Modulation of Na+/K+- ATPase activityby triterpene 3β, 6β, 16β-trihidroxilup-20 (29)-ene (TTHL) limits the long-term secondary degeneration after traumatic brain injury in mice

Abstract Traumatic brain injury (TBI) is a public health problem characterized by a combination of immediate mechanical dysfunction of the brain tissue, and secondary damage. Based on the hypothesis that selected targets, such as Na + K + -ATPase are involved in the secondary damage after TBI and modulation of this enzyme activity by triterpene 3β, 6β, 16β-trihidroxilup-20 (29)-ene (TTHL) supports the ethnomedical applications of this plant, we decided to investigate whether previous TTHL treatment interrupts the progression of pathophysiology induced by TBI. Statistical analyses revealed that percussion fluid injury (FPI) increased Na + ,K + -ATPase activity in all isoform (α 1 and α 2/3 ) 15 min after neuronal injury. The FPI protocol inhibited Na + ,K + -ATPase activity total and α 1 isoform, increased [ 3 H]MK-801 binding but did not alter Dichloro-dihydro-fluorescein diacetate (DCFH-DA) oxidation, carbonylated proteins and free –SH groups 60 min after injury. The increase of immunoreactivity of protein PKC and state of phosphorylation of at Ser 16 of Na + ,K + -ATPase 60 min after FPI suggest the involvement of PKC on Na + ,K + -ATPase activity oscillations characterized by inhibition of total and α 1 isoform. Our experimental data also revealed that natural product rich in compounds such as triterpenes (TTHL; 30 mg/kg) attenuates [ 3 H]MK-801 binding increase, phosphorylation of the PKC and the Na + ,K + -ATPase alpha 1 subunit (Ser 16 ) induced by FPI. The previous TTHL treatment had not effect on motor disability but protected against spatial memory deficit, BDNF, TrKB expression decrease, protein carbonylation and hippocampal cell death 7 days after FPI. These data suggest that TTHL-induced reduction on initial damage limits the long-term secondary degeneration and supports neural repair or behavioral compensation after neuronal injury.