Current status and prospects for development of therapy targeting post-ischemic inflammation in ischemic stroke

Abstract

Although post-ischemic stroke process is essential for the repair of the infarcted area, excessive inflammation during this process can induce tissue damage. Damage-associated molecular patterns (DAMPs) released from injured cells in the early phase of ischemic stroke induce cytokine and chemokine production by activating microglia, thereby facilitating neutrophil and lymphocyte infiltration. However, the inhibition of neutrophils, lymphocytes, and their associated proinflammatory molecules has shown no apparent improvement in the functional outcomes and prognosis of post-ischemic stroke. Therefore, the selection of molecules and cell types that regulate cytokine production is important. Considering that the increase and infiltration of activated microglia/macrophages (M/M) is the major pathological change in ischemic stroke in humans and that DAMP/toll-like receptor (TLR) signaling is the starting point for microglial activation, the regulation of TLR signaling in M/M may be an important therapeutic strategy in the management of ischemic stroke.We found that receptor activator of NF-κB ligand (RANKL)/receptor activator of NF-κB (RANK) signaling, expressed in activated M/Ms, inhibited DAMPs and TLR4 signaling. We also developed a partial peptide of RANKL, named microglial healing peptide 1 (MHP1), which regulates multiple TLR signaling pathways via RANK and CD14. This peptide was effective in mouse and monkey models and could be used in combination with tissue plasminogen activators in humans. Currently, we are attempting to improve the stability and efficacy of these peptides.Drug discovery in the field of acute ischemic stroke remains challenging. Continued research on the molecular mechanisms and development of novel drugs is important for the development of drugs intended for patients with ischemic stroke.