Abstract
Previous studies have indicated that the pathogenesis of amyotrophic lateral sclerosis (ALS) is closely linked to 5-hydroxytryptamine (5-HT). To investigate this further, we administered 5-HT receptor antagonists to SOD1*G93A transgenic (ALS mouse model) and wide-type mice. This involved intraperitoneal injections of either granisetron, piboserod, or ritanserin, which inhibit the 5-HT3, 5-HT4, and 5-HT2 receptors, respectively. The transgenic mice were found to have fewer 5-HT-positive cells in the spinal cord compared with wide-type mice. We found that the administration of granisetron reduced the body weight of the transgenic mice, while piboserod and ritanserin worsened the motor functioning, as assessed using a hanging wire test. However, none of the 5-HT receptor antagonists affected the disease progression. We analyzed the distribution and/or expression of TAR DNA binding protein 43 (TDP-43) and superoxide dismutase 1 G93A (SOD1-G93A), which form abnormal aggregates in ALS. We found that the expression of these proteins increased following the administration of all three 5-HT receptor antagonists. In addition, the disease-related mislocalization of TDP-43 to the cytoplasm increased markedly for all three drugs. In certain anatomical regions, the 5-HT receptor antagonists also led to a marked increase in the number of astrocytes and microglia and a decrease in the number of neurons. These results indicate that 5-HT deficiency may play a role in the pathogenesis of amyotrophic lateral sclerosis by inducing the abnormal expression and/or distribution of TDP-43 and SOD1-G93A and by activating glial cells. 5-HT could therefore be a potential therapeutic target for amyotrophic lateral sclerosis.