PEA reduces markers of spinal cord inflammation and neuronal degeneration. After 14-day PEA treatment (IP 20 mg/kg per day), spinal cords of female HbSS mice compared with vehicle (Veh) show a significant reduction in (A) MDA, a marker of lipid peroxidation and oxidative stress; (B) IL-1β, a marker of inflammation; and (C) Cas3, marker of apoptosis. (D) ROCK activity is significantly increased in HbSS spinal cords compared with HbAA mice, and this was abrogated with 14-day PEA (IP 20 mg/kg per day) treatment. (E) Incitement of a sickle microenvironment with TNF-α (1 ng/mL) and hemin (40 μM) significantly increases ROCK activity in differentiated PC12 cells, which was ameliorated with NEP1-40 (2 μM) or PEA (30 μM). Mean ± SD. In panels A-C, data were analyzed using 2-way ANOVA and the Tukey post hoc multiple comparisons test. In panels D-E, data were analyzed with unpaired Student 2-tailed t test. ∗Indicates a difference compared with Veh. ∗P < .05; ∗∗∗P < .001. Age: 3.5 to 5.0 months. For panels A-C, n = 6 per condition; and panels D-E, n = 3 per condition. Cas3, caspase-3.