Infarct tolerance induced by intra-cerebral infusion of recombinant brain-derived neurotrophic factor

Neuronal expression of brain-derived neurotrophic factor (BDNF) has been im plicated in the mechanism of infarct tolerance (resistance to stroke) (H. Y anamoto et al., Infarct tolerance accompanied enhanced BDNF-like immunoreac tivity in neuronal nuclei, submitted to Brain Res.), a process that takes m ore than 7 days following a preconditioning of repetitive cortical spreadin g depression (CSD). To investigate whether an elevated level of BDNF protei n in the brain solely protects neurons against temporary focal ischemia, re combinant (r)BDNF was infused into the rat neocortex. Recombinant BDNF (or vehicle: saline) was administered into the left neocortex via an implanted osmotic minipump for 2.5, 7, 10 or 14 days pre-ischemia, during ischemia an d for 2 days post-ischemia (8 mu g in total) in male Sprague-Dawley rats (n = 6 each). Temporary focal ischemia was induced in the left middle cerebra l artery (MCA) territory by three-vessel occlusion of bilateral common caro tid arteries (CCAs) and MCA for 2 h, and the cerebral infarct volume was an alyzed 2 days after ischemia using TTC staining. Regional cerebral blood fl ow (rCBF) of the left neocortex was monitored after 14 days of intracerebra l administration of BDNF or vehicle (n = 10 each). The distribution of BDNF following different periods of rBDNF or vehicle-infusion was analyzed usin g immunohistochemical techniques (n = 5 each). In the groups treated with 8 mu g of rhBDNF for 7, 10, or 14 days pre-ischemia, there were significant reductions of neocortical infarct volume compared to in the control or vehi cle-treated groups (p < 0.05). In the rCBF study, there was no significant change after the infusion of 8 mu g rhBDNF for 14 days, hi the histological study, a wide distribution of BDNF-like immunoreactivity in the neuronal n uclei in the ipsilateral neocortex was demonstrated after the infusion of 8 mu g 8 rhBDNF for 14 days. The BDNF-like immunoreactivity in the neuronal nuclei was enhanced at the time that the resistance to stroke was achieved by direct intra-cerebral infusion of exogenous rBDNF. Elucidating the funct ion of the BDNF-like protein located in the neuronal nuclei should reveal a new strategy for neuroprotection against ischemic brain attack in humans. (C) 2000 Elsevier Science B.V. All rights reserved.