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Gemfibrozil Pretreatment Resulted in a Sexually Dimorphic Outcome in the Rat Models of Global Cerebral Ischemia–Reperfusion via Modulation of Mitochondrial Pro-survival and Apoptotic Cell Death Factors as well as MAPKs

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Abstract

Inducers of mitochondrial biogenesis are widely under investigation for use in a novel therapeutic approach in neurodegenerative disorders. The ability of Gemfibrozil, a fibrate, is investigated for the first time to modulate mitochondrial pro-survival factors involved in the mitochondrial biogenesis signaling pathway, including peroxisome proliferator-activated receptor coactivator-1α (PGC-1α), nuclear respiratory factor (NRF-1), and mitochondrial transcription factor A (TFAM) in the brain. Gemfibozil is clinically administered to control hyperlipidemia. It secondarily prevents cardiovascular events such as cardiac arrest in susceptible patients. In this study, pretreatment of animals with gemfibrozil prior to ischemia–reperfusion (I/R) resulted in a sexually dimorphic outcome. While the expression of NRF-1 and TFAM were induced in gemfibrozil-pretreated met-estrous females, they were suppressed in males. Gemfibrozil also proved to be neuroprotective in met-estrous females, as it inhibited caspase-dependent apoptosis while in males it led to hippocampal neurodegeneration via activation of both the caspase-dependent and caspase-independent apoptosis. In the mitogen-activated protein kinase (MAPKs) pathway, gemfibrozil pretreatment induced the expression of extracellular signal-regulated kinases (ERK1/2) in met-estrous females and reduced it in males. These findings correlatively point to the sexual-dimorphic effects of gemfibrozil in global cerebral I/R context by affecting important factors involved in the mitochondrial biogenesis, MAPKs, and apoptotic cell death pathways.

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Abbreviations

AIF:

Apoptosis-inducing factor

DAB:

Diaminobenzidine

ER-α:

Estrogen-related receptor-α

ERK1/2:

Extracellular signal-regulated kinases

I/R:

Ischemia–reperfusion

JNK:

C-Jun N-terminal kinases

MAPK:

Mitogen-activated protein kinase

MCAO:

Middle cerebral artery occlusion

mtDNA:

Mitochondrial DNA

NRF:

Nuclear respiratory factor

PARP:

Poly (ADP-ribose) polymerase

PBS:

Phosphate-buffered saline

PGC-1α:

Peroxisome proliferator-activated receptor coactivator-1α

TFAM:

Mitochondrial transcription factor A

TUNEL:

Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling

4VO:

Four-vessel occlusion model

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Acknowledgment

We thank the research council of Shahid Beheshti University of Medical Sciences for the funding of this project. The authors declare that there are no competing and conflicts of interest.

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Authors and Affiliations

  1. Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Fatemeh Mohagheghi, Abolhassan Ahmadiani, Behrouz Rahmani & Fatemeh Moradi

  2. Department of Pharmacology, Medical Faculty, University Malaya, Kuala Lumpur, Malaysia

    Abolhassan Ahmadiani

  3. Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane, Australia

    Nathalie Romond

  4. Medical School, Alborz University of Medical Sciences, Eshteraki Ave, P.O. Box: 3148/561, Baghestan Blvd, Karaj, Iran

    Leila Khalaj

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  1. Fatemeh Mohagheghi
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  2. Abolhassan Ahmadiani
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  3. Behrouz Rahmani
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  4. Fatemeh Moradi
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  5. Nathalie Romond
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Correspondence to Leila Khalaj.

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Mohagheghi, F., Ahmadiani, A., Rahmani, B. et al. Gemfibrozil Pretreatment Resulted in a Sexually Dimorphic Outcome in the Rat Models of Global Cerebral Ischemia–Reperfusion via Modulation of Mitochondrial Pro-survival and Apoptotic Cell Death Factors as well as MAPKs. J Mol Neurosci 50, 379–393 (2013). https://doi.org/10.1007/s12031-012-9932-0

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