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Recurrent Hypoglycemia Exacerbates Cerebral Ischemic Damage in Diabetic Rats via Enhanced Post-Ischemic Mitochondrial Dysfunction

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Abstract

Diabetes significantly increases the risk of stroke and post-stroke mortality. Recurrent hypoglycemia (RH) is common among diabetes patients owing to glucose-lowering therapies. Earlier, we showed that RH in a rat model of insulin-dependent diabetes exacerbates cerebral ischemic damage. Impaired mitochondrial function has been implicated as a central player in the development of cerebral ischemic damage. Hypoglycemia is also known to affect mitochondrial functioning. The present study tested the hypothesis that prior exposure of insulin-treated diabetic (ITD) rats to RH exacerbates brain damage via enhanced post-ischemic mitochondrial dysfunction. In a rat model of streptozotocin-induced diabetes, we evaluated post-ischemic mitochondrial function in RH-exposed ITD rats. Rats were exposed to five episodes of moderate hypoglycemia prior to the induction of cerebral ischemia. We also evaluated the impact of RH, both alone and in combination with cerebral ischemia, on cognitive function using the Barnes circular platform maze test. We observed that RH exposure to ITD rats leads to increased cerebral ischemic damage and decreased mitochondrial complex I activity. Exposure of ITD rats to RH impaired spatial learning and memory. Our results demonstrate that RH exposure to ITD rats potentially increases post-ischemic damage via enhanced post-ischemic mitochondrial dysfunction.

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Abbreviations

CA:

cornus ammonis

ETC:

electron transport chain

ITD:

insulin-treated diabetic

MMP:

mitochondrial membrane potential

MPTP:

mitochondrial permeability transition pores

RH:

recurrent hypoglycemia

ROS:

reactive oxygen species

STZ:

streptozotocin

s.c.:

subcutaneous

T1D:

type 1 diabetes

T2D:

type 2 diabetes

TNF-α:

tumor necrosis factor α

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Acknowledgements

We would like to thank Dr. Brant Watson for critical reading of this manuscript.

Funding

The present study is supported by NIH grant NS073779 and the Evelyn F. McKnight Brain Institute. The funding agency had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the manuscript; and in the decision to submit the article for publication.

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Authors and Affiliations

  1. Cerebral Vascular Disease Research Laboratories, University of Miami School of Medicine, 1420 NW 9th Ave, NRB/203E, Miami, FL, 33136, USA

    Vibha Shukla, Perry Fuchs, Allen Liu, Charles H. Cohan, Miguel A. Perez-Pinzon & Kunjan R. Dave

  2. Department of Neurology, University of Miami School of Medicine, Miami, FL, 33136, USA

    Vibha Shukla, Perry Fuchs, Allen Liu, Charles H. Cohan, Chuanhui Dong, Clinton B. Wright, Miguel A. Perez-Pinzon & Kunjan R. Dave

  3. Evelyn F. McKnight Brain Institute, University of Miami School of Medicine, Miami, FL, 33136, USA

    Charles H. Cohan, Chuanhui Dong, Clinton B. Wright, Miguel A. Perez-Pinzon & Kunjan R. Dave

  4. Neuroscience Program, University of Miami School of Medicine, Miami, FL, 33136, USA

    Clinton B. Wright, Miguel A. Perez-Pinzon & Kunjan R. Dave

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  1. Vibha Shukla
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  6. Clinton B. Wright
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  7. Miguel A. Perez-Pinzon
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  8. Kunjan R. Dave
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Correspondence to Kunjan R. Dave.

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The authors declare that they have no competing interests.

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All animal experiments were carried out in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals and were approved by an institutional animal care and use committee.

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Shukla, V., Fuchs, P., Liu, A. et al. Recurrent Hypoglycemia Exacerbates Cerebral Ischemic Damage in Diabetic Rats via Enhanced Post-Ischemic Mitochondrial Dysfunction. Transl. Stroke Res. 10, 78–90 (2019). https://doi.org/10.1007/s12975-018-0622-2

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  • DOI: https://doi.org/10.1007/s12975-018-0622-2

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