Inhibition of RIPK1 by ZJU-37 promotes oligodendrocyte progenitor proliferation and remyelination via NF-κB pathway

Abstract

Receptor interacting serine/threonine protein kinase 1 (RIPK1) activation and necroptosis have been genetically and mechanistically linked with human multiple sclerosis and neurodegenerative diseases for which demyelination is a common key pathology. Demyelination can be healed through remyelination which is mediated by new oligodendrocytes derived from the adult oligodendrocyte progenitor cells (OPCs). Unfortunately, the efficiency of remyelination declines with progressive aging partially due to the depletion of OPCs following chronic or repeated demyelination. However, to our knowledge, so far there is no drug which enhances proliferation of OPCs, and it is unknown whether inhibiting RIPK1 activity directly affect OPCs, the central player of remyelination. Using TNFα induced RIPK1-dependent necroptosis in Jurkat FADD−/− cells as a cell death assay, we screened from 2112 FDA-approved drugs and the drug candidates of new RIPK1 inhibitors selected by ourselves, and identified ZJU-37, a small molecule modified by introducing an amide bond to Nec-1s, is a new RIPK1 kinase inhibitor with higher potency than Nec-1s which has the best reported potency. We unveil in addition to protecting myelin from demyelination and axons from degeneration, ZJU-37 exhibits a new role on promoting proliferation of OPCs and enhancing remyelination by inhibiting RIPK1 kinase activity with higher potency than Nec-1s. Mechanistically, ZJU-37 promotes proliferation of OPCs by enhancing the transcription of platelet derived growth factor receptor alpha via NF-κB pathway. This work identifies ZJU-37 as a new drug candidate which enhances remyelination by promoting proliferation of OPCs, paving the way for a potential drug to enhance myelin repair.

Recognizing Alzheimer's disease from perspective of oligodendrocytes: Phenomena or pathogenesis?

“…Premature aging through transgenic methods can damage the myelin sheath, thereby promoting amyloid‐β deposition. In fact, the impact of aging on OLs has been widely recognized, 58,59 including inhibition of OLs proliferation and differentiation, cell death, etc (as reviewed in Ref. 60).…”

Inhibition of receptor interacting protein kinase-1 (RIPK1) in the treatment of murine lupus

“…14 In addition, dominant autoinflammatory diseases caused by RIPK1 kinase activation have been found in both humans and mice. 15 16 Furthermore, RIPK1 has emerged as a promising therapeutic target for the treatment of a wide range of human autoimmune and inflammatory diseases, 17 such as multiple sclerosis, [18][19][20][21] inflammatory bowel disease 22 23 and rheumatoid arthritis. 24 Although decreased expression of RIPK1 in neutrophils from patients with SLE, increasing evidence suggests RIPK1's relationship with autoimmunity, for example, mice with RIPK1 deficiency in dendritic cells develop systemic inflammation and autoimmunity.…”

Role of Necroptosis in Central Nervous System Diseases

“…The experimental autoimmune encephalomyelitis (EAE) model included RIPK3 –/– mice to block necroptosis, and RIPK1 inhibition exhibited significant protective effect against EAE-induced symptoms by maintaining BBB integrity and decreasing the number and infiltration of monocytes. Ma et al suggested that the novel RIPK1 inhibitor ZJU-37 provides protection against demyelination and axonal degeneration and promotes oligodendrocyte progenitor cell proliferation and remyelination via NF-κB …”