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Recruitment of several neuroprotective pathways after permanent focal ischemia in mice
C Guégan1, I Ceballos-Picot, A Nicole
1Laboratoire de Neurosciences, Université de Caen, CNRS UMR 6551, Caen, 14074, France.
Abstract:
After an ischemic episode induced by the electrocoagulation of the left middle cerebral artery (MCA) in mouse, neurons within the damaged territory die either by an apoptotic or by a necrotic process. Most of the cortical neurons within the ischemic area display both morphological and biochemical signs of programmed cell death: nuclear condensation, DNA degradation, formation of apoptotic bodies, and glutathione depletion. In fact, apoptosis essentially contributes to the expansion of the ischemic lesion and the maximum of damaged territory is reached 24 h postocclusion. Several potentially neuroprotective pathways have been evidenced in different experimental models of ischemia including the activation of antioxidant enzyme activities and/or the recruitment of neurotrophic as well as antiapoptotic factors. In our model of permanent focal ischemia induced by MCA occlusion, we measured the temporal synthesis of nerve growth factor (NGF) and examined the status of antioxidant enzymes as well as Bcl-2 antiapoptotic product. We detected in both cortices a transient increase of NGF which peaks at 6 h. Moreover, we reported that glutathione peroxidase is recruited with a time course which parallels NGF synthesis. Finally, we observed the induction of Bcl-2 in safe neurons; this may represent a self-protective response against ischemia-induced apoptosis. We provide evidence that in a model of permanent focal ischemia, several neuroprotective pathways could be coactivated.
Insights
In mouse models of stroke, apoptosis contributes to brain damage expansion. Neuroprotective pathways, including nerve growth factor (NGF) and antioxidant enzymes, are coactivated to combat this cell death.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Ischemic stroke causes neuronal death via apoptosis and necrosis.
- Apoptosis significantly expands the ischemic lesion area within 24 hours post-occlusion.
- Potential neuroprotective strategies involve antioxidant enzymes, neurotrophic factors, and antiapoptotic factors.
Purpose of the Study:
- To investigate the temporal synthesis of nerve growth factor (NGF).
- To examine the status of antioxidant enzymes, specifically glutathione peroxidase.
- To assess the expression of the antiapoptotic protein Bcl-2 following focal ischemia.
Main Methods:
- Induction of permanent focal ischemia via electrocoagulation of the middle cerebral artery (MCA) in mice.
- Measurement of NGF synthesis over time post-ischemia.
- Analysis of glutathione peroxidase activity and Bcl-2 protein levels in cortical tissue.
Main Results:
- A transient increase in NGF synthesis was observed, peaking at 6 hours post-MCA occlusion.
- Glutathione peroxidase recruitment paralleled NGF synthesis, indicating coordinated antioxidant response.
- Bcl-2 was induced in neurons surrounding the ischemic core, suggesting a protective mechanism against apoptosis.
Conclusions:
- Coactivation of multiple neuroprotective pathways occurs in response to permanent focal ischemia.
- NGF synthesis, antioxidant enzyme activity, and Bcl-2 induction represent a coordinated endogenous defense against ischemic brain injury.
- These findings highlight potential therapeutic targets for mitigating stroke-induced neuronal death.