Traumatic brain injury (TBI) is a global public health concern, and few effective treatments for its delayed damages are available.
Oridonin (Ori) recently has been reported to show a promising neuroprotective efficacy, but its potential
therapeutic effect on TBI has not been thoroughly elucidated. The TBI mouse models were established and treated with Ori or vehicle 30 min post-operation and every 24 h since then. Impairments in cognitive and motor function and neuropathological changes were evaluated and compared. The therapeutic efficacy and mechanisms of action of Ori were further investigated using animal tissues and cell cultures. Ori restored motor function and cognition after TBI-induced impairment and exerted
neuroprotective effects by reducing
cerebral edema and cortical lesion volume. Ori increased neuronal survival, ameliorating
gliosis and the accumulation of macrophages after injury. It suppressed the increased production of
reactive oxygen species,
lipid peroxide, and
malondialdehyde and reversed the decrease of mitochondrial membrane potential and
adenosine triphosphate content, which was also identified in oxidatively stressed neuronal cultures. Further, Ori inhibited the expression of
nucleotide-binding domain
leucine-rich repeats family
protein 3 (NLRP3)
inflammasome proteins and NLRP3-dependent
cytokine interleukin-1β that can be induced by oxidative stress after TBI. Regarding underlying mechanisms, Ori significantly enhanced expression of key
proteins of the nuclear factor erythroid 2-related factor 2/
heme oxygenase-1 (Nrf2/HO-1) pathway. Our results demonstrated that Ori effectively improved functional impairments and neuropathological changes in animals with TBI. By activating the Nrf2 pathway, it improved mitochondrial function and
antioxidant capacity and suppressed the
neuroinflammation induced by oxidative stress. The results therefore suggest Ori as a potent candidate for managing neurological damage after TBI.