Fluoxetine pre-treatment exacerbates bleeding in a mouse model of intracerebral hemorrhage_West China Medical Journal

Authors：

GUO Tingting ^1,2 , ZHOU Jie ¹ ,  GUO Jian ¹

1. Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Department of Cardiology and Neurology, Chengfei Hospital, Chengdu, Sichuan 610091, P. R. China;

Corresponding author：

GUO Jian, Email: jian_guo@scu.edu.cn

Keywords：

Fluoxetine; intracerebral hemorrhage; mouse model; selective serotonin reuptake inhibitors

DOI：

10.7507/1002-0179.202104046

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To determine whether fluoxetine, a commonly used selective serotonin reuptake inhibitors (SSRIs), could exacerbate bleeding in a intracerebral hemorrhage (ICH) mouse model. Methods Forty two 12-14 month old female specific pathogen free C57BL/6 mice were selected. Mice were randomly divided into fluoxetine group (fluoxetine pre-treatment) and control group, with 21 mice in each group. After treated with fluoxetine for 7 days, ICH was induced by injecting collagenase Ⅶ-S into the right striatum of middle-aged female mice. Effects of fluoxetine on exacerbating bleeding were evaluated by a combination of histologic, molecular, cellular, and behavioral assessments. Results On the third day after ICH, the hemorrhage volumes of the control group and fluoxetine group were (4.59±1.80) mm³ and (6.09±1.08) mm³, respectively. In middle-aged female mice subjected to collagenase-induced ICH, fluoxetine pre-treatment significantly exacerbated neurological deficit, cerebral hemorrhage volume, myelin damage, hemoglobin and iron deposition, neuronal degeneration, and brain edema (P<0.05). Although there was no significant difference in tail bleeding time between the two groups, fluoxetine pre-treatment might increase tail bleeding time [(276.73±211.06) vs. (438.00±236.79) s; t=−1.686, P=0.055]. Conclusions The use of fluoxetine and more generally of SSRIs, which inhibits platelet aggregation, may exacerbate bleeding after ICH. Thus, patients with depression after ICH may avoid concomitant use of such drugs when choosing an antidepressant.

Citation： GUO Tingting, ZHOU Jie, GUO Jian. Fluoxetine pre-treatment exacerbates bleeding in a mouse model of intracerebral hemorrhage. West China Medical Journal, 2022, 37(3): 431-436. doi: 10.7507/1002-0179.202104046 Copy

1.	Wang X, Li J, Wang C, et al. The effects of mindfulness-based intervention on quality of life and poststroke depression in patients with spontaneous intracerebral hemorrhage in china. Int J Geriatr Psychiatry, 2020, 35(5): 572-580.
2.	Renoux C, Vahey S, Dell’Aniello S, et al. Association of selective serotonin reuptake inhibitors with the risk for spontaneous intracranial hemorrhage. JAMA Neurol, 2017, 74(2): 173-180.
3.	Scheitz JF, Turc G, Kujala L, et al. Intracerebral hemorrhage and outcome after thrombolysis in stroke patients using selective serotonin-reuptake inhibitors. Stroke, 2017, 48(12): 3239-3244.
4.	Liu L, Fuller M, Behymer TP, et al. Selective serotonin reuptake inhibitors and intracerebral hemorrhage risk and outcome. Stroke, 2020, 51(4): 1135-1141.
5.	Marquez-Romero JM, Reyes- Martínez M, Huerta-Franco MR, et al. Fluoxetine for motor recovery after acute intracerebral hemorrhage, the FMRICH trial. Clin Neurol Neurosurg, 2020, 190: 105656.
6.	Sanders J, Mayford M. Chronic fluoxetine dissociates contextual from auditory fear memory. Neurosci lett, 2016, 632: 152-156.
7.	Li Q, Lan X, Han X, et al. Expression of Tmem119/Sall1 and Ccr2/CD69 in facs-sorted microglia- and monocyte/macrophage-enriched cell populations after intracerebral hemorrhage. Front Cell Neurosci, 2018, 12: 520.
8.	Wu H, Wu T, Li M, et al. Efficacy of the lipid-soluble iron chelator 2, 2’-dipyridyl against hemorrhagic brain injury. Neurobiol Dis, 2012, 45(1): 388-394.
9.	Kubiszewski P, Sugita L, Kourkoulis C, et al. Association of selective serotonin reuptake inhibitor use after intracerebral hemorrhage with hemorrhage recurrence and depression severity. JAMA Neurol, 2020, 78(1): 1-8.
10.	Jensen MP, Ziff OJ, Banerjee G, et al. The impact of selective serotonin reuptake inhibitors on the risk of intracranial haemorrhage: a systematic review and meta-analysis. Eur Stroke J, 2019, 4(2): 144-152.
11.	Tang WK, Chen Y, Liang H, et al. Cerebral microbleeds as a predictor of 1-year outcome of poststroke depression. Stroke, 2014, 45(1): 77-81.
12.	Aarts N, Akoudad S, Noordam R, et al. Inhibition of serotonin reuptake by antidepressants and cerebral microbleeds in the general population. Stroke, 2014, 45(7): 1951-1957.
13.	de Abajo FJ. Effects of selective serotonin reuptake inhibitors on platelet function: mechanisms, clinical outcomes and implications for use in elderly patients. Drugs Aging, 2011, 28(5): 345-367.
14.	Carneiro AM, Cook EH, Murphy DL, et al. Interactions between integrin alphaiibbeta3 and the serotonin transporter regulate serotonin transport and platelet aggregation in mice and humans. J Clin Invest, 2008, 118(4): 1544-1552.
15.	Deyama S, Bang E, Wohleb ES, et al. Role of neuronal VEGF signaling in the prefrontal cortex in the rapid antidepressant effects of ketamine. Am J Psychiatry, 2019, 176(5): 388-400.
16.	Zhao C, Wang H, Xiong C, et al. Hypoxic glioblastoma release exosomal VEGF-A induce the permeability of blood-brain barrier. Biochem Biophys Res Commun, 2018, 502(3): 324-331.
17.	Greene TK, Schiviz A, Hoellriegl W, et al. Towards a standardization of the murine tail bleeding model. J Thromb Haemost, 2010, 8(12): 2820-2822.
18.	Medeiros GC, Roy D, Kontos N, et al. Post-stroke depression: a 2020 updated review. Gen Hosp Psychiatry, 2020, 66: 70-80.

1. Wang X, Li J, Wang C, et al. The effects of mindfulness-based intervention on quality of life and poststroke depression in patients with spontaneous intracerebral hemorrhage in china. Int J Geriatr Psychiatry, 2020, 35(5): 572-580.
2. Renoux C, Vahey S, Dell’Aniello S, et al. Association of selective serotonin reuptake inhibitors with the risk for spontaneous intracranial hemorrhage. JAMA Neurol, 2017, 74(2): 173-180.
3. Scheitz JF, Turc G, Kujala L, et al. Intracerebral hemorrhage and outcome after thrombolysis in stroke patients using selective serotonin-reuptake inhibitors. Stroke, 2017, 48(12): 3239-3244.
4. Liu L, Fuller M, Behymer TP, et al. Selective serotonin reuptake inhibitors and intracerebral hemorrhage risk and outcome. Stroke, 2020, 51(4): 1135-1141.
5. Marquez-Romero JM, Reyes- Martínez M, Huerta-Franco MR, et al. Fluoxetine for motor recovery after acute intracerebral hemorrhage, the FMRICH trial. Clin Neurol Neurosurg, 2020, 190: 105656.
6. Sanders J, Mayford M. Chronic fluoxetine dissociates contextual from auditory fear memory. Neurosci lett, 2016, 632: 152-156.
7. Li Q, Lan X, Han X, et al. Expression of Tmem119/Sall1 and Ccr2/CD69 in facs-sorted microglia- and monocyte/macrophage-enriched cell populations after intracerebral hemorrhage. Front Cell Neurosci, 2018, 12: 520.
8. Wu H, Wu T, Li M, et al. Efficacy of the lipid-soluble iron chelator 2, 2’-dipyridyl against hemorrhagic brain injury. Neurobiol Dis, 2012, 45(1): 388-394.
9. Kubiszewski P, Sugita L, Kourkoulis C, et al. Association of selective serotonin reuptake inhibitor use after intracerebral hemorrhage with hemorrhage recurrence and depression severity. JAMA Neurol, 2020, 78(1): 1-8.
10. Jensen MP, Ziff OJ, Banerjee G, et al. The impact of selective serotonin reuptake inhibitors on the risk of intracranial haemorrhage: a systematic review and meta-analysis. Eur Stroke J, 2019, 4(2): 144-152.
11. Tang WK, Chen Y, Liang H, et al. Cerebral microbleeds as a predictor of 1-year outcome of poststroke depression. Stroke, 2014, 45(1): 77-81.
12. Aarts N, Akoudad S, Noordam R, et al. Inhibition of serotonin reuptake by antidepressants and cerebral microbleeds in the general population. Stroke, 2014, 45(7): 1951-1957.
13. de Abajo FJ. Effects of selective serotonin reuptake inhibitors on platelet function: mechanisms, clinical outcomes and implications for use in elderly patients. Drugs Aging, 2011, 28(5): 345-367.
14. Carneiro AM, Cook EH, Murphy DL, et al. Interactions between integrin alphaiibbeta3 and the serotonin transporter regulate serotonin transport and platelet aggregation in mice and humans. J Clin Invest, 2008, 118(4): 1544-1552.
15. Deyama S, Bang E, Wohleb ES, et al. Role of neuronal VEGF signaling in the prefrontal cortex in the rapid antidepressant effects of ketamine. Am J Psychiatry, 2019, 176(5): 388-400.
16. Zhao C, Wang H, Xiong C, et al. Hypoxic glioblastoma release exosomal VEGF-A induce the permeability of blood-brain barrier. Biochem Biophys Res Commun, 2018, 502(3): 324-331.
17. Greene TK, Schiviz A, Hoellriegl W, et al. Towards a standardization of the murine tail bleeding model. J Thromb Haemost, 2010, 8(12): 2820-2822.
18. Medeiros GC, Roy D, Kontos N, et al. Post-stroke depression: a 2020 updated review. Gen Hosp Psychiatry, 2020, 66: 70-80.

West China Medical Journal

Fluoxetine pre-treatment exacerbates bleeding in a mouse model of intracerebral hemorrhage

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