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Neuroprotective Natural Products Against Experimental Autoimmune Encephalomyelitis: a Review T Neurochemistry International 129 (2019) 104516 Contents lists available at ScienceDirect Neurochemistry International journal homepage: www.elsevier.com/locate/neuint Neuroprotective natural products against experimental autoimmune encephalomyelitis: A review T Leila Mohtashamia, Abolfazl Shakeria, Behjat Javadib,* a Department of Pharmacognosy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran b Department of Traditional Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran 1. Introduction acids, amino acids and sugars), cellular structure forming compounds (cellulose, lignins and proteins) and secondary metabolites. Most pri- Multiple sclerosis is a chronic inflammatory demyelinating disease mary metabolites play their pharmacological role in the organism or of the CNS which leads to the demyelination in the white and gray cell that has produced them, whilst, secondary metabolites are able to matter (Lassmann, 2014). MS is the most frequent neurological disease biologically affect other organisms (Hanson, 2003). A tremendous in- in young adults between the ages of 20–40 years and approximately vestigation on the effectiveness of pure compounds and plant extracts in affects 2.5 million people around the world (Tullman, 2013). Clinical slowing the progression of EAE has resulted in the identification of manifestations of MS typically appear in the thirties and forties, and it valuable lead compounds and drugs. Gilenya® (fingolimod) is the first affects women almost three times more than men (Constantinescu et al., oral treatment for relapsing multiple sclerosis that has been derived 2011). It has a high prevalence in regions with high geographic lati- from myriocin-a metabolite of the fungus Isaria sinclairii (Miyake et al., tudes such as North America and Northern Europe and has low rates in 1995)-by SAR studies to determine the active parts of the molecule. Eastern Asia and sub-Saharan Africa (Emami et al., 2016; Leray et al., Other extracts and natural products specifically Cannabis-based drugs 2016). Little is known about the etiology of MS. However, susceptible are being studied in clinical trials as well. genes and environmental factors seem to play a role in the pathogenesis Here in this review, we have summarized the mechanisms of natural of this disease. Blood–brain barrier (BBB) dysfunction, immune cells products as well as plant powders, extracts and essential and fatty oils infiltration into the CNS and antigens attack against the neurons and in treating inflammatory and immunological processes involved in the oligodendrocytes are responsible for the main inflammatory processes. pathogenesis of EAE. Moreover, several autoimmune mechanisms account for axonal and neuronal degeneration (Ellwardt and Zipp, 2014). Oxidative stress 2. Pathogenesis of multiple sclerosis which leads to mitochondrial damage is also a major factor in demye- lination and neurodegeneration in MS patients (Lassmann, 2014). MS is The mechanisms of neurodegeneration in MS are not well under- considered to be a predominantly T cell-mediated autoimmune disease stood yet. Demyelination, axonal injury and chronic inflammation as supported by evidence derived from its principal model, experi- occur in both relapsing and progressive stage of the disease (Haider mental autoimmune encephalomyelitis (EAE) (Stadelmann et al., et al., 2011) It is believed that MS is primarily caused by increased 2011). EAE is the animal model used for evaluating inflammatory de- migration of autoreactive T lymphocytes (T cells) through a disrupted myelinating disease of the CNS. It is induced by triggering an immune BBB (Compston and Coles, 2008). The T cells recognize and attack the response against myelin and has been used extremely as a prototype of myelin sheath, resulting in the formation of demyelinated lesions in the Th1- and/or Th17-driven organ-specific autoimmune conditions and as brain and spinal cord which in turn leads to the impairment of nerve an animal model for multiple sclerosis (Rao and Segal, 2012). EAE conduction and axonal loss (Babbe et al., 2000). The most important experimental model has already led directly to the development of four morphological trait of MS is demyelination of axons leading to the FDA-approved medicines for the treatment of MS: glatiramer acetate, blockade or slowing of signal conduction at the site of demyelination. mitoxantrone, natalizumab (Leuschner et al., 1986) and fingolimod. Neurological symptoms gradually appear after involvement of a sig- Natural products are defined as organic compounds that are pro- nificant proportion of axonal fibers within a specific pathway (Fletcher duced by living systems. Their structure elucidation and biosynthesis et al., 2010). Generally, key players of neurodegeneration in MS include are among the popular fields in organic chemistry. Natural products can microglia activation, mitochondrial damage in axons, chronic oxidative be classified into three categories i.e. primary metabolites (nucleic injury, and iron accumulation in the brain (Mahad et al., 2015). * Corresponding author. Department of Traditional Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, P.O. Box: 9188617871, Mashhad, Iran. E-mail addresses: [email protected], [email protected] (B. Javadi). https://doi.org/10.1016/j.neuint.2019.104516 Received 24 May 2019; Received in revised form 29 July 2019; Accepted 31 July 2019 Available online 31 July 2019 0197-0186/ © 2019 Elsevier Ltd. All rights reserved. L. Mohtashami, et al. Neurochemistry International 129 (2019) 104516 Microglia are resident glial cells in the CNS, that normally remove the (Haghmorad et al., 2017). Flavonoids have positive effects during the damaged neurons by phagocytosis. However, the chronic activation of pathogenesis of MS and EAE because of their potent inhibitory effect on microglia may result in neuronal damage by releasing cytotoxic mole- proliferation of auto antigen specific T cells and IFN-γ production cules including proinflammatory cytokines, ROS, proteinases and (Verbeek et al., 2005). Capparis ovata, as a rich source of flavonoids, complement proteins. Accordingly, suppression of microglia-mediated suppressed the development of EAE in C57BL/6 mice via down-reg- inflammatory response would be an important therapeutic strategy in ulating some inflammatory genes such as IL-6, CCL5, CXCL10, CXCL9, the treatment of neurodegenerative diseases (Dheen et al., 2007). Ex- NF-κB, and TNF-α (Ozgun-Acar et al., 2016). cessive ROS, primarily generated by macrophages, is also the key ele- ment in the pathogenesis of MS through mediating oligodendrocytes 3.1.1. Hesperidin injury, neurons demyelination and axonal damage (Haider et al., 2011; Hesperidin (3,5,7-trihydroxy flavanone-7-rhamnoglucoside), is a Gilgun-Sherki et al., 2004). Mitochondrial injurycan be triggered by flavonoid glycoside isolated from the rinds of some Citrus species such ROS and NO (Haider et al., 2011). Mitochondria are the most efficient as sweet orange and lemon (Sun et al., 2017). Considering the im- ATP generators and are crucial players in many cellular processes such portant role of oxidative stress in the pathogenesis of EAE, hesperidin as as fatty acid oxidation, apoptosis, and calcium homeostasis. Therefore, a strong anti-oxidant flavonoid, may show neuroprotective activity in mitochondrial injury may result in energy deficit, chronic cell stress and diseases like MS. Hesperidin prevents the oxidative stress, decreases an increase in the susceptibility of axons to excitotoxic injury through lipid peroxidation and inhibits immunological and histological damage high levels of calcium ions entrance into the neurons (Mahad et al., caused by EAE (Ciftci et al., 2015). EAE development in C57BL/6 mice 2009). Age-related iron deposition is an important factor in the pa- can be suppressed by hesperidin in a dose-dependent manner via re- thophysiologic changes that happen especially in the neurodegenera- ducing proinflammatory cytokines (TNF-α, IL-6 and IL-17) and evoking tive processes of MS (Ge et al., 2007). Nonheme iron is the most form of the polarization of CD4+ T cells to regulatory T cells. This inhibits auto- iron that deposits in oligodendrocytes and myelin, the primary target of reactive T cells proliferation and migration into the CNS (Haghmorad inflammatory activities in MS (Hametner et al., 2013). Quantitative et al., 2017). evaluation of iron content has indicated its enhanced accumulation in the deep gray matter of MS patients (Ge et al., 2007). Pathological and 3.1.2. Genistein MRI studies revealed that iron deposits at the edges of chronic MS le- Genistein (4′,5,7-trihydroxy isoflavone), an isoflavone with phy- sions. Also, injecting iron-containing ferritin into the rat spinal cord toestrogenic properties, has different biological effects including anti- promotes the formation and differentiation of oligodendrocyte from cancer, anti-angiogenic, anti-oxidant, anti-inflammatory, anti-nocicep- OPCs (Hametner et al., 2013). Therefore, iron-chelating therapies for tive and neuro-protective (Hu et al., 2017). Genistein oral administra- MS patients may not be of therapeutic utility. tion in the early phase of EAE, decreased the severity of the disease via EAE was first described in 1930s and is still widely used as an ex- inhibiting T cells proliferation, decreasing IFN-γ, IL-12 and TNF-α perimental model of MS. Typically, sensitization to myelin antigens in (Jahromi et al., 2014) and increasing IL-10 secretion (Jahromi et al., EAE happens
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