Title : Therapeutic inhibition of PI3K? attenuates neuronal endoplasmic reticulum stress improves functional recovery after traumatic brain injury in mice
Abstract:
Traumatic brain injury (TBI) is a major cause of death and disability, often leading to persistent motor and cognitive deficits. Phosphoinositide 3-kinase γ (PI3Kγ), primarily expressed in immune cells, has been implicated in neuroinflammation in various neuropathological conditions. Our previous study demonstrated that genetic deletion of PI3Kγ reduced secondary brain tissue loss and mitigated long-term white matter injury following TBI in mice, leading to significant functional improvements, including motor and cognitive functions. However, the therapeutic potential of targeting PI3Kγ for TBI treatment remains to be determined.
In this study, we utilized controlled cortical impact (CCI) to produce moderate to severe TBI in young mice. AS605240, a selective PI3Kγ inhibitor, was administered orally two hours after TBI. Functionally, AS605240 treatment dose & time dependently (1 to 50 mg/kg) improved motor functions (Day 3, 7, 14, 21, 28), as assessed by the beam-walking test, rotarod test, and grip test, as well as cognitive functions, as measured by the open field test (OFT) (Day 28), Barnes maze test (from day 29 to 34) and novel object recognition (NOR) test (day 35) at various time points post-TBI. We identified 30 mg/kg as an optimal dose for improving behavioral functions. Mechanistically, AS605240 treatment (30 mg/kg) attenuated TBI-induced microglia and astrocyte activation, decreased ER stress pathways (including p-eIF2α, ATF-4, CHOP, p-PERK), and reduced neuronal cell death three days post-TBI. Overall, our results suggest that therapeutic inhibition of PI3Kγ with its selective inhibitor represents a promising therapeutic intervention for the treatment of TBI.
Keyword: Traumatic Brain Injury TBI, ER Stress, Cognitive Function
