Polyunsaturated fatty acids (ω-3 acids, PUFAs) are essential components of cell membranes in all mammals. A multifactorial beneficial influence of ω-3 fatty acids on the health of humans and other mammals has been observed for many years. Therefore, ω-3 fatty acids and their function in the prophylaxis and treatment of various pathologies have been subjected to numerous studies. Regarding the documented therapeutic influence of ω-3 fatty acids on the nervous and immune systems, the aim of this paper is to present the current state of knowledge and the critical assessment of the role of ω-3 fatty acids in the prophylaxis and treatment of spinal cord injury (SCI) in rodent models. The prophylactic properties (pre-SCI) include the stabilization of neuron cell membranes, the reduction of the expression of inflammatory cytokines (IL-1β, TNF-α, IL-6, and KC/GRO/CINC), the improvement of local blood flow, reduced eicosanoid production, activation of protective intracellular transcription pathways (dependent on RXR, PPAR-α, Akt, and CREB), and increased concentration of lipids, glycogen, and oligosaccharides by neurons. On the other hand, the therapeutic properties (post-SCI) include the increased production of endogenous antioxidants such as carnosine and homocarnosine, the maintenance of elevated GSH concentrations at the site of injury, reduced concentrations of oxidative stress marker (MDA), autophagy improvement (via increasing the expression of LC3-II), and p38 MAPK expression reduction in the superficial dorsal horns (limiting the sensation of neuropathic pain). Paradoxically, despite the well-documented protective activity of ω-3 acids in rodents with SCI, the research does not offer an answer to the principal question of the optimal dose and treatment duration. Therefore, it is worth emphasizing the role of multicenter rodent studies with the implementation of standards which initially may even be based on arbitrary criteria. Additionally, basing on available research data, the authors of this paper make a careful attempt at referring some of the conclusions to the human population.
Polyunsaturated fatty acids (ω-3 acids, PUFAs) are essential components of cell membranes in all mammals . They facilitate normal functioning of the body, but many mammals are unable to synthesize them which necessitates their dietary supply. The group of ω-3 includes alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) [1, 2]. A multifactorial beneficial influence of ω-3 fatty acids on the health of humans and other mammals has been observed for many years. Therefore, ω-3 fatty acids and their function in the prophylaxis and treatment of various pathologies have been subjected to numerous studies. The research includes mainly cardiovascular, immune, and nervous system diseases [3–5]. The treatment of patients after spinal cord injury (SCI) constitutes a particular challenge for contemporary medicine, as those injuries primarily contribute to disorders of the nerve tissue and the immune system during inflammation.
Complexity of the natural course of SCI-related pathophysiological events occurs as a result of two subsequent phases such as primary and secondary (delayed) injuries where all parts and compartments of the spinal cord are vulnerable and could be affected . Occurring primary injury is associated with application of external physical force whose character determines the severity of the initial injury . Therefore, primary injury in the case of SCI could in this case result from an external mechanical force (direct/indirect) as well as rapid acceleration/deceleration, ballistic penetration, and less blast exposure arising from shock wave . The macrostructural changes after primary injury in the spinal cord cover damage, laceration, and swelling of the neural tissue as well as various types of structural damage of meninges, ligaments, and bone structures . These events are also connected to the observed changes associated with alternations in circulation of the cerebrospinal fluid (CSF) including an increase of intraspinal pressure (ISP) resulting in subsequent reduction of spinal cord perfusion pressure (SCPP) . The main effects of primary injury cover immediate death of various cell populations associated with rapid reflux of neurotransmitters, dysregulation of transmembrane permeability, and dysfunction of neurovascular units forming blood-spinal cord barrier . Secondary damage includes nonlinear phenomena, including several self-propagating immunology, neurometabolic, and neurochemical events resulting in progressive neurodegeneration . The main mechanisms involved in secondary injury cover local and systemic immunoactivation that involves a multitude of inflammatory mediators and cells, cell death via necrosis or apoptosis, glutamate excitotoxicity, induction of oxidative stress and free-radical generation, altered energy metabolism due to mitochondria dysfunction, and impairment of adenosine-5-triphosphate (ATP) production and calcium- (Ca²⁺-) mediated neurotoxicity associated with abnormal cell membrane permeability . Both, primary and secondary injury-associated events in all neurostructural levels finally lead to progressive neuronal loss, demyelination, lesion expansion, and glial scar formation which results in neurodegeneration of affected parts of the spinal cord manifesting themselves as neurological deficits due to interruption of axonal connections [13, 14]. SCI should be treated not only as local damage but also as systemic pathology, which is manifested in an immune response involving changes in the transcriptome set, proteome set, immune cell recruitment, and the production of inflammatory mediators . One of the main events in SCI is the activation and proliferation of microglial cells (Iba-1⁺) and astrocytes (GFAP⁺) which together with immune cells participate in the creation of a tightly regulated inflammatory microenvironment . In this case, activated microglia cells and astrocytes serve as one of the main sources of cytokines, proteinases, extracellular matrix molecules (ECMs), and growth factors at the epicenter of lesions . Of all secreted cytokines, both in experimental and clinical conditions, tumor necrosis factor alpha (TNF-α) together with interleukin 1 beta (IL-1β) and interleukin 6 (IL-6) dominate in the pathogenesis of SCI and other neurological diseases .
It is estimated that approximately 6 million patients are affected by SCI worldwide. Those patients suffer from impaired mobility manifesting as paraplegia or tetraplegia . SCI is associated with the occurrence of numerous complications with the most common ones being the infections of the urinary or respiratory system, development of pressure ulcers, cardiovascular disorders, sleep disturbance, depression, muscle atrophy, and osteoporosis . Circumstances in which SCIs occur in people are commonly heterogenous, sudden, and difficult to predict (e.g., traffic accidents and falls from a height) which makes it hard to formulate reliable conclusions from the implemented treatment. It is much easier to introduce reliable conditions of research on SCI on the animal model during controlled laboratory trials. Rodents, such as mice and rats, belong to the group of animals whose physiology of life processes presents numerous similarities to that of humans. Therefore, this kind of research is currently the most preferred.
Regarding the documented therapeutic influence of ω-3 fatty acids on the nervous and immune systems [21, 22], the aim of this paper is to present the current state of knowledge and the critical assessment of the role of ω-3 fatty acids in the prophylaxis and treatment of SCI in rodent models. Basing on available research data in this area, the authors of this paper make a careful attempt at referring some of the conclusions to the human population.
2. The Structure of ω-3 Fatty Acids
Fatty acids are characterized by the presence of the carbon chain with a methyl group (-CH3) at one end and a carboxyl group (–COOH) at the other . Unsaturated fatty acids are characterized by the carbon chain which includes at least one double bond. Compounds including one double bond are called monounsaturated fatty acids (MUFAs), while those with two or more double bonds, PUFAs . Another criterion of fatty acid classification is the number of carbon atoms in the carbon chain. Short-chain fatty acids contain up to 13 carbon atoms; long-chain ones, between 14 and 19; and very long-chain fatty acids, over 20 carbon atoms. Notably, fatty acids which occur in humans are mainly characterized by the even number of carbon atoms in the carbon chain. ω-3 fatty acids are a group of chemical compounds with the common feature—the presence of the last double bond in the carbon chain three carbon atoms away from the -CH3 group. They include polyunsaturated fatty acids such as ALA (the carbon chain consists of 18 carbon atoms), EPA (20 carbon atoms in the carbon chain), and DHA (22 carbon atoms in the carbon chain) [23, 24]. Their structure and more, including the location of the double bonds, are presented in Figure 1.