidemology is different in Sikkim and North Eastern India in comparison with rest of Indian state and major cause of spinal injury is fall from height followed by motor vehicle accidents. In younger age group, RTA is the main cause and elderly group fall from height is the major cause. Geographical factors also play a crucial role in incidence, prevalence, mortality, and morbidity of TSI patients. In one of the recent study, Kang et al. [7] state that the epidemiology in different regions is of significant difference, which may be resulted from economic, science and technology, medical, geographical, and even social conditions. Therefore, it needs to establish appropriate intervention measures according to the particularity of population, and the scenario of SCI has also changed motor vehicle and fall has been the major cause of it. The number of male patients was significantly more than female, and the average age of patients with SCI had a tendency to increase gradually. The cervical level of spine was the most common part of injury; there were more number of patients with tetraplegia than patients with paraplegia. Electrolyte disturbances, pulmonary infections, urinary tract infections, and bedsores were the four most common complications. There is no effective neuroprotective or neuroregenerative therapy for patients with traumatic spinal cord injury (TSCI), despite the potential devastating consequences with life-long disabilities and a permanent need of multidisciplinary treatment including surgery, medication, and long-term rehabilitation. McKinley et al. [8] demonstrated that the final degree of impairment can only be determined after the fourth phase, whereas clinical experience shows if no improvement of complete impairment (AIS (ASIA Impairment Scale) grade A) can be observed within 72 h after injury, and chances are inferior to reach any remission. In one of his latest study [9] in his prospective observational study, level of magnesium decreases within first 4 h after SCI. Mg levels of patients with neurological remission were significantly lower than those of the patients without remission 1 week after injury.

2. Spinal cord injury: scenario around globe

The WHO global burden of disease study predicts that trauma by road traffic injury will become the third ranked most disabling condition by Murray et al. [10]. As per report of the International conference (Spinal Injuries Management, New Delhi, [11]), the incidence of spinal injury was estimated at 15 new cases per million per year in India. This translates into 15,000 new cases per year and with a backlog of ten years, the prevalence exceeds 0.15 million. As per WHO estimates, the incidence of this disease is on the rise in developing countries such as Brazil, China, Pakistan, and India [12]. In India, estimated incidence is 20 per million per year populations. Singh et al. [13] in an epidemiological study mention that approximately 20,000 new cases of SCI are added every year; 60–70% of them were illiterate, poor villagers. The published research on epidemiology of traumatic SCI in India is very limited.

Sana Rai et al. [14] on his reterospective study conducted on patient ADMITTED IN A TERTIARY CARE HOSPITAL IN AHMADNAGAR, INDIA has concluded in his study that the proportion of males was higher than the proportion of females. Skilled workers, semi-skilled workers, and the students comprised the high-risk occupational categories. Male gender, having a spinal fracture, having a thoracic injury, and having complications, was the major risk factor for a complete injury. They recommend that preventive measures should focus on high-risk populations, such as young males.

Syed Uzair [15] demonstrated in one of his recent study that People of Aboriginal (Indigenous) ancestry are more likely to experience TSCI than other Canadians.

Rui Yang et al. [16] in their reterospective study Guangdon China demonstrates that proportion of males are more than females. Workers, peasants, and the unemployed comprised the high-risk occupational categories. Male gender, having a spinal fracture, having a thoracic injury, and having complications, were the major risk factor for a complete injury. Rathore et al. [17] identified the challenges faced in traumatic SCI management in Pakistan.

Harvey et al. [18] state that traumatic spinal cord injuries most commonly occur as a result of motor vehicle and motor-bike accidents, followed by falls. Sport, in particular, water-based activities and work-related injuries are also common, with a further small but increasing contribution from a gun, knife, or war-related injury.

SCI has negative impact on quality of life (QOL) is a significant public health concern in India. Around 250,000 and 500,000 people all over the world suffer from this disastrous disability [19]. It is very devasting condition as the SCI subject suffers from serious health condition and they mostly lead to temporary and permanent impairment in sensory & motor function, economic, and social consequences. It is a life-threatening condition as it affects the functioning of central nervous, musculoskeletal, cardiovascular, urinary, and reproductive systems and also leads to anatomical damages [20]. SCI subjects mostly suffer from physical and mental health complications, and they are highly vulnerable to infections; chances of getting infection is more in SCI subjects due to increases in the absence of quality health and personal care [21]. The personal, sexual, family, occupational, and social aspects of life of an individual are also affected from this life-threatening condition [22].

In one of his retrospective hospital-based analysis in Jhalawar Rajasthan state of India from January 2018 to Dec. 2019 (period of 2 years) Malav RA et al. [23] observed 158 cases of SCI between these 2 years and male-to-female ratio was 2.16:1, and the most common age group was 30–39 years (27.8%) followed by 20–29 years (19%), and common mode of injury is fall from height (unprotected roof, well, tree, construction site/electric pole) (44.9%) followed by road traffic accidents (43%). Lumbar spine (55%) is most common level of injury site followed by thoracic spine (22.78%), whereas head injuries (9.5%) and extremities injuries (9.5%) are other associated injuries with TSI. In Rajasthan India, TSI cases are mostly activated during summer season (May 14.5% and June 15.8%).

In one of the surveys conducted by the Canadian Paraplegic Association in 1995–1996 on a random sample of 966 Canadian Subjects suffering from SCI who had been injured for at least 5 years, the majority of the population were male subjects (81%), more than half of the subjects were injured between 15 and 24 years of age group and 78% were injured between 15 and 34 years of age group, and cervical level of injury is reported in 47.4% of subjects [24], whereas in data from the Ontario Trauma Registry of 2385 hospital admissions for SCI over the five-year study period, it is also reported that male subjects mostly suffer from SCI (68.4%), and the major cause of SCI injury is falls and transport-related incidents, including motor vehicle, non-motorized road vehicle injury (43.2%), and other transport injury that is almost 42.8%, respectively [24].

One of the studies from Canada-collected data of 450 SCI subjects from April 1, 1997 to March 31, 2000, three provincial sources, that is, administrative data from the Alberta Ministry of Health and Wellness, records from the Alberta Trauma Registry, and death certificates from the Office of the Medical Examiner, demonstrated that out of 450 subjects 71 died prior to hospitalization (15.8%), males had higher incidence rates in comparison with females for all age groups, and common mode of injury is motor vehicle collisions (56.4%) followed by fall (19.1%). Motor vehicle collision is common mode of injury in males between 20 and 29 years of age and in case of females at age group between 15 and 19 years. In comparison with urban residents, rural residents were 2.5 times likely to be injured [24].

3. Pathophysiology of SCI

Most frequent mechanism of SCI is compression of spinal cord and this compression continues after the injury. In neural tissues or vascular structure of cord penetrating injury, strain occurs due to dislocation, flexion, extension, or distraction forces related to rotation. In the spinal cord, channel hematomas are seen due to the consequences related to cord compression due to other mechanical damages to bone structures and ligaments. In case of spinal trauma, bleeding occurs during the early period of SCI and is later followed by the interruption of blood supply. Due to disruption of blood flow following SCI, it gives rise to hypoxia and local ischemic infraction in the spinal cord, and these two mentioned consequences mostly damage the gray matter of the cord where metabolic function is mostly very high. In the fractured area of the cord, neurons are physically damaged and the thickness of myelin sheath is reduced. In addition, due to edema and the accumulation of macrophages in the damaged tissue, there is deterioration in neuronal transmission occurs.

At the cellular level, lack of energy due to ischemia and impaired perfusion is the most notable mechanism. If ischemia that occurs immediately after traumatic SCI is left untreated, then it gives rise to additional damage that may commence within the first 3 h and continue for at least 24 h. Following SCI several crucial changes occur such as hemorrhage, demyelination, edema, and cavity formation with axonal and neuronal necrosis, including series of pathological changes in the nerve tissue, which can further increase infarction. Excitotoxicity, oxidative damage and ischemia can occur because of high level of glutamate, whereas secondary spinal cord damage occurs because of calcium-dependent nitric oxide synthesis. Following secondary injuries, neuronal and axonal death occurs because after secondary injury, there is increased production of free radical that induced lipid peroxidation in the cell membrane and secondary injury signaling cascades at the injured tissue.

Immediately after SCI, there is loss of electrical activity, extracellular potassium level increases, whereas there is decrease in sodium-potassium ATPase, leading to membrane dysfunction and failure of ionic pump mechanisms [25]. Destruction of spinal cord by any trauma causes changes in the fluid microenvironment of the spinal cord and thus plays role in the pathogenesis of the secondary cell changes, the so-called autodestructive process. Ischemia and impairment of autoregulation of blood flow are two common consequences after the secondary injury [26], and these two consequences made spinal cord vulnerable to reductions in arterial pressure and oxygen tension, both of which are frequent after cord injury [27]. Several injury factors are involved in the mechanisms of cell damage and edema following trauma to the spinal cord [28], and some of the proposed factors or injury factors are hydrolysis of phospholipid such as polyunsaturated fatty acids, eicosanoids, free radicals, neuropeptides, monoamines, and changes of cations and amino acids [29].

4. Opioid peptides in the spinal cord

Opioid peptides are found in abundance in spinal cord as it involves in the regulation of sensory, and autonomic and somato-motor functions [30, 31]. These peptides are also co-localized with other transmitters [31]. Different classes of opioid receptors are present in spinal cord. Thus, treatment with naloxone is one of the antagonistic of opioid receptor, 1 hour after experimental injury, at doses of 2 mg/kg bolus followed by the same dose per hour during 4 h, and it was observed that during a follow up of 6 week, there is significant increased in spinal blood flow and improved neurological outcome was seen [32, 33]. As major role of naloxone, drug is that it blocks these receptors and thus protects against cellular damage as well as preventing release of cellular contents [34].

5. Role of apoptosis

Apoptosis is activated soon after spinal cord injury because of the release of inflammatory cytokines and free radicals, which leads to inflammation and excitotoxicity [35]. Soon after SCI between 3 h and 8 weeks around the injured areas of the spinal cord tissues apoptosis begins [36]. Many studies have proven that demyelination is boosted due to apoptosis of the oligodendrocytes [36]. Study by David et al. [37] suggested that oligodendrocytic changes occur in response to SCI. In case of SCI, the phenomenon of apoptosis adversely affects the condition by increasing loss of neurons. Studies have proved that apoptosis is the only factor that is responsible for the deterioration of the microglia and thus promotes secondary inflammatory injury [38].

Destruction of neurons, nerve fibers, glial cells, and blood vessels at the site of injury are the ultimate consequences of spinal cord trauma, which happens due to the degradation of approximately 30% of neurofilament constitutive proteins within 1 hour of injury, and almost 70% are lost within 4 h after the injury [39]. Some proteins that are the members of the cysteine lysosomal proteases and papain superfamily, like cathepsin B, Y, and S, are also involved in the destruction of neurofilament, and this link is believed due to the fact that cathepsin B is involved in degradation of myelin basic protein. Compared to the involvement of cathepsin Y in the production of bradykinin, and in degradation of extracellular molecules through inflammatory mediators, cathepsin S plays major role. Cathepsin S is the only protein that is able to retain its activity after prolonged incubation at neutral pH, more than 24 h [40]. In cells of mononuclear phagocytic system such as microglia and macrophages, the expression of this protease is limited [41]. In vitro condition this cathepsin S is involved in degradation of linear polysaccharide carbohydrate basement membrane protein heparan sulfate proteoglycan (HSPG), perlecan which is involved in mitogenesis and angiogenesis, adhesion, protease binding sites, regulation of growth factor such as basic fibroblast growth factor (bFGF) [42]. At acidic or neutral pH laminin, fibronectin, collagens, and elastin are also degraded by this protease, Stimulation of release of active cathepsin S into an environment with a neutral pH is mainly promoted by TNFα, interferon-γ (IFNγ), IL-1α, and granulocyte macrophage colony-stimulating factor (GMCSF) [40].

MCP-1 mRNA that is expressed by astrocyte cells is found in the normal spinal cord, and its level increases 1 h after SCI, reaches to its peak at 24 h, and returned to a low level by day 14. Whereas MIP-1𝛼 mRNA is also present in normal spinal cord whose expression also increases 1 h after SCI, it reaches to its peak at 3 to 6 h, decreased by day 1, and remained unchanged until day 7, whereas return to its low level by day 14. Following injury MIP-1𝛽 expression in astrocytes was observed from day 3 to day 6. Additionally, the expression of this molecule was found at the contusion site and in rostral and caudal sections to this location, and at 5th day of injury, the expression of MIP-1𝛽 returned to baseline levels. Another mRNA known as IP-10 mRNA is found in low level in the normal spinal cord, and after 1 hour of injury, its level increases and reaches to its peak at 6 h, and remained high up to day 5 after SCI, and start decreasing to baseline levels by day 14 [43].

Within 5 min after the injury, there is occurrence of early posttraumatic lipid peroxidation (LP), and it is a mechanism that disrupts the normal structure and function of the lipid bilayers that surround the cell and membrane-bound organelles. Lipid radical (L) gets generated as peroxynitrite or other FR takes an electron off a polyunsaturated lipid, this lipid radical further interacts with molecular oxygen and is converted into lipid peroxyl radical (LOO), and if this lipid peroxyl radical LOO∙is not reduced by antioxidants, then LP associated with SCI damages spinal microvascular endothelium (within 2–3 h), which gives rise to crater formation, platelet adherence, leucocyte presence, and the formation of microemboli, events that are concurrent with the reduced blood flow to the white matter of the spinal cord. This free radical formation is mainly responsible for the demyelination process that is mainly responsible for neurodegenerative process [44]. Because of presence of high content peroxidation-susceptible lipids such as arachidonic, linoleic, and docosahexaenoic acid in CNS, it is particularly sensitive to lipid peroxidation and the primarily radical-mediated oxidative protein damage; thus within time frame of the injury, the occurrence of the oxidative damage to DNA and lipids was seen, and within the first week after injury, there is occurrence of protein nitration [45]. The concentration of reactive nitrogen species NO∙increases three to five times more than baseline levels and within 12 h it reaches to its peak after SCI, and at the same time, there is an increased production of inducible nitric oxide synthase (iNOS) and peroxynitrite [46]. Hence, due to its involvement in the previous processes, RNS participates in inducing excitotoxicityindirectly due to the development of the excessive glutamate and calcium concentrations [47]. RNS (NO) is mainly produced by different synthases. In the production of high concentration of RNS, for a prolonged period of time mainly nitric oxide synthase (iNOS) is responsible [48]. Collectively, major cells such as astrocytes, neutrophils, monocytes, and microglia induce the expression of iNOS at the presence of proinflammatory stimuli such as lipopolysaccharide (LPS), ultraviolet radiation (UV), and TNF𝛼, IL-6, IL-1, and IFN𝛾 [49]. Studies have proved that after SCI expressions of iNOS and its protein activity were found 3 h, 4 h, 24 h, and 72 h [50, 51].

6. Role of nutraceuticals in SCI

Mediterranean diet including anti-inflammatory diet is advised as the best diet for SCI individual. As anti-inflammatory diet has ability to increase the intake of vitamins C (ascorbic acid) and E (alpha-tocopherol) in individuals with SCI (after 3 months), proinflammatory markers are negatively correlated with carotenoids [52, 53]. SCI subjects (from at least 2 years) have lower serum level of vitamins C and E and beta-carotene in comparison with healthy controls [54, 55].

Vitamins (C and E) and several bioactive compounds (such as carotenoids, phenolic compounds, and glucosinolates) are exogenous antioxidants that account for the antioxidant capacity of dietary sources.

7. Some common sources of antioxidants of the Mediterranean diet

Superoxide dismutase level is mostly increased by curcumin, whereas malondialdehyde (MDA), a final product of polyunsaturated fatty acids peroxidation in the cells, increases in the level of free radicals causes its overproduction, and status is suppressed by curcumin [56]. Levels of proinflammatory cytokines, such as TNF-α and IL-1, are also suppressed by curcumin. Study by Daverey and Agrawal [57] observed that treatment by curcumin helps in inhibiting the hypoxia, inflammation, and apoptosis associated with white matter injury. Curcumin also exerted its neuroprotective effect through cross-talk between nuclear factor kappa-light-chain-enhancer of activated B and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that is localized into the cytoplasm bound to the Kelch-like ECH-associating protein 1 (Keap1) that contains cysteine residues sensitive to oxidants or electrophiles and it suppressed the activation of oxidative stress-mediated NFκB by suppressing the level of reactive oxygen species and thus regulates the antioxidant response system [58]. Disulfide bond is formed by Keap1 upon its oxidation and conformational changes, which results in the release of Nrf2, allowing its translocation into the nucleus. The transcription of target genes containing the ARE in their promoter regions is promoted by Nrf-2 including antioxidant enzymes and heme oxygenase 1 (HO-1). Activation of NF-κB is suppressed by heme oxygenase 1 (HO-1) gene.

8. Role of omega 3 fatty acid in spinal cord injury

Study by King et al. [59] state in their study that after lateral hemisection of the spinal cord, omega-3 fatty acids such as linolenic acid and docosahexaenoic acid (DHA) were injected into rats 30 minutes after the injury, with a significant improvement in locomotor performance within 6 weeks after the injury and neuroprotection, including decreased lesion size and apoptosis, and increased neuronal and oligodendrocyte survival has been observed, and decreased oxidation of RNA/DNA suggests a neuroprotective effect of omega-3 fatty acids and proves their antioxidant nature. In contrast, omega-6 fatty acids like arachidonic acid worsened the results, so the study shows a striking difference between the two fatty acids.

Another study by Bi et al. [60] using the SCI rat model shows the therapeutic effect of omega-3 fatty acids, and they divided rats into four groups, such as sham, control, SCI plus 50 mg / kg omega-3 fatty acids, and SCI plus 100 mg/kg omega-3 fatty acids, and observed that the group that supplemented with omega-3 fatty acids had suppressed tumor necrosis factor alpha (TNF) and interleukin6 (IL6) levels by>50%, the mRNA expression of TNF and IL6 was also reduced, while in the control rat group, an increase in the expression of Caspase3-, p53-, Bax, and proNGF mRNA levels around 1.3, 1.4, 1.2 and protein expression by >30% and proNGF mRNA by >40% and an increased expression of bcl2 mRNA by 286.9% and reduced expression of Bax was also observed. The above result indicated that omega-3 fatty acid supplementation helps to reduce oxidative stress, apoptosis, and levels of inflammatory markers in rats with ischemic reperfusion.

Study by Baazm et al. [61] states that omega-3 fatty acid supplementation supports neurological function in the event of neuronal injury and suppresses the activity of inflammatory markers.

Mahadewa Tjokorda et al. [62] state the intervention of both alphatocopherol and omega-3 fatty acids (30 mg/kg + 5 ml/kg for 2 weeks) and the highest BBB score found in the combination treatment group, so their results match the combination of both drugs showing promising therapy for SCI.

Study by Lim et al. [63] demonstrated in their study that a raised omega-3 polyunsaturated fatty acid level and an altered tissue omega-6/omega-3 ratio prior to injury lead to a much improved outcome after SCI, and by this study, they proved the hypothesis that neuroprotective effect of omega 3 fatty acid is also seen when its level is already very high in tissues prophylactically, prior to injury.

Omega-3 fatty acids play an important role in anxiety and depression, as several studies have shown. A study by Javidan et al. [64] showed in its double-blind, randomized clinical study that after 14 months of supplementation with omega-3 fatty acids (435 mg docosahexaenoic acid and 65 mg eicosapentaenoic acid), in patients with traumatic paraplegia, the longer than lasted 1 year after an injury, and found no significant omega supplementation in their disability scores either on the locomotion subscale or in sphincter control; hence, they conclude that omega-3 fatty acids exert its neuroprotective effect only in the acute phase of SCI, but has no effect in chronic SCI cases.

Reduced spinal cord edema, white matter cavitation, demyelination, and vessel ingrowth were observed on 35th day after SCI in mice fed with omega 3 diet [65]. Similar effects were observed in mice who were fed with ω-3 acids prior to planned SCI, and these findings indicate the preventive action of omega 3 fatty acid against inflammation following neurotrauma.

Ward et al. [66] state the beneficial effect of DHA intervention in SCI rat model and observed that white matter damage is prevented after DHA supplementation, and reduced axonal dysfunction was seen.

One of the studies showed that there is no difference in the likelihood of depression, anxiety or stress among respondents in the case of traumatic SCL and NON-traumatic SCL, depression 37%, anxiety 30%, and clinically significant stress 25% [67].

In the treatment and prevention of spinal cord-associated neurological deficits, long-chain omega-3 polyunsaturated fatty acids (LC-O3PUFAs) play a therapeutic role in oil-derived LC-O3PUFAs for 8 weeks prior to spinal contusion and have been observed to be in both cases and controls regulating important biochemical signatures associated with amino acid metabolism and free radical capture, The dietary supplement of LC-O3PUFAs helps in increasing the reduced glucose level (48%) and polar uncharged/hydrophobic amino acids (< 20%), while the content of antioxidant/anti-inflammatory amino acids and peptide metabolites such as alanine (+24%), carnosine (+33%), homocarnosine (+27%), kynurenine (+88%), compared to animals with a normal diet. An increase in neurotransmitters and mitochondrial metabolism such as N-acetylglutamate (+43%) and acetyl-CoA levels (+27%) was reported in the group with PUFA supplementation. Thus, the dietary intervention of PUFA in SCI helps to target the global correction and improve the pro-oxidative metabolic profile that characterized SCI-mediated sensorimotor dysfunction [68].

Mills et al. [69] point to the positive role of O3FA supplementation against diffuse axonal damage in rats. They divided the rats into three groups: The first and second groups received 10 or 40 mg /kg/day O3FA and the third group received no supplementation (fish oil), increased O3FA serum levels, decreased number of positive axons after 30 days of supplementation, amyloid beta precursor protein in the supplemented group as shown by immunohistochemical analysis.

In vivo study by Paterniti et al. [70] shows that in acute SCI, DHA supplementation helps to reduce the degree of spinal cord inflammation and tissue damage, the expression of proinflammatory cytokine (TNF-), glial fibrillary acid protein (GFAP). formation of nitrotyrosine, and apoptosis (Fas-L, Bax, and Bcl-2 expression) and helps restore limb function, and DHA also promotes neurite length and branching in the spinal ganglion, reducing the effects of oxidative stress. Many studies have shown that elevated EPA levels were associated with less atrophy of the gray matter of the hippocampus, parahippocampus, and amygdala in people over 65 years of age, and slower cognitive decline has been reported [71].

9. Miscalleneous nutrition supplementation data

Taurine plays a potential role against trauma-mediated brain and spinal cord injuries, and it (2, 5, 15, and 50 mg/kg, i.v. for 7 days) protected the brain against closed head injury by enhancing neurological functions in injured rats, also decreasing brain edema and permeability of the BBB. Taurine treatment also increased SOD activity and glutathione levels but decreased malondialdehyde and lactic acid levels in traumatized tissue. Taurine treatment also prevented cell death in the hippocampus (CA1 and CA3 subfields [72]). Dionyssiotis [73] demonstrated that most of the SCI individuals are malnourished.

Khalil [74] explained properly design dietary interventions are required that suit the adaptations following SCI. Bhagat [75] suggested that routine nutritional screening should result in early identification of risk of developing pressure ulcers.

In another study conducted on TBI, the administration of taurine (200 mg/kg for 7 days) by tail intravenous injection protected against neuronal damage in rats. Mitochondrial electron transport chain complexes I and II displayed greater activity in the taurine-treated group, and taurine treatment in cerebral blood flow may alleviate edema and elevated intracranial pressure [76].

In SCI, the neutrophils that migrate to the site of injury have been shown to contain high taurine concentrations. Using a spinal cord compression model, treatment with taurine was shown to inhibit expression of the proinflammatory cytokine IL-6 and to decrease phosphorylation of STAT3 and expression of COX2. In the taurine-fed mice, there was a reduced accumulation of neutrophils in addition to recovery of function of the mouse hind-limb [77]. In addition to prior studies, taurine treatment (200 mg/kg for 7 days. i.p.) also alleviated brain damage severity in rats by ameliorating the excited activity of astrocytes and edema along with proinflammatory cytokine [78]. Moreover, taurine (25, 80, 250, and 800 mg/kg, i.p.) treatment ameliorated motor disturbance and pathological anomalies in a mouse model of SCI. It suggestively reduced the SCI-mediated increase in the levels of IL-6 and myeloperoxidase in a dose-dependent manner. Additionally, taurine significantly reduced SCI-mediated cyclooxygenase-2 and phosphorylated signal transducer and activator of transcription 3 expression. In addition, taurine treatment reduced neutrophil accumulation exclusively in the subarachnoid spaces and induced secondary degenerative deviations in the gray matter [77].

Nakajima et al. [77] proposed that taurine has multiple functions in the central nervous system (CNS), serving as an osmoregulatory, antioxidant, inhibitory neuromodulator, and regulator of intracellular Ca2þ flux, and his findings indicate that taurine has anti-inflammatory effects against SCI and may play a neuroprotective role against secondary damage, and thus, it may have therapeutic potential.

Sobrido-Cameán et al. [79] proposed that taurine is one of the most abundant free amino acids in the brain. From his experiments, he proved that an acute taurine treatment enhances axonal regeneration following SCI in lampreys. This offers a novel way to try to promote axon regeneration after nervous system injuries in mammalian models.

According to Cordero et al. [80], dietary supplementation with the antioxidant vitamin E (alpha-tocopherol) improves functional recovery after SCI.

According to Yan et al. [81], high-dose AA administration during the acute phase post SCI significantly reduced secondary injury-induced tissue necrosis and improved functional performance in rats.

According to Robert et al. [82], the administration of alpha-tocopherol enhances the reparative effects against SCI and it is more effective than ascorbic acid.

Study conducted by Nesrine Salem et al. [83] showed that BMMSCs in combination with VC induced more obvious improvements. These results suggest that VC can enhance the neuroprotective effects of BMMSCs against SCI.

Packer et al. [84] showed correlation between vitamins C and E and proved that in CNS injury decreased level of vitamin C does not reflect the degree of injury but vitamin C is able to regenerate vitamin E.

According to Mostafa Hosseini et al. [85], it is revealed that intraperitonial administration of vitamin C is the most effective, and in animal model recovery of motor function is significantly affected when daily supplemented with vitamins C and E. Better result is shown in recovery when treated alone by vitamins c and E than concurrent supplementation.

According to Zhang et al. [86], high-dose vitamin C and vitamin E treatment can alleviate nerve injury and oxidative stress response, and improve neurotrophic state in patients with acute craniocerebral injury.

Parastoo Mojtahed Zadeh-Ardabil et al. [87] showed the neuroprotective effect of dietary derived antioxidant such as palm vitamin E on locomotor function and morphological damage induced SCI.

10. Conclusion

Studies have proved that nutraceuticals such as taurine, vitamin C, and vitamin E supplementation improve AIS Scale, Sensory-Motor, and SCIM Scores following in ASCI subjects. The most expected outcome of nutritional supplementation is that these patients from ambulatory wheel chair begin to move, stand. SCI patients mostly suffer from malnutrition because of immobility, nutritional supplementation will heal them as well as they will get rid from bed score and urinary tract disease and by providing the large doses of vitamins C and E can help in reducing the level of NSE. S100B proteins can act as biomarker in diagnosing the disease. Nutritional supplementation is easy to accommodate and they are cost effective too. Till date most of the studies have been done on animals and it needs more trial to be performed to establish their potency.