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Ischemic brain damage in mice after selectively modifying BDNF or NT4 gene expression
1Stroke and Neurovascular Regulation Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston 02129, USA.
Abstract:
The neurotrophins and the tyrosine kinase (Trk) B receptor may play a protective role in the pathophysiology of cerebral ischemia. In this study, the authors investigated whether reducing endogenous expression of TrkB-binding neurotrophins modifies the susceptibility to ischemic injury after 1-hour middle cerebral artery occlusion followed by 23 hours of reperfusion in a filament middle cerebral artery occlusion model. Mice lacking both alleles for neurotrophin-4 (nt4-/-) or deficient in a single allele for brain-derived neurotrophic factor (bdnf+/-) exhibited larger cerebral infarcts compared to wild-type inbred 129/SVjae mice (68% and 91%, respectively, compared to controls). Moreover, lesions were larger (21%) in nt4-/- mice after permanent middle cerebral artery occlusion. Hence, expression of both NT4 and BDNF, and by inference the TrkB receptor, confers resistance to ischemic injury.
Insights
Reduced levels of neurotrophin-4 (NT4) and brain-derived neurotrophic factor (BDNF) increase susceptibility to cerebral ischemia. This suggests that NT4 and BDNF, via the TrkB receptor, offer neuroprotection against ischemic injury.
Area of Science:
- Neuroscience
- Neurobiology
- Cerebrovascular Research
Background:
- Neurotrophins, including NT4 and BDNF, and their receptor TrkB are implicated in neuroprotection.
- Cerebral ischemia can lead to significant brain damage, and understanding protective mechanisms is crucial.
Purpose of the Study:
- To investigate if reduced endogenous expression of TrkB-binding neurotrophins affects susceptibility to ischemic brain injury.
- To determine the role of NT4 and BDNF in protecting against cerebral ischemia.
Main Methods:
- Utilized a filament middle cerebral artery occlusion (MCAO) model in mice.
- Compared cerebral infarct sizes in wild-type mice with those lacking NT4 (nt4-/-) or deficient in BDNF (bdnf+/-) after MCAO and reperfusion.
Main Results:
- Mice lacking NT4 (nt4-/-) or deficient in BDNF (bdnf+/-) exhibited significantly larger cerebral infarcts compared to wild-type controls.
- nt4-/- mice showed increased lesion size following permanent MCAO, indicating a protective role for NT4.
Conclusions:
- Endogenous expression of both NT4 and BDNF confers resistance to ischemic injury.
- The TrkB receptor pathway, influenced by NT4 and BDNF, plays a critical role in neuroprotection against cerebral ischemia.