The Role of Acid Sphingomyelinase Inhibition in Repetitive Mild Traumatic Brain Injury
| Autor: | Richard S. Hoehn, Michael D. Goodman, Aaron P. Seitz, Grace M. Niziolek, Erich Gulbins, Michael J. Edwards, Peter L. Jernigan, Amy T. Makley |
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| Rok vydání: | 2019 |
| Předmět: |
Male
medicine.medical_specialty Traumatic brain injury Amitriptyline Medizin tau Proteins Hippocampal formation Protein Aggregation Pathological Article 03 medical and health sciences Mice 0302 clinical medicine Internal medicine medicine Animals Brain Concussion biology business.industry Neurogenesis medicine.disease Doublecortin Mice Inbred C57BL Chronic traumatic encephalopathy Disease Models Animal Endocrinology Sphingomyelin Phosphodiesterase 030220 oncology & carcinogenesis biology.protein 030211 gastroenterology & hepatology Surgery Tauopathy Acid sphingomyelinase business medicine.drug |
| Zdroj: | J Surg Res |
| ISSN: | 1095-8673 |
| Popis: | BACKGROUND: Chronic traumatic encephalopathy is a consequence of repetitive mild traumatic brain injury (rmTBI). These injuries can result in psychiatric disorders that are treated with amitriptyline. Amitriptyline improves neuronal regeneration in major depression via inhibition of acid sphingomyelinase. We hypothesized that acid sphingomyelinase inhibition would preserve neuronal regeneration and decrease depressive symptoms following rmTBI in a murine model. METHODS: A murine model of rmTBI was established using a weight-drop method. Mice were subjected to mild TBI every other day for 7 days. Mice received amitriptyline injection 2 hours prior to each mild TBI. After the final mild TBI, mice underwent behavioral studies or biochemical analysis. Hippocampi were analyzed for markers of neurogenesis and phosphorylated tau aggregation. RESULTS: Mice that underwent rmTBI showed increased hippocampal phosphorylated tau aggregation one month following rmTBI as well as decreased neuronal regeneration by bromodeoxyuridine uptake and doublecortin immunohistochemistry. Mice with either genetic deficiency or pharmacologic inhibition of acid sphingomyelinase demonstrated improved neuronal regeneration and decreased phosphorylated tau aggregation compared to untreated rmTBI mice. Behavioral testing showed rmTBI mice spent significantly more time in the dark and waiting to initiate feeding compared to sham mice. These behaviors were partially prevented by the inhibition of acid sphingomyelinase. CONCLUSIONS: We established a murine model of rmTBI that leads to tauopathy, depression, and impaired hippocampal neurogenesis. Inhibition of acid sphingomyelinase prevented the harmful neurologic and behavioral effects of rmTBI. These findings highlight an important opportunity to improve recovery or prevent neuropsychiatric decline in patients at risk for chronic traumatic encephalopathy. |
| Databáze: | OpenAIRE |
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