Low-molecular weight protamine enhances neuroprotection and remyelination by mitigating chondroitin sulfate proteoglycan inhibition in models of demyelination

Chondroitin sulfate proteoglycans (CSPGs) are inhibitory molecules deposited in the extracellular matrix of lesions in multiple sclerosis (MS). CSPGs maintain ongoing inflammatory processes and prevent oligodendrocyte progenitor cell (OPC) differentiation, resulting in impaired remyelination and chronic pathology in MS. Here, we profile low-molecular weight protamine (LMWP) as a small, positively charged peptide that binds to the negatively charged inhibitory sections of CSPGs. We show that LMWP overcomes CSPG inhibition of OPC differentiation and increases remyelination following toxin-based focal demyelination. Moreover, LMWP ameliorates disease progression in experimental autoimmune encephalomyelitis (EAE) model. LMWP is blood brain barrier-penetrant, and peripheral administration in EAE mice results in significantly lowered concentrations of serum neurofilament light-chain. Additionally, tissue analyses show increased myelin thickness and a reduction in axonal degeneration with LMWP treatment in EAE mice, supporting its role as a neuroprotective compound. Finally, LMWP reduces microgliosis and fibrosis in EAE, most likely, favoring tissue repair. Thus, LMWP supports remyelination as well as neuroprotection resulting in a promising strategy for the treatment of demyelinating disease, such as MS.