NeuProHRI project is the first study ever to address the novel application of eIF2α-mediated signaling as a neuroprotective pathway following ischemic stroke. Many compounds have been successfully developed as activators of UPR, such as PERK activators and inhibitors of eIF2α dephosphorylation. However, these approaches have caveats due to the irreversible inhibition of eIF2α dephosphorylation, and the multifactor and unspecific activation by PERK. NeuProHRI project proposes a new approach that would improve the previous ones, based on the facts that eIF2α is the sole substrate of HRI kinase, and BTdCPU is a specific and reversible activator of HRI kinase without causing toxicity in primary cultured neurons.
Overall, in vivo application of BTdCPU results in decreased lesion volumes in two different animal models of cerebral ischemia, targeting the HRI kinase as a promising target to promote neuroprotection following cerebral ischemia. Importantly, our experiments prove the necessity of the HRI kinase in the cellular response following cerebral ischemia, as inhibiting this kinase exacerbates the damage acutely. Of note, results from NeuProHRI can be also applied to other cellular stress-related diseases such as hemorrhagic stroke and Alzheimer´s disease (AD).
The results of the project were patented. Specifically, an EP24383003 patent application protecting BTdCPU, or pharmaceutical composition comprising thereof, for use in a method for the treatment of a neurological disorder or for use as a neuroprotective agent.
