Neuroprotection in experimental stroke with targeted neurotrophins

Abstract

Summary:More than 30 neurotrophins have been identified, and many of them have neuroprotective effects in brain ischemia or injury. However, all the clinical trials with several neurotrophins for the treatment of acute ischemic stroke or neurodegenerative diseases have failed so far, primarily because of their poor blood-brain barrier (BBB) permeability. This article is an overview of recent progress in the research focused on BBB targeted neurotrophins using a chimeric peptide approach, in which antitransferrin receptor antibody was used as a BBB delivery vector, and neurotrophin peptide was conjugated to the antibody via the avidin/biotin technology. Vasoactive intestinal peptide was the first model chimeric peptide to show an enhanced CNS effect after noninvasive peripheral administration. Brain-derived neurotrophic factor (BDNF) chimeric peptide was neuroprotective in rats subjected to transient forebrain ischemia, permanent focal ischemia, or transient focal ischemia. Delayed treatments with the BDNF chimeric peptide showed an effective time window of 1-2 h after ischemia. Basic FGF chimeric peptide was highly effective in the reduction of infarct volume in the rat model of permanent focal ischemia, with lowest effective dose of 1 g per rat. Future studies in this exciting area include genetically engineered fusion proteins or humanized antibodies for BBB drug targeting with less immunogenicity and reduced working burden in the chemical conjugation, the use of antihuman insulin receptor antibody for higher BBB delivery efficiency, and combination therapies using chimeric neurotrophins plus other neuroprotectants to achieve additive or synergistic effects.

Time-dependent contribution of non neuronal cells to BDNF production after ischemic stroke in rats

“…For instance, BDNF has been identified as a neuroprotective agent (Schabitz et al, 1997;Wu, 2005), a promoter of angiogenesis (Kermani and Hempstead, 2007), neurogenesis (Keiner et al, 2009;Schabitz et al, 2007), and synaptic plasticity (Waterhouse and Xu, 2009). The present study, demonstrating the implication of non neuronal cells in stroke-induced BDNF neosynthesis, identifies these cells as potential targets of strategies aimed at improving recovery after stroke.…”

Mechanisms and targets for angiogenic therapy after stroke

“…23,[64][65][66] However, many human clinical trials in the USA and Europe were aborted because of high dose toxicity and inconclusive results. 67 It is suggested that a combinational therapy of growth factors and/or their inhibitors may provide powerful therapeutic potential for enhancing stroke-induced neurogenesis and restoring the damaged tissue to function. 68 Yet the translation of in vitro findings to in vivo studies and then finally to clinical initiatives will have to overcome the typical challenges of toxicity, untoward side-effects and questions in timing, dosage and patient selection.…”

Beta-amyloid toxicity and reversal in embryonic rat septal neurons

“…IGF1 acts via several pathways in the processing of the AβPP [1], and in prevention of vascular dysfunction [23]. Protection against stroke is conferred by bFGF in rats [39] and FGF protects against Aβ toxicity in endothelial cells [7]. Rat temporal cortex is protected against Aβ by IGF1 [2].…”