**1. Introduction**

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system [1–5]. Experimental animal models are one of the useful tools because they can increase our knowledge about the central system disorders [6]. Unfortunately in MS, there is no model that can reflect all of the pathological features [7].

The use of experimental animal models, including MS models, has recently been the focus of several reports [8]. These subjects are mentioned in the ARRIVE guidelines as well [9]. Adherence to the guidelines on reporting and referring papers using experimental models of MS will be key for the translation from the bench to experimental models and eventually to the bedside of MS patients [10].

Animal models are the advantageous way to identify the immunopathological mechanisms involved in MS [11]. Animal models help scientists to develop novel therapeutic and in regenerative medicine approaches [12]. Animal models of MS have provided a beneficial platform for evaluating its efficacy in MS treatment and how this may be targeted for therapy lastly [13]. Indeed, choosing an appropriate animal model to study a complex disease like MS presents several challenges, chiefly associated with heterogeneity [14, 15]. It is well established that MS is highly heterogeneous in terms of its genetic basis, environmental triggers, clinical course, pathology, and therapeutic responsiveness in each treatment [16]. Important factors such as genetic and environmental contribute toward MS development; however, etiology is complex and not completely assumed. Ideally, an advanced animal model has to include this heterogeneity [15, 17].

Certainly, studies in MS model need to be carefully covered the pathogenesis of the disease. A high degree of consistency between models and experimental conditions makes possible translation into therapeutic achievement [18].

Not remarkably, most of our present facts of MS have been derived from the EAE model [19]. Although EAE must be induced by artificial immunization against myelin, most therapies tested in MS patients are based on concepts derived from the EAE model, which continues to be the model system of choice. EAE models are vital for studying general concepts other than specific processes of autoimmunity; however infrequently, they predict success in clinical trials [20].

There are many mismatched aspects of pathology and immunology between EAE and multiple sclerosis. These differences are significant. For example, persistent imbalances in immune regulation are vital to the progression of multiple sclerosis, but these orders of complexity have not yet been summarized in the MS models [21]. This, in combination with a diversity of animal models that mimic specific features and processes of MS, has contributed to filling the gap of knowledge in the cascade of events underlying MS pathophysiology [22].

Until now several different EAE models have been developed, differing in the immunological reaction, inflammatory processes, and the neuropathophysiology in the CNS.

Access to up-to-date knowledge of the dynamic responses of neural cells, such as microglia in the commonly used animal models of MS, specifically the immunemediated experimental autoimmune encephalomyelitis (EAE) model, and the chemically induced cuprizone and lysolecithin EAE models can be really helpful [23]. It is essential to elucidate the spectrum of microglial functions in these models, from harmful to protective roles, to identify emerging therapeutic targets and guide drug discovery efforts [24].

In all models, it can be observed that the harmful activation of microglial cells is in the acute stage of diseases such as encephalitis, cuprizone-induced demyelination, PCL, and FAE. However, in subacute and chronic stages, regenerative healing by microglial cells may be observed [25]. The role of T lymphocytes in EAE, CPL, and cuprizone models is important too; however, they cannot impact like microglial cells [26]. This makes these models the cleanest method for studying microglial mechanisms in innate immune systems and also all aspects of oligodendrocytes such has proliferation, differentiation, and especially the cause of remyelination [27, 28].

Briefly, this overview of the *in vitro* and *in vivo* models is commonly used to recapitulate the different faces of MS immunopathology; thus, a degree of confidence that findings with these puppets may be translated to MS therapy.
