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Minocycline suppresses oxidative stress and attenuates fetal cardiac myocyte apoptosis triggered by in utero cocaine exposure

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Abstract

This study investigates the molecular mechanisms by which minocycline, a second generation tetracycline, prevents cardiac myocyte death induced by in utero cocaine exposure. Timed mated pregnant Sprague-Dawley (SD) rats received one of the following treatments twice daily from embryonic (E) day 15–21 (E15–E21): (i) intraperitoneal (IP) injections of saline (control); (ii) IP injections of cocaine (15 mg/kg BW); and (iii) IP injections of cocaine + oral administration of 25 mg/kg BW of minocycline. Pups were killed on postnatal day 15 (P15). Additional pregnant dams received twice daily IP injections of cocaine (from E15–E21) + oral administration of a relatively higher (37.5 mg/kg BW) dose of minocycline. Minocycline treatment continued from E15 until the pups were sacrificed on P15. In utero cocaine exposure resulted in an increase in oxidative stress and fetal cardiac myocyte apoptosis through activation of c-Jun-NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK)-mediated mitochondria-dependent apoptotic pathway. Continued minocycline treatment from E15 through P15 significantly prevented oxidative stress, kinase activation, perturbation of BAX/BCL-2 ratio, cytochrome c release, caspase activation, and attenuated fetal cardiac myocyte apoptosis after prenatal cocaine exposure. These results demonstrate in vivo cardioprotective effects of minocycline in preventing fetal cardiac myocyte death after prenatal cocaine exposure. Given its proven clinical safety and ability to cross the placental barrier and enter into the fetal circulation, minocycline may be an effective therapy for preventing cardiac consequences of in utero cocaine exposure.

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Acknowledgments

This work was supported by MIDARP grant from NIH (to I.S-H and A.P.S-H). Additional support was provided by the NIH/NIGMS Program (S06 GM068510; A.P.S-H) and by the NIH-NCCR Accelerating Excellence in Translation Science Grant (U54 RR026138; Norris, KC). S.K.M. is supported by grants form the Department of Veteran Affairs and the National Institutes of Health (RO1 DA011311 and PO HL58120).

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Authors and Affiliations

  1. Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, 90059, CA, USA

    Indrani Sinha-Hikim, Ruoqing Shen, Ify Nzenwa, Robert Gelfand & Amiya P. Sinha-Hikim

  2. Department of Medicine, UCSD, San Diego, CA, USA

    Sushil K. Mahata

  3. VA San Diego Healthcare System, San Diego, CA, USA

    Sushil K. Mahata

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  1. Indrani Sinha-Hikim
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  6. Amiya P. Sinha-Hikim
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Correspondence to Amiya P. Sinha-Hikim.

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Sinha-Hikim, I., Shen, R., Nzenwa, I. et al. Minocycline suppresses oxidative stress and attenuates fetal cardiac myocyte apoptosis triggered by in utero cocaine exposure. Apoptosis 16, 563–573 (2011). https://doi.org/10.1007/s10495-011-0590-4

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