Anterograde delivery of brain-derived neurotrophic factor to striatum via nigral transduction of recombinant adeno-associated virus increases neuronal death but promotes neurogenic response following stroke

被引:52
作者
Gustafsson, E
Andsberg, G
Darsalia, V
Mohapel, P
Mandel, RJ
Kirik, D
Lindvall, O
Kokaia, Z
机构
[1] Lund Univ, Sect Restorat Neurol, Wallenberg Neurosci Ctr, SE-22184 Lund, Sweden
[2] Univ Florida, Coll Med, Dept Neurosci, Powell Gene Therapy Ctr,McKnight Brain Inst, Gainesville, FL 32610 USA
[3] Lund Univ, Neurobiol Sect, Wallenberg Neurosci Ctr, SE-22184 Lund, Sweden
关键词
anterograde transport; BDNF; BrdU; focal cerebral ischaemia; GFP; neurogenesis; neuroprotection; substantia nigra;
D O I
10.1046/j.1460-9568.2003.02713.x
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
To explore the role of brain-derived neurotrophic factor for survival and generation of striatal neurons after stroke, recombinant adeno-associated viral vectors carrying brain-derived neurotrophic factor or green fluorescent protein genes were injected into right rat substantia nigra 4-5 weeks prior to 30 min ipsilateral of middle cerebral artery occlusion. The brain-derived neurotrophic factor-recombinant adeno-associated viral transduction markedly increased the production of brain-derived neurotrophic factor protein by nigral cells. Brain-derived neurotrophic factor was transported anterogradely to the striatum and released in biologically active form, as revealed by the hypertrophic response of striatal neuropeptide Y-positive interneurons. Animals transduced with brain-derived neurotrophic factor-recombinant adeno-associated virus also exhibited abnormalities in body posture and movements, including tilted body to the right, choreiform movements of left forelimb and head, and spontaneous, so-called 'barrel' rotation along their long axis. The continuous delivery of brain-derived neurotrophic factor had no effect on the survival of striatal projection neurons after stroke, but exaggerated the loss of cholinergic, and parvalbumin- and neuropeptide Y-positive, gamma-aminobutyric acid-ergic interneurons. The high brain-derived neurotrophic factor levels in the animals subjected to stroke also gave rise to an increased number of striatal cells expressing doublecortin, a marker for migrating neuroblasts, and cells double-labelled with the mitotic marker, 5-bromo-2'-deoxyuridine-5'monophosphate, and early neuronal (Hu) or striatal neuronal (Meis2) markers. Our findings indicate that long-term anterograde delivery of high levels of brain-derived neurotrophic factor increases the vulnerability of striatal interneurons to stroke-induced damage. Concomitantly, brain-derived neurotrophic factor potentiates the stroke-induced neurogenic response, at least at early stages.
引用
收藏
页码:2667 / 2678
页数:12
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