Prohibitin viral gene transfer protects hippocampal CA1 neurons from ischemia and ameliorates postischemic
Hitomi Kurinami1, Munehisa Shimamura, Tao Ma
1From the Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY (H.K., M.S., L.Q., K.K., L.P., G.M., C.I., P.Z.); and Center for Neural Science, New York University, New York, NY (T.M., E.K.).
Insights
Prohibitin overexpression protects vulnerable hippocampal CA1 neurons from ischemic injury in vivo. This neuroprotection preserves spatial memory and synaptic function, suggesting therapeutic potential for brain injury.
Area of Science:
- Neuroscience
- Cellular Biology
- Mitochondrial Function
Background:
- Prohibitin is a key protein regulating cellular processes.
- While prohibitin shows neuroprotective effects in vitro, its role in vivo against ischemic injury in vulnerable neurons remains unclear.
- The functional recovery of neurons protected by prohibitin is also not well understood.
Purpose of the Study:
- To investigate the in vivo neuroprotective effects of prohibitin in a clinically relevant model of transient forebrain ischemia.
- To determine if prohibitin overexpression can protect selectively vulnerable hippocampal CA1 neurons.
- To assess the functional competence of prohibitin-protected neurons post-ischemia.
Main Methods:
- A mouse model of transient forebrain ischemia was employed.
- Prohibitin expression was upregulated in the mouse hippocampus using a prohibitin-expressing viral vector.
- Neuronal injury, reactive oxygen species generation, mitochondrial integrity, apoptosis, spatial memory, and synaptic plasticity were assessed.
Main Results:
- Prohibitin overexpression significantly protected hippocampal CA1 neurons from ischemic injury.
- This protection was linked to reduced reactive oxygen species, decreased mitochondrial cytochrome c release, and inhibited caspase-3 activation.
- Prohibitin expression improved spatial memory deficits and restored long-term potentiation, confirming functional recovery of salvaged neurons.
Conclusions:
- Prohibitin overexpression provides robust neuroprotection to vulnerable CA1 neurons in vivo following ischemic injury.
- The protective mechanism involves mitigating oxidative stress and preserving mitochondrial integrity, thereby preventing apoptosis.
- Enhancing prohibitin levels represents a potential therapeutic strategy for ischemic brain injury and other conditions involving mitochondrial dysfunction.
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.
