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

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

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.

Keywords

Ischemic damage Mitochondria Hippocampus Barnes maze test Open field Type 1 diabetes 

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

Notes

Acknowledgements

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

Funding Information

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.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

Ethical Approval

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.

Supplementary material

12975_2018_622_MOESM1_ESM.pdf (119 kb)
ESM 1 (PDF 119 kb)

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Copyright information

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Authors and Affiliations

  • Vibha Shukla
    • 1
    • 2
  • Perry Fuchs
    • 1
    • 2
  • Allen Liu
    • 1
    • 2
  • Charles H. Cohan
    • 1
    • 2
    • 3
  • Chuanhui Dong
    • 2
    • 3
  • Clinton B. Wright
    • 2
    • 3
    • 4
  • Miguel A. Perez-Pinzon
    • 1
    • 2
    • 3
    • 4
  • Kunjan R. Dave
    • 1
    • 2
    • 3
    • 4
  1. 1.Cerebral Vascular Disease Research LaboratoriesUniversity of Miami School of MedicineMiamiUSA
  2. 2.Department of NeurologyUniversity of Miami School of MedicineMiamiUSA
  3. 3.Evelyn F. McKnight Brain InstituteUniversity of Miami School of MedicineMiamiUSA
  4. 4.Neuroscience ProgramUniversity of Miami School of MedicineMiamiUSA

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