Prohibitin viral gene transfer protects hippocampal CA1 neurons from ischemia and ameliorates postischemic hippocampal dysfunction

Hitomi Kurinami, Munehisa Shimamura, Tao Ma, Liping Qian, Kenzo Koizumi, Laibaik Park, Eric Klann, Giovanni Manfredi, Costantino Iadecola, Ping Zhou

Research output: Contribution to journalArticle

Abstract

BACKGROUND AND PURPOSE - : Prohibitin is a multi-functional protein involved in numerous cellular activities. Prohibitin overexpression protects neurons from injury in vitro, but it is unclear whether prohibitin can protect selectively vulnerable hippocampal CA1 neurons in a clinically relevant injury model in vivo and, if so, whether the salvaged neurons remain functional. METHODS - : A mouse model of transient forebrain ischemia that mimics the brain damage produced by cardiac arrest in humans was used to test whether prohibitin expression protects CA1 neurons from injury. Prohibitin-expressing viral vector was microinjected in mouse hippocampus to upregulate prohibitin. RESULTS - : Prohibitin overexpression protected CA1 neurons from transient forebrain ischemia. The protection was associated with dampened postischemic reactive oxygen species generation, reduced mitochondrial cytochrome c release, and decreased caspase-3 activation. Importantly, the improvement in CA1 neuronal viability translated into an improvement in hippocampal function: prohibitin expression ameliorated the spatial memory deficit induced by ischemia, assessed by the Y-maze test, and restored postischemic synaptic plasticity assessed by long-term potentiation, indicating that the neurons spared form ischemic damage were functionally competent. CONCLUSIONS - : These data demonstrate that prohibitin overexpression protects highly vulnerable CA1 neurons from ischemic injury in vivo and suggest that the effect is mediated by reduction of postischemic reactive oxygen species generation and preservation of mitochondrial outer membrane integrity that prevents activation of apoptosis. Measures to enhance prohibitin expression could have translational value in ischemic brain injury and, possibly, other forms of brain injury associated with mitochondrial dysfunction.

Original languageEnglish (US)
Pages (from-to)1131-1138
Number of pages8
JournalStroke
Volume45
Issue number4
DOIs
StatePublished - 2014

Fingerprint

Viral Genes
Ischemia
Neurons
Wounds and Injuries
Prosencephalon
Brain Injuries
Reactive Oxygen Species
prohibitin
Transfer (Psychology)
Neuronal Plasticity
Long-Term Potentiation
Memory Disorders
Mitochondrial Membranes
Cytochromes c
Heart Arrest
Brain Ischemia
Caspase 3
Hippocampus
Up-Regulation
Apoptosis

ASJC Scopus subject areas

  • Clinical Neurology
  • Advanced and Specialized Nursing
  • Cardiology and Cardiovascular Medicine

Cite this

Prohibitin viral gene transfer protects hippocampal CA1 neurons from ischemia and ameliorates postischemic hippocampal dysfunction. / Kurinami, Hitomi; Shimamura, Munehisa; Ma, Tao; Qian, Liping; Koizumi, Kenzo; Park, Laibaik; Klann, Eric; Manfredi, Giovanni; Iadecola, Costantino; Zhou, Ping.

In: Stroke, Vol. 45, No. 4, 2014, p. 1131-1138.

Research output: Contribution to journalArticle

Kurinami, H, Shimamura, M, Ma, T, Qian, L, Koizumi, K, Park, L, Klann, E, Manfredi, G, Iadecola, C & Zhou, P 2014, 'Prohibitin viral gene transfer protects hippocampal CA1 neurons from ischemia and ameliorates postischemic hippocampal dysfunction', Stroke, vol. 45, no. 4, pp. 1131-1138. https://doi.org/10.1161/STROKEAHA.113.003577
Kurinami, Hitomi ; Shimamura, Munehisa ; Ma, Tao ; Qian, Liping ; Koizumi, Kenzo ; Park, Laibaik ; Klann, Eric ; Manfredi, Giovanni ; Iadecola, Costantino ; Zhou, Ping. / Prohibitin viral gene transfer protects hippocampal CA1 neurons from ischemia and ameliorates postischemic hippocampal dysfunction. In: Stroke. 2014 ; Vol. 45, No. 4. pp. 1131-1138.
@article{03c7d11052c84511985c9971affbaf49,
title = "Prohibitin viral gene transfer protects hippocampal CA1 neurons from ischemia and ameliorates postischemic hippocampal dysfunction",
abstract = "BACKGROUND AND PURPOSE - : Prohibitin is a multi-functional protein involved in numerous cellular activities. Prohibitin overexpression protects neurons from injury in vitro, but it is unclear whether prohibitin can protect selectively vulnerable hippocampal CA1 neurons in a clinically relevant injury model in vivo and, if so, whether the salvaged neurons remain functional. METHODS - : A mouse model of transient forebrain ischemia that mimics the brain damage produced by cardiac arrest in humans was used to test whether prohibitin expression protects CA1 neurons from injury. Prohibitin-expressing viral vector was microinjected in mouse hippocampus to upregulate prohibitin. RESULTS - : Prohibitin overexpression protected CA1 neurons from transient forebrain ischemia. The protection was associated with dampened postischemic reactive oxygen species generation, reduced mitochondrial cytochrome c release, and decreased caspase-3 activation. Importantly, the improvement in CA1 neuronal viability translated into an improvement in hippocampal function: prohibitin expression ameliorated the spatial memory deficit induced by ischemia, assessed by the Y-maze test, and restored postischemic synaptic plasticity assessed by long-term potentiation, indicating that the neurons spared form ischemic damage were functionally competent. CONCLUSIONS - : These data demonstrate that prohibitin overexpression protects highly vulnerable CA1 neurons from ischemic injury in vivo and suggest that the effect is mediated by reduction of postischemic reactive oxygen species generation and preservation of mitochondrial outer membrane integrity that prevents activation of apoptosis. Measures to enhance prohibitin expression could have translational value in ischemic brain injury and, possibly, other forms of brain injury associated with mitochondrial dysfunction.",
author = "Hitomi Kurinami and Munehisa Shimamura and Tao Ma and Liping Qian and Kenzo Koizumi and Laibaik Park and Eric Klann and Giovanni Manfredi and Costantino Iadecola and Ping Zhou",
year = "2014",
doi = "10.1161/STROKEAHA.113.003577",
language = "English (US)",
volume = "45",
pages = "1131--1138",
journal = "Stroke",
issn = "0039-2499",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

TY - JOUR

T1 - Prohibitin viral gene transfer protects hippocampal CA1 neurons from ischemia and ameliorates postischemic hippocampal dysfunction

AU - Kurinami, Hitomi

AU - Shimamura, Munehisa

AU - Ma, Tao

AU - Qian, Liping

AU - Koizumi, Kenzo

AU - Park, Laibaik

AU - Klann, Eric

AU - Manfredi, Giovanni

AU - Iadecola, Costantino

AU - Zhou, Ping

PY - 2014

Y1 - 2014

N2 - BACKGROUND AND PURPOSE - : Prohibitin is a multi-functional protein involved in numerous cellular activities. Prohibitin overexpression protects neurons from injury in vitro, but it is unclear whether prohibitin can protect selectively vulnerable hippocampal CA1 neurons in a clinically relevant injury model in vivo and, if so, whether the salvaged neurons remain functional. METHODS - : A mouse model of transient forebrain ischemia that mimics the brain damage produced by cardiac arrest in humans was used to test whether prohibitin expression protects CA1 neurons from injury. Prohibitin-expressing viral vector was microinjected in mouse hippocampus to upregulate prohibitin. RESULTS - : Prohibitin overexpression protected CA1 neurons from transient forebrain ischemia. The protection was associated with dampened postischemic reactive oxygen species generation, reduced mitochondrial cytochrome c release, and decreased caspase-3 activation. Importantly, the improvement in CA1 neuronal viability translated into an improvement in hippocampal function: prohibitin expression ameliorated the spatial memory deficit induced by ischemia, assessed by the Y-maze test, and restored postischemic synaptic plasticity assessed by long-term potentiation, indicating that the neurons spared form ischemic damage were functionally competent. CONCLUSIONS - : These data demonstrate that prohibitin overexpression protects highly vulnerable CA1 neurons from ischemic injury in vivo and suggest that the effect is mediated by reduction of postischemic reactive oxygen species generation and preservation of mitochondrial outer membrane integrity that prevents activation of apoptosis. Measures to enhance prohibitin expression could have translational value in ischemic brain injury and, possibly, other forms of brain injury associated with mitochondrial dysfunction.

AB - BACKGROUND AND PURPOSE - : Prohibitin is a multi-functional protein involved in numerous cellular activities. Prohibitin overexpression protects neurons from injury in vitro, but it is unclear whether prohibitin can protect selectively vulnerable hippocampal CA1 neurons in a clinically relevant injury model in vivo and, if so, whether the salvaged neurons remain functional. METHODS - : A mouse model of transient forebrain ischemia that mimics the brain damage produced by cardiac arrest in humans was used to test whether prohibitin expression protects CA1 neurons from injury. Prohibitin-expressing viral vector was microinjected in mouse hippocampus to upregulate prohibitin. RESULTS - : Prohibitin overexpression protected CA1 neurons from transient forebrain ischemia. The protection was associated with dampened postischemic reactive oxygen species generation, reduced mitochondrial cytochrome c release, and decreased caspase-3 activation. Importantly, the improvement in CA1 neuronal viability translated into an improvement in hippocampal function: prohibitin expression ameliorated the spatial memory deficit induced by ischemia, assessed by the Y-maze test, and restored postischemic synaptic plasticity assessed by long-term potentiation, indicating that the neurons spared form ischemic damage were functionally competent. CONCLUSIONS - : These data demonstrate that prohibitin overexpression protects highly vulnerable CA1 neurons from ischemic injury in vivo and suggest that the effect is mediated by reduction of postischemic reactive oxygen species generation and preservation of mitochondrial outer membrane integrity that prevents activation of apoptosis. Measures to enhance prohibitin expression could have translational value in ischemic brain injury and, possibly, other forms of brain injury associated with mitochondrial dysfunction.

UR - http://www.scopus.com/inward/record.url?scp=84897436282&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84897436282&partnerID=8YFLogxK

U2 - 10.1161/STROKEAHA.113.003577

DO - 10.1161/STROKEAHA.113.003577

M3 - Article

VL - 45

SP - 1131

EP - 1138

JO - Stroke

JF - Stroke

SN - 0039-2499

IS - 4

ER -