Year: 2025
Type: article
Abstract: Excitotoxicity is a pathological process that occurs in many neurological diseases, such as stroke or epilepsy, and is characterized by the extracellular accumulation of high concentrations of glutamate or other excitatory amino acids (EAAs). Nicotinamide adenine dinucleotide (NAD) depletion is an early event following excitotoxicity in many in vitro and in vivo excitotoxic-related models and contributes to the deregulation of energy homeostasis. However, the interplay between glutamate excitotoxicity and the NAD biosynthetic pathway is not fully understood. To address this question, we used a primary culture of rat cortical neurons and found that an excitotoxic glutamate insult alters the expression of the NAD biosynthetic enzymes. Additionally, using a fluorescent NAD mitochondrial sensor, we observed that glutamate induces a significant decrease in the mitochondrial NAD pool, which was reversed when exogenous NAD was added. We also show that exogenous NAD protects against the glutamate-induced decrease in mitochondrial membrane potential (MMP). Glutamate excitotoxicity changed mitochondrial retrograde transport in neurites, which seems to be reversed by NAD addition. Finally, we show that NAD and NAD precursors protect against glutamate-induced cell death. Together, our results demonstrate that glutamate-induced excitotoxicity acts by compromising the NAD biosynthetic pathway, particularly in the mitochondria. These results also uncover a potential role for mitochondrial NAD as a tool for central nervous system (CNS) regenerative therapies.
Source: Cells
Authors: Bruna S. Paiva, Diogo Neves, Diogo Tomé, Filipa J. Costa, Inês C. Bruno, Diogo Trigo, Raquel M. Silva, Ramiro D. Almeida
Language: English
Subfield: Geriatrics and Gerontology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,258
Awards: G121659266, G1390952213, G1516346500, G1577006909, G1578237752, G1654777293, G1763632427, DIAMOND-CONNECT: Plataformas fotônicas de diamante para o estudo da conectividade em modelos de células neuronais, G1781739789, The effect of mesenchymal stem cells secretome on axon regeneration and post-injury synapse formation, Centro de Inovação em Biomedicina e Biotecnologia, G2120309575, G2126414381, G2195151728, G3209507826, G3533113517, G3660205263, G3831966561, G3840324753, G3981349085, Unveiling the functions of NMRK1- and NMRK2-mediated NAD+ synthesis in neuronal and glial cells, G4781291319, G4993383890, G5132640529, G5221664942, G5224927334, Sem título, G5454278309, G5642561709, Investigate the interplay between coronary artery disease and nervous system function, G6193589897, G6293975412, Centro de Inovação em Biomedicina e Biotecnologia, G6624520663, G6682296850, G6682635355, G6886798228, G7194136402, Instituto de Biomedicina - Aveiro, G7278841680, G7302627091, G7423102242, G7665495773, G7685134749, Instituto de Biomedicina - Aveiro, G826989945, Centro de Investigação Interdisciplinar em Saúde
OpenAlex ID: W4409410989