Defining a role for laquinimod in multiple sclerosis

Abstract

Multiple sclerosis (MS), an inflammatory disease affecting the central nervous system, is considered to exhibit an important neurodegenerative component as well. Laquinimod is an orally administered quinoline-3-carboxamide under development for the treatment of MS. In vitro and animal studies have revealed various mechanisms by which laquinimod may exert its effects on the immune and nervous systems. These include effects on the innate immune system that promote the differentiation of anti-inflammatory/regulatory T cells, the activation of microglia cells, an increase in the expression of brain-derived neurotrophic factor, as well as the prevention of inflammation-induced excitotoxicity. Two phase III studies revealed the clinical benefits of laquinimod in patients with relapsing-remitting MS and exhibited a benign safety profile for this drug. Ongoing clinical trials will help to define the optimal dose and indication for laquinimod in MS. This article reviews current experimental and clinical evidence on the role of laquinimod in patients with this disabling disease.

Keywords: laquinimod; multiple sclerosis; neuroprotection; relapsing–remitting multiple sclerosis.

Figure 1.

Upper panel: One hallmark of the pathology of multiple sclerosis (MS) is inflammation involving B cells, T cells, and macrophages, which results in tissue damage within the central nervous system (CNS). Dendritic cells present neural antigens, thereby stimulating the expansion of activated T-cell and B-cell populations that then migrate en masse through the blood–brain barrier (BBB) into the CNS. T cells differentiate into T helper 1 (Th1) and Th2 cells, the former stimulating macrophage activation. Correspondingly, B cells mature and produce immunoglobulin (Ig) G antibodies, which bind to the neuronal membrane, thereby targeting marked cells for phagocytic attack by activated macrophages. These inflammatory events stimulate astrogliosis, demyelination, axonal degeneration, and programmed cell death, and ultimately manifest in tissue damage and brain lesions, core physiologic symptoms of MS. Lower panels: Laquinimod acts at various points within the normal pathology of MS (a–f). Laquinimod promotes an anti-inflammatory system by altering the cytokine profile of T cells, B cells, and monocytes (a) and increasing the population of anti-inflammatory cells (b). Furthermore, laquinimod restricts cell migration by reducing the amount of VLA-4 adhesion molecule on the surface of T cells (c) and increasing the integrity of the BBB (d). Finally, laquinimod demonstrates its role in neuroprotection by inhibiting astrogliosis (e) and triggering the production and release of brain-derived neurotrophic factor (BDNF) (f). ICAM, intercellular adhesion molecule 1; IL, interleukin; IFN, interferon; TGF, transforming growth factor; TNF, tumor necrosis factor; VLA-4, very late antigen 4.