Effects of astrocytic PKM2 gene deletion on neuronal death following traumatic brain injury

Traumatic brain injury (TBI) is a critical condition caused by physical trauma to the head, leading to primary brain edema, hemorrhage, and swelling, along with secondary injuries such as oxidative damage, neuroinflammation, and mitochondrial dysfunction. Astrocytes play a vital role in the astrocyte-neuron lactate shuttle (ANLS), which facilitates the transfer of lactate from astrocytes to neurons as an energy source. This study investigates the role of the pyruvate kinase M2 (PKM2) gene in astrocytes and its impact on neuronal survival following TBI. We hypothesized that deletion of the PKM2 gene in astrocytes would result in increased neuronal death due to impaired lactate supply via the ANLS. Additionally, we hypothesized that lactate administration post-TBI would mitigate neuronal death and alleviate cognitive impairment. To test these hypotheses, we utilized tamoxifen to specifically delete the PKM2 gene in astrocytes of Aldh1l1-Cre^ERT2; PKM2^f/f mice. Following TBI induction, sodium L-lactate was administered, and the mice were sacrificed 24 h later. Our analysis included assessments of neuronal death, microtubule disruption, oxidative damage, and the activity of enzymes associated with the ANLS. The findings confirmed that PKM2 gene deletion in astrocytes exacerbated neuronal death and worsened cognitive impairment. Conversely, lactate administration post-TBI reduced neuronal death and improved cognitive outcomes. These results suggest that lactate administration could serve as a potential therapeutic strategy for preventing and treating neurological damage following TBI.