부산대학교 도서관

Sickle cell disease (SCD) is characterized by chronic pain and bouts of extreme acute pain from vasoocclusive crises (VOC). Sickle pain has both neuropathic and inflammatory features (Tran et al., Blood 2017). Mechanisms underlying neural injury remain unknown in SCD. Neurite outgrowth inhibitor (NOGO-A/reticulon-4) and its receptor NGR1 contribute to pain, neuronal damage, and inhibition of neurite outgrowth (Hu et al., FASEB J 2019). We examined if NOGO-A pathway is activated in a sickle microenvironment and if its inhibition will ameliorate hyperalgesia in BERK sickle mice. We used Rho kinase activity (ROCK) downstream of NGR1 as a readout of activation of NOGO-A/NGR1 pathway. We observed increased expression of NOGO-A (~260%, p<0.05) and NGR1 (~180%, p<0.05) in the dorsal root ganglia, and increased NOGO-A and ROCK activity in spinal cords of sickle mice compared to control mice expressing normal human hemoglobin A. Earlier, we found that an endogenous cannabinoid, palmitoylethanolamide (PEA) inhibits spinal NOGO-A expression and ROCK activity in sickle mice (Argueta et al., ASH 2020 #225). We hypothesized that sickle microenvironment with cell-free heme and inflammation activates NOGO-A/NGR1-ROCK pathway leading to nerve injury and pain, and inhibition of this pathway will ameliorate hyperalgesia in sickle mice.