Ferrer I, Ballabriga J, Martí E, Pérez E, Alberch J, Arenas E
Unitat de Neuropatologia, Servei d'Anatomia Patolïgica, Hospital Princeps d'Espanya, Spain.
Brain Pathol. 1998 Apr;8(2):253-61. doi: 10.1111/j.1750-3639.1998.tb00151.x.
The neurotrophin family of growth factors, which includes Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT3) and Neurotrophin-4/5 (NT4/5) bind and activate specific tyrosine kinase (Trk) receptors to promote cell survival and growth of different cell populations. For these reasons, growing attention has been paid to the use of neurotrophins as therapeutic agents in neurodegeneration, and to the regulation of the expression of their specific receptors by the ligands. BDNF expression, as revealed by immunohistochemistry, is found in the pre-subiculum, CA1, CA3, and dentate gyrus of the hippocampus. Strong TrkB immunoreactivity is present in most CA3 neurons but only in scattered neurons of the CA1 area. Weak TrkB immunoreactivity is found in the granule cell layer of the dentate gyrus. Unilateral grafting of BDNF-transfected fibroblasts into the hippocampus resulted in a marked increase in the intensity of the immunoreaction and in the number of TrkB-immunoreactive neurons in the granule cell layer of the dentate gyrus, pre-subiculum and CA1 area in the vicinity of the graft. No similar effects were produced after the injection of control mock-transfected fibroblasts. Delayed cell death in the CA1 area was produced following 5 min of forebrain ischemia in the gerbil. The majority of living cells in the CA1 area at the fourth day were BDNF/TrkB immunoreactive. Unilateral grafting of control mock-transfected or BDNF fibroblasts two days before ischemia resulted in a moderate non-specific protection of TrkB-negative, but not TrkB-positive cells, in the CA1 area of the grafted side. This finding is in line with a vascular and glial reaction, as revealed, by immunohistochemistry using astroglial and microglial cell markers. This astroglial response was higher in the grafted side than in the contralateral side in ischemic gerbils, but no differences were seen between BDNF-producing and non-BDNF-producing grafts. However, grafting of BDNF-producing fibroblasts two days before ischemia significantly and specifically prevented nerve cells from dying in the CA1 area of the ipsilateral hippocampus. Cell survival was associated with increased TrkB immunoreactivity as the majority of living cells were TrkB immunoreactive. Thus, our results show that BDNF is able to up-regulate the expression of TrkB in control and pathological states, and that BDNF prevention of neuronal death following transient forebrain ischemia is associated with increased expression of its specific receptor.
神经营养因子家族的生长因子，包括神经生长因子（NGF）、脑源性神经营养因子（BDNF）、神经营养因子-3（NT3）和神经营养因子-4/5（NT4/5），它们结合并激活特定的酪氨酸激酶（Trk）受体，以促进不同细胞群体的存活和生长。基于这些原因，人们越来越关注将神经营养因子用作神经退行性疾病的治疗药物，以及配体对其特定受体表达的调节。免疫组织化学显示，BDNF表达见于海马的前下托、CA1、CA3和齿状回。大多数CA3神经元存在强烈的TrkB免疫反应性，但仅在CA1区的散在神经元中存在。在齿状回的颗粒细胞层中发现弱的TrkB免疫反应性。将BDNF转染的成纤维细胞单侧移植到海马中，导致齿状回颗粒细胞层、前下托和移植附近CA1区的免疫反应强度和TrkB免疫反应性神经元数量显著增加。注射对照mock转染的成纤维细胞后未产生类似效果。沙鼠前脑缺血5分钟后，CA1区出现延迟性细胞死亡。第4天时，CA1区的大多数存活细胞为BDNF/TrkB免疫反应性。缺血前两天单侧移植对照mock转染的或BDNF成纤维细胞，对移植侧CA1区的TrkB阴性细胞有中度非特异性保护作用，但对TrkB阳性细胞无保护作用。这一发现与使用星形胶质细胞和小胶质细胞标记物的免疫组织化学所显示的血管和胶质反应一致。在缺血沙鼠中，移植侧的这种星形胶质细胞反应高于对侧，但产生BDNF的移植和不产生BDNF的移植之间未见差异。然而，缺血前两天移植产生BDNF的成纤维细胞可显著且特异性地防止同侧海马CA1区的神经细胞死亡。细胞存活与TrkB免疫反应性增加相关，因为大多数存活细胞为TrkB免疫反应性。因此，我们的结果表明，BDNF能够在对照和病理状态下上调TrkB的表达，并且BDNF预防短暂性前脑缺血后神经元死亡与其特异性受体表达增加有关。
