Chronically altered NMDAR signaling in epilepsy mediates comorbid depression

Acta Neuropathologica Communications

Hasan Yousefi-Manesh¹  Ahmad Reza Dehpour²  Sara Hemmati³  Mohammad Amin Sadeghi³  Sina Mohammadi⁴  Meysam Zare⁵  Ali Vafaei⁶ 

[1]Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran

[2]Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran

[3]Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran

[4]Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran

[5]Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

[6]Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran

[7]Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran

[8]School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

[9]Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran

[10]Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran

[11]Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran

[12]School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

[13]Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

[14]Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran

[15]School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

关键词: Depression;    Epilepsy;    Intracellular signaling;    Nitric oxide;    Nitrosative stress;    N-methyl-D-aspartate receptors;    MAP kinase signaling system;    Nitric oxide synthase type I;    Brain-derived neurotrophic factor;    Immediate early genes;   

DOI  :  10.1186/s40478-021-01153-2

来源: Springer

【 摘 要 】

Depression is the most common psychiatric comorbidity of epilepsy. However, the molecular pathways underlying this association remain unclear. The NMDA receptor (NMDAR) may play a role in this association, as its downstream signaling has been shown to undergo long-term changes following excitotoxic neuronal damage. To study this pathway, we used an animal model of fluoxetine-resistant epilepsy-associated depression (EAD). We determined the molecular changes associated with the development of depressive symptoms and examined their response to various combinations of fluoxetine and a selective neuronal nitric oxide synthase inhibitor, 7-nitroindazole (NI). Depressive symptoms were determined using the forced swim test. Furthermore, expression and phosphorylation levels of markers in the ERK/CREB/ELK1/BDNF/cFOS pathway were measured to determine the molecular changes associated with these symptoms. Finally, oxidative stress markers were measured to more clearly determine the individual contributions of each treatment. While chronic fluoxetine (Flxc) and NI were ineffective alone, their combination had a statistically significant synergistic effect in reducing depressive symptoms. The development of depressive symptoms in epileptic rats was associated with the downregulation of ERK2 expression and ELK1 and CREB phosphorylation. These changes were exactly reversed upon Flxc + NI treatment, which led to increased BDNF and cFOS expression as well. Interestingly, ERK1 did not seem to play a role in these experiments. NI seemed to have augmented Flxc’s antidepressant activity by reducing oxidative stress. Our findings suggest NMDAR signaling alterations are a major contributor to EAD development and a potential target for treating conditions associated with underlying excitotoxic neuronal damage.

【 授权许可】

CC BY