mRNA Expression of SMPD1 Encoding Acid Sphingomyelinase Decreases upon Antidepressant Treatment

Abstract

Major depressive disorder (MDD) is a severe psychiatric condition with key symptoms of low mood and lack of motivation, joy, and pleasure. Recently, the acid sphingomyelinase (ASM)/ceramide system has been implicated in the pathogenesis of MDD. ASM is a lysosomal glycoprotein that catalyzes the hydrolysis of sphingomyelin, an abundant component of membranes, into the bioactive sphingolipid ceramide, which impacts signaling pathways. ASM activity is inhibited by several common antidepressant drugs. Human and murine studies have confirmed that increased ASM activity and ceramide levels are correlated with MDD. To define a molecular marker for treatment monitoring, we investigated the mRNA expression of SMPD1, which encodes ASM, in primary cell culture models, a mouse study, and a human study with untreated MDD patients before and after antidepressive treatment. Our cell culture study showed that a common antidepressant inhibited ASM activity at the enzymatic level and also at the transcriptional level. In a genetically modified mouse line with depressive-like behavior, Smpd1 mRNA expression in dorsal hippocampal tissue was significantly decreased after treatment with a common antidepressant. The large human study showed that SMPD1 mRNA expression in untreated MDD patients decreased significantly after antidepressive treatment. This translational study shows that SMPD1 mRNA expression could serve as a molecular marker for treatment and adherence monitoring of MDD.

Acid Sphingomyelinase, a Lysosomal and Secretory Phospholipase C, Is Key for Cellular Phospholipid Catabolism

“…A low dose of radiation (2 Gy) upregulates miR-15a and lowers SMPD1 levels, whereas a high dose of radiation (more than 10 Gy) lowers miR-15a and activates the SMPD1 gene, increasing ASM biosynthesis. Antidepressant treatment also decreases expression of SMPD1-mRNA [128]. In a similar manner, the NO-donor diethylenetriamine/NO also decreased mRNA and protein expression of ASM in HepG2 cells, triggering apoptosis and cell death [129].…”

Volumetric changes in specific neurofunctional subfields of the hippocampus in major depressive disorder

“…One study reported that hippocampal atrophy in female MDD patients was mainly limited to the posterior cluster [27]. Moreover, the effect of amitriptyline was observed specifically in the dorsal hippocampus [28]. Based on these observations, we infer that the volumetric reductions in the L1, L2, L3, and R4 subfields of the hippocampus can serve as imaging markers of mood disorders and cognitive impairment in MDD.…”

Acid Sphingomyelinase Inhibitor, Imipramine, Reduces Hippocampal Neuronal Death after Traumatic Brain Injury

“…In addition, ASMase and ceramide levels are also highly elevated, resulting in mitochondrial dysfunction and apoptosis [ 43 , 44 , 45 ]. However, the functional inhibitors of acid sphingomyelinase detach ASMase from the lysosomal inner membrane and degrade it [ 46 ]. Therefore, we hypothesized that one of the ASMase inhibitors, imipramine, may reduce TBI-induced neuronal death and cognitive dysfunction.…”

“…However, under pathologic conditions, ASMase and ceramide levels are abnormally increased and induce neuronal death. In this study, we used imipramine, which attached to the lysosomal membrane instead of ASMase [ 31 , 46 ]. ASMase is most activated 2–3 h after injury [ 51 , 52 ].…”