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Decreased calcineurin immunoreactivity in the postmortem brain of a patient with schizophrenia who had been prescribed the calcineurin inhibitor, tacrolimus, for leukemia.

Wada A, Kunii Y, Matsumoto J, Hino M, Nagaoka A, Niwa S, Yabe H - Neuropsychiatr Dis Treat (2016)

Bottom Line: Tacrolimus may decrease CaN immunoreactivity in some regions of the human brain.Thus, tacrolimus may introduce side effects such as cognitive dysfunction and extrapyramidal symptoms.In addition, we also found that the effect of tacrolimus on CaN immunore-activity in human brain was stronger than the effect of schizophrenia.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima City, Fukushima; Department of Neuropsychiatry, The University of Tokyo Hospital, Bunkyo-ku, Tokyo.

ABSTRACT

Background: The calcineurin (CaN) inhibitor, tacrolimus, is widely used in patients undergoing allogeneic organ transplantation and in those with certain allergic diseases. Recently, several reports have suggested that CaN is also associated with schizophrenia. However, little data are currently available on the direct effect of tacrolimus on the human brain.

Case: A 23-year-old Japanese female experienced severe delusion of persecution, delusional mood, suspiciousness, aggression, and excitement. She visited our hospital and was diagnosed with schizophrenia. When she was 27 years old, she had severe general fatigue, persistent fever, systemic joint pain, gingival bleeding, and breathlessness and was diagnosed with acute myelomonocytic leukemia. Later she underwent bone marrow transplantation (BMT), she was administered methotrexate and cyclosporin A to prevent graft versus host disease (GVHD). Three weeks after BMT, she showed initial symptoms of GVHD and was prescribed tacrolimus instead of cyclosporin A. Seven months after BMT at the age of 31 years, she died of progression of GVHD. Pathological anatomy was examined after her death, including immunohistochemical analysis of her brain using anti-CaN antibodies. For comparison, we used our previous data from both a schizophrenia group and a healthy control group. No significant differences were observed in the percentage of CaN-immunoreactive neurons among the schizophrenia group, healthy control group, and the tacrolimus case (all P>0.5, analysis of covariance). Compared with the healthy control group and schizophrenia group, the percentages of CaN-immunoreactive neurons in layers III-VI of the BA46 and the putamen tended to be lower in the tacrolimus case.

Conclusion: Tacrolimus may decrease CaN immunoreactivity in some regions of the human brain. Thus, tacrolimus may introduce side effects such as cognitive dysfunction and extrapyramidal symptoms. In addition, we also found that the effect of tacrolimus on CaN immunore-activity in human brain was stronger than the effect of schizophrenia.

No MeSH data available.


Related in: MedlinePlus

CaN-IR neurons in brain sections from controls, patients with schizophrenia, and a patient with both schizophrenia and acute myelomonocytic leukemia treated with tacrolimus.Notes: (A) Calcineurin-immunoreactive (CaN-IR) cells in the prefrontal cortex (BA46, layers V–VI) of a control brain (72-year-old male with a postmortem interval [PMI] of 12.5 hours). (B) CaN-IR cells in the prefrontal cortex (BA46, layers V–VI) of the brain of a patient with schizophrenia (48-year-old male with a PMI of 10 hours). (C) CaN-IR cells in prefrontal cortex (BA46, layers V–VI) in the brain of a patient with both schizophrenia and acute myelomonocytic leukemia treated with tacrolimus (31-year-old female with a PMI of 9.5 hours). Immunopositive neurons are indicated by arrows, and immunonegative neurons are indicated by arrowheads. Magnification ×200.
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f2-ndt-12-1645: CaN-IR neurons in brain sections from controls, patients with schizophrenia, and a patient with both schizophrenia and acute myelomonocytic leukemia treated with tacrolimus.Notes: (A) Calcineurin-immunoreactive (CaN-IR) cells in the prefrontal cortex (BA46, layers V–VI) of a control brain (72-year-old male with a postmortem interval [PMI] of 12.5 hours). (B) CaN-IR cells in the prefrontal cortex (BA46, layers V–VI) of the brain of a patient with schizophrenia (48-year-old male with a PMI of 10 hours). (C) CaN-IR cells in prefrontal cortex (BA46, layers V–VI) in the brain of a patient with both schizophrenia and acute myelomonocytic leukemia treated with tacrolimus (31-year-old female with a PMI of 9.5 hours). Immunopositive neurons are indicated by arrows, and immunonegative neurons are indicated by arrowheads. Magnification ×200.

Mentions: The percentages of CaN-IR neurons in the BA46, hippocampus, caudate nucleus, and putamen are shown in Figure 1A–C. To compare this patient with a schizophrenia group and healthy control group, we used previously reported data.9 No significant differences were observed in the percentage of CaN-IR neurons among the schizophrenia group, healthy control group, and the tacrolimus case (all P>0.5, analysis of covariance). Compared with the healthy control group and schizophrenia group, the percentages of CaN-IR neurons in layers III–VI of the BA46 and the putamen tended to be lower in the tacrolimus case (Figure 1A and C). Representative images of CaN-IR neurons in the prefrontal cortex (BA46, layers V–VI) are shown in Figure 2.


Decreased calcineurin immunoreactivity in the postmortem brain of a patient with schizophrenia who had been prescribed the calcineurin inhibitor, tacrolimus, for leukemia.

Wada A, Kunii Y, Matsumoto J, Hino M, Nagaoka A, Niwa S, Yabe H - Neuropsychiatr Dis Treat (2016)

CaN-IR neurons in brain sections from controls, patients with schizophrenia, and a patient with both schizophrenia and acute myelomonocytic leukemia treated with tacrolimus.Notes: (A) Calcineurin-immunoreactive (CaN-IR) cells in the prefrontal cortex (BA46, layers V–VI) of a control brain (72-year-old male with a postmortem interval [PMI] of 12.5 hours). (B) CaN-IR cells in the prefrontal cortex (BA46, layers V–VI) of the brain of a patient with schizophrenia (48-year-old male with a PMI of 10 hours). (C) CaN-IR cells in prefrontal cortex (BA46, layers V–VI) in the brain of a patient with both schizophrenia and acute myelomonocytic leukemia treated with tacrolimus (31-year-old female with a PMI of 9.5 hours). Immunopositive neurons are indicated by arrows, and immunonegative neurons are indicated by arrowheads. Magnification ×200.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC4940021&req=5

f2-ndt-12-1645: CaN-IR neurons in brain sections from controls, patients with schizophrenia, and a patient with both schizophrenia and acute myelomonocytic leukemia treated with tacrolimus.Notes: (A) Calcineurin-immunoreactive (CaN-IR) cells in the prefrontal cortex (BA46, layers V–VI) of a control brain (72-year-old male with a postmortem interval [PMI] of 12.5 hours). (B) CaN-IR cells in the prefrontal cortex (BA46, layers V–VI) of the brain of a patient with schizophrenia (48-year-old male with a PMI of 10 hours). (C) CaN-IR cells in prefrontal cortex (BA46, layers V–VI) in the brain of a patient with both schizophrenia and acute myelomonocytic leukemia treated with tacrolimus (31-year-old female with a PMI of 9.5 hours). Immunopositive neurons are indicated by arrows, and immunonegative neurons are indicated by arrowheads. Magnification ×200.
Mentions: The percentages of CaN-IR neurons in the BA46, hippocampus, caudate nucleus, and putamen are shown in Figure 1A–C. To compare this patient with a schizophrenia group and healthy control group, we used previously reported data.9 No significant differences were observed in the percentage of CaN-IR neurons among the schizophrenia group, healthy control group, and the tacrolimus case (all P>0.5, analysis of covariance). Compared with the healthy control group and schizophrenia group, the percentages of CaN-IR neurons in layers III–VI of the BA46 and the putamen tended to be lower in the tacrolimus case (Figure 1A and C). Representative images of CaN-IR neurons in the prefrontal cortex (BA46, layers V–VI) are shown in Figure 2.

Bottom Line: Tacrolimus may decrease CaN immunoreactivity in some regions of the human brain.Thus, tacrolimus may introduce side effects such as cognitive dysfunction and extrapyramidal symptoms.In addition, we also found that the effect of tacrolimus on CaN immunore-activity in human brain was stronger than the effect of schizophrenia.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima City, Fukushima; Department of Neuropsychiatry, The University of Tokyo Hospital, Bunkyo-ku, Tokyo.

ABSTRACT

Background: The calcineurin (CaN) inhibitor, tacrolimus, is widely used in patients undergoing allogeneic organ transplantation and in those with certain allergic diseases. Recently, several reports have suggested that CaN is also associated with schizophrenia. However, little data are currently available on the direct effect of tacrolimus on the human brain.

Case: A 23-year-old Japanese female experienced severe delusion of persecution, delusional mood, suspiciousness, aggression, and excitement. She visited our hospital and was diagnosed with schizophrenia. When she was 27 years old, she had severe general fatigue, persistent fever, systemic joint pain, gingival bleeding, and breathlessness and was diagnosed with acute myelomonocytic leukemia. Later she underwent bone marrow transplantation (BMT), she was administered methotrexate and cyclosporin A to prevent graft versus host disease (GVHD). Three weeks after BMT, she showed initial symptoms of GVHD and was prescribed tacrolimus instead of cyclosporin A. Seven months after BMT at the age of 31 years, she died of progression of GVHD. Pathological anatomy was examined after her death, including immunohistochemical analysis of her brain using anti-CaN antibodies. For comparison, we used our previous data from both a schizophrenia group and a healthy control group. No significant differences were observed in the percentage of CaN-immunoreactive neurons among the schizophrenia group, healthy control group, and the tacrolimus case (all P>0.5, analysis of covariance). Compared with the healthy control group and schizophrenia group, the percentages of CaN-immunoreactive neurons in layers III-VI of the BA46 and the putamen tended to be lower in the tacrolimus case.

Conclusion: Tacrolimus may decrease CaN immunoreactivity in some regions of the human brain. Thus, tacrolimus may introduce side effects such as cognitive dysfunction and extrapyramidal symptoms. In addition, we also found that the effect of tacrolimus on CaN immunore-activity in human brain was stronger than the effect of schizophrenia.

No MeSH data available.


Related in: MedlinePlus