Tweak Promotes Neovascularization And Brain Damage Reduction In A Rat Model Of Intracerebral Hemorrhage

Non-traumatic intracerebral hemorrhage (ICH) is one of the most devastating and disabling forms of stroke; however, there are no effective pharmacological therapies following the insult. Angiogenesis appears as a key step to overcome the damage and promote functional recovery. In this context, endothelial progenitor cells (EPCs) mobilization promotes neovascularization which has been linked to beneficial outcomes following both ischemic and hemorrhagic stroke. The TNF-like weak inducer of apoptosis (TWEAK), binding to its receptor Fn14, has been suggested as an inducer of EPCs differentiation, viability and migration to the injury site in a model of myocardial infarction. Here, we have performed a proof-of-concept preclinical study in a rat model of ICH where we report that a 50 µg/kg dose of rat recombinant TWEAK (rTWEAK) promotes EPCs mobilization, as soon as 72 h post-injury, brain neovascularization, and, importantly, long-term hematoma reduction and functional recovery. In contrast, a higher dose of 150 µg/kg blocked those beneficial outcomes. Therefore, a low-dose of rTWEAK treatment promotes neovascularization and reduces brain damage in a rat model of ICH. Further clinical studies will be needed to demonstrate if rTWEAK could represent a new strategy to promote recovery following ICH.