Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that affects more than 2.5 million people worldwide, with the majority of cases occurring in women aged 20 to 40 years [1]. MS is defined by the dysfunction or loss of oligodendrocytes and damage to the myelin sheath, resulting in demyelination. The blood–brain barrier (BBB) typically prevents the uncontrolled entry of leukocytes into the CNS, but in MS, this barrier is impaired [2]. Therefore, the migration of lymphocytes through the BBB and their penetration into the CNS is crucial in triggering the neuroinflammatory cascade that leads to disease recurrence. As a result, brain microvascular endothelial cells' permeability increases, prompting self-reacting leukocytes to attack and damage the myelin sheath, finally leading to neurodegeneration [3]. MS genetic studies have collected many genes associated with disease susceptibility [4]. In this regard, the DRB1 * 15:01 HLA genotype on chromosome 6, which functions as a tissue-compatible complex (MHC), may contribute to an increased risk of MS [5].

Animal models are used to further explore and explain the pathological changes in the course of the disease and to advance new therapies, as access to human tissues and biopsies at MS is limited [6]. Several experimental models of MS are available, which have been verified to be highly useful for evaluating different aspects of neuroinflammation, de- and re-myelination, and neurodegeneration. However, the significance of outcomes from animal models for MS pathogenesis has to be censoriously confirmed. Nevertheless, no one animal model covers the complete range of the clinical, pathological, or immunological features of MS in patients. The most commonly used animal models to study agents aimed at improving the pathophysiological processes of MS are the cuprizone (CPZ) and experimental autoimmune encephalomyelitis (EAE) mouse models [7].

The EAE model is triggered by immunization with myelin peptides or homogenized CNS tissue.

Moreover, an immune-activating adjuvant (containing bacterial components) results in the inflammatory infiltrate, gliosis, axonal loss, and demyelination, pathogenic features similar to those of MS [8], [9]. The CPZ model is based on a copper chelator (cuprizone intoxication). Cuprizone-induced neurotoxicity is caused by disruption of copper homeostasis and inhibition of enzymes [particularly copper-zinc superoxide dismutase-1 (SOD1)] in the CNS, leading to neuroinflammation, oxidative stress, myelin sheath degeneration, oligodendrocyte apoptosis, neurotransmitter metabolism disorders, axonal perforation, microgliosis, and astrogliosis [10].

In the most recent study [11], several genes with differential expression in different autoimmune diseases were grouped and assigned to known susceptibility loci. Although potentially useful, this study was limited to a single expression dataset, making it vulnerable to sampling, platform selection, and analytical bias. However, this result suggests that their position in the genome does not determine the expression of these genes, supporting the idea that inherited “hot spots” of the face may contribute to susceptibility to complex diseases like MS [12]. For all these reasons, selecting a suitable animal model to answer specific questions in MS research is essential.

Next-generation sequencing (NGS) analyses have recently been used in MS and animal models to detect differentially expressed genes. However, in most cases, these studies lead to a long list of accession IDs or genes up or down-regulated in specific brain regions [13]. Therefore, the observed phenotypes may be caused by the differential expression of one or a few genes, as in monogenic diseases. In contrast, the rest of the differentially expressed transcripts are caused by trans-regulation by the underlying genetic network [14]. Alternatively, some of these differentially expressed genes could be clustered in specific parts of the genome and controlled in cis by a definitive collection of enhancers, transcription factors, chromatin condensation patterns, or other processes [15]. Therefore, in this study, we compared microarray data from two frequently used experimental models (EAE and CPZ) and found shared genes were subsequently involved in the unique inflammatory axis to determine whether or not the gene expression patterns of these models share similarities and are consistent with disease pathogenesis.