Exercise ameliorates microglial activation and cognitive impairment induced by GFAT1 knockdown after traumatic brain injury.

BACKGROUND

The potential of exercise to prevent traumatic brain injury (TBI) has been extensively studied. Microglia play a critical role in TBI pathogenesis. Glutamine-fructose-6-phosphate transaminase 1 (GFAT1), the key enzyme regulating the hexosamine biosynthetic pathway (HBP), not only controls glucose influx but also plays an important role in the neuroinflammatory process. However, the relationship between GFAT1 expression and microglial metabolic activity during treadmill exercise in TBI mice remains unclear.

METHODS

A mouse TBI model was established via needle puncture, with mice randomly divided into sedentary and 14-day voluntary treadmill-running exercise groups. GFAT1 knockdown was achieved using GFAT1 shRNA lentivirus. Behavioral tests, electrophysiological recordings, immunohistochemistry, immunofluorescence, and Western blotting evaluated microglial activation and neurological function. An in vitro cell model was constructed with irisin and LPS, using Western blotting and TUNEL staining to assess inflammatory proteins and neuronal apoptosis.

RESULTS

The TBI group showed higher GFAT1 expression than the sham group. Following TBI induction, GFAT1 knockdown increased Interleukin-6(IL-6) expression and aggravate cognitive impairment. While exercise training promoted cognitive function recovery, reduced IL-6 expression, and upregulated the expressions of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). In vitro LPS stimulation induced the expression of GFAT1, IL-6, and iNOS; however, GFAT1 knockdown further exacerbated the expression of IL-6 and iNOS. Furthermore, irisin pretreatment led to a reduction in neuronal apoptosis, an increase in Nrf2 and HO-1 expression, and a decrease in IL-6 and iNOS expression.

CONCLUSION

Exercise ameliorates microglial activation and cognitive impairment induced by GFAT1 knockdown after traumatic brain injury.