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Laquinimod is currently being tested as a therapeutic drug in multiple sclerosis. However, its exact mechanism of action is still under investigation. Tracking of fluorescently-tagged encephalitogenic T cells during experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, revealed that laquinimod significantly reduces the invasion of pathogenic effector T cells into the CNS tissue. T-cell activation, differentiation and amplification within secondary lymphoid organs after immunization with myelin antigen, their migratory capacity and re-activation within the nervous tissue were either only mildly affected or remained unchanged. Instead, laquinimod directly impacted the functionality of the CNS vasculature. The expression of tight junction proteins p120 and ZO-1 in human brain endothelial cells was up-regulated upon laquinimod treatment, resulting in a significant increase in the transendothelial electrical resistance of confluent monolayers of brain endothelial cells. Similarly, expression of the adhesion molecule activated leukocyte cell adhesion molecule (ALCAM) and inflammatory chemokines CCL2 and IP-10 was suppressed, leading to a significant reduction in the migration of memory T H 1 and T H 17 lymphocytes across the blood brain barrier (BBB). Our data indicate that laquinimod exerts its therapeutic effects by tightening the BBB and limiting parenchymal invasion of effector T cells, thereby reducing CNS damage. [ABSTRACT FROM AUTHOR]

Neuropeptide Y (NPY) and NPY receptors are widely expressed in the mammalian central nervous system. Studies in both humans and rodent models revealed that brain NPY levels are altered in some neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Machado-Joseph disease. In this review, we will focus on the roles of NPY in the pathological mechanisms of these disorders, highlighting NPY as a neuroprotective agent, as a neural stem cell proliferative agent, as an agent that increases trophic support, as a stimulator of autophagy and as an inhibitor of excitotoxicity and neuroinflammation. Moreover, the effect of NPY in some clinical manifestations commonly observed in Alzheimer's disease, Parkinson's disease, Huntington's disease and Machado-Joseph disease, such as depressive symptoms and body weight loss, are also discussed. In conclusion, this review highlights NPY system as a potential therapeutic target in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), for which current treatments are unable to prevent disease progression. Based on its neuroprotective and neuroregenerating properties, leukemia inhibitory factor (LIF), a member of the interleukin-6 (IL-6) cytokine family, is proposed as a novel candidate for MS therapy. However, its effect on the autoimmune response remains unclear. In this study, we determined how LIF modulates T cell responses that play a crucial role in the pathogenesis of MS. We demonstrate that expression of the LIF receptor was strongly increased on immune cells of MS patients. LIF treatment potently boosted the number of regulatory T cells (Tregs) in CD4 + T cells isolated from healthy controls and MS patients with low serum levels of IL-6. Moreover, IL-6 signaling was reduced in the donors that responded to LIF treatment in vitro . Our data together with previous findings revealing that IL-6 inhibits Treg development, suggest an opposing function of LIF and IL-6. In a preclinical animal model of MS we shifted the LIF/IL-6 balance in favor of LIF by CNS-targeted overexpression. This increased the number of Tregs in the CNS during active autoimmune responses and reduced disease symptoms. In conclusion, our data show that LIF downregulates the autoimmune response by enhancing Treg numbers, providing further impetus for the use of LIF as a novel treatment for MS and other autoimmune diseases. [ABSTRACT FROM AUTHOR]

Multiple Sclerosis (MS) is a chronic inflammatory neurodegenerative disease of central nervous system (CNS). Although the main cause of MS is not clear, studies suggest that MS is an autoimmune disease which attacks myelin sheath of neurons. There are different therapeutic regimens for MS patients including interferon (IFN)-β, glatiramer acetate (GA), and natalizumab. However, such therapies are not quite effective and are associated with some side effects. So which, there is no complete therapeutic method for MS patients. Regarding the potent immunomodulatory effects of mesenchymal stem cells (MSCs) and their ameliorative effects in experimental autoimmune encephalopathy (EAE), it seems that MSCs may be a new therapeutic method in MS therapy. MSC transplantation is an approach to regulate the immune system in the region of CNS lesions. In this review, we have tried to discuss about the immunomodulatory properties of MSCs and their therapeutic mechanisms in MS patients. [ABSTRACT FROM AUTHOR]

Abstract: The de novo synthesis of the amino acid l-serine plays an essential role in the development and functioning of the central nervous system (CNS). l-Serine displays many metabolic functions during different developmental stages; among its functions providing precursors for amino acids, protein synthesis, nucleotide synthesis, neurotransmitter synthesis and l-serine derived lipids. Patients with congenital defects in the l-serine synthesizing enzymes present with severe neurological abnormalities and underscore the importance of this synthetic pathway. In this review, we will discuss the cellular functions of the l-serine pathway, structure and enzymatic properties of the enzymes involved and genetic defects associated with this pathway. [Copyright &y& Elsevier]