5-Hydroxytryptamine: a potential therapeutic target in amyotrophic lateral sclerosis

Area of Science:

• Neuroscience
• Neurodegenerative Diseases
• Pharmacology

Background:

• Amyotrophic lateral sclerosis (ALS) pathogenesis is increasingly linked to alterations in serotonin (5-hydroxytryptamine, 5-HT) signaling.
• Previous research suggests a connection between 5-HT and the progression of ALS.

Purpose of the Study:

• To investigate the role of 5-HT receptors in ALS pathogenesis using a SOD1*G93A transgenic mouse model.
• To evaluate the effects of 5-HT receptor antagonists on disease progression, protein aggregation, and neuropathology in ALS mice.

Main Methods:

• Administration of 5-HT receptor antagonists (granisetron, piboserod, ritanserin) to SOD1*G93A transgenic and wild-type mice.
• Assessment of motor function using the hanging wire test, body weight changes, and analysis of TDP-43 and SOD1-G93A protein expression and localization.
• Histological analysis of spinal cords to quantify neuronal, glial cell (astrocytes, microglia), and 5-HT-positive cell populations.

Main Results:

• Transgenic mice exhibited reduced 5-HT-positive cells in the spinal cord compared to wild-type controls.
• 5-HT receptor antagonists did not alter overall ALS disease progression but negatively impacted motor function and body weight in some cases.
• Administration of antagonists increased the expression and cytoplasmic mislocalization of TDP-43 and SOD1-G93A, alongside glial cell activation and neuronal loss in specific regions.

Conclusions:

• 5-HT deficiency may contribute to ALS pathogenesis by promoting abnormal TDP-43 and SOD1-G93A aggregation and activating glial cells.
• These findings suggest that 5-HT signaling pathways represent a potential therapeutic target for managing ALS.
• Further research into 5-HT's role could elucidate novel treatment strategies for neurodegenerative conditions like ALS.