Abstract
Transient receptor potential melastatin member 4 (TRPM4), a Ca2+-activated nonselective cation channel, has been found to mediate cell membrane depolarization in immune response, insulin secretion, cardiovascular diseases, and cancer. In murine experimental autoimmune encephalomyelitis (EAE), TRPM4 deletion and administration of glibenclamide were found to ameliorate clinical symptoms and attenuate disease progression. However, the exact role of TRPM4 in EAE, as well as the molecular mechanisms underlining TRPM4 contribution in EAE, remain largely unclear. In the present study, EAE was induced in WT C57BL/6 N mice using myelin oligodendrocyte glycoprotein 35–55 (MOG35–55) and TRPM4 protein and mRNA expression were examined in spinal cord membrane extracts. Our results showed that TRPM4 protein and mRNA are upregulated in EAE, and that their upregulation correlated with disease progression. Moreover, newly-developed TRPM4 inhibitors, named compound 5 and compound 6, were shown to exert a better neuroprotection compared to currently used TRPM4 inhibitors in an in vitro model of glutamate-induced neurodegeneration. These results support the hypothesis that TRPM4 is crucial from early stages of EAE, and suggest that these more potent TRPM4 inhibitors could be used as novel protective therapeutic tools in glutamate-induced neurodegeneration.
Highlights
Multiple sclerosis (MS) is a multifocal demyelinating disease of the central nervous system (CNS) leading to the progressive destruction of the myelin sheath surrounding axons [1]
Multiple sclerosis is the most common autoimmune disorder of the central nervous system, affecting approximately 2.5 million people worldwide [1]. It is primarily an inflammatory disorder of the brain and spinal cord in which focal lymphocytic infiltration leads to damage of myelin and axons; a growing body of evidence suggests that non-immunological factors, such as changes in neuronal ion channel expression and/or function, are of pathophysiological importance [29]
In a recent study by Schattling and colleagues, Transient receptor potential melastatin member 4 (TRPM4) was found to be expressed in axons and neurons of mice and humans, and suggested to mediate neurodegeneration by contributing in glutamate-induced cell swelling and cell death without affecting the immune response triggered in the EAE model [12]
Summary
Multiple sclerosis (MS) is a multifocal demyelinating disease of the central nervous system (CNS) leading to the progressive destruction of the myelin sheath surrounding axons [1]. TRPM4 is a calcium-activated non-selective cation channel widely expressed in several tissues and reported to be involved in a variety of physiological and pathological processes, including modulation of immune cells activity, such as T-cells [13], mast cells [14] and dendritic cells [15], insulin secretion by pancreatic β cells [16], mechano-trans duction in cerebral arteries [17], Ca2+ signaling in cancer [18], and several cardiac conduction disorders [19,20,21,22] In addition, TRPM4 has been linked to several neurological disorders such as experimental autoimmune encephalomyelitis and multiple sclerosis [12], spinal cord injuries [23], and traumatic brain injuries [24]. Newly-developed TRPM4 inhibitors, anthranilic amides named compound 5 and compound 6, are shown to be able to protect neuronal cells from glutamate-induced neurodegeneration, confirming TRPM4 as a potential therapeutic target for glutamate-induced neuronal cell death in EAE
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