Propofol induces short- and long-term neurotoxicity. Our previous study showed that dexmedetomidine (Dex) can attenuate the propofol-induced acute neurotoxicity in rodents by enhancing the PI3K/Akt signaling. However, whether treatment of young rats with Dex could protect them from long-term neurotoxicity induced by propofol is unclear.
MATERIALS AND METHODS:
Seven-day-old male Sprague Dawley rats were randomized and injected intraperitoneally with saline (100 μL, NS), propofol (100 mg/kg), Dex (75 μg/kg), propofol (100 mg/kg) plus Dex (25, 50 or 75 μg/kg), 10% dimethyl sulfoxide (DMSO, 100 μL) or TDZD-8 (a GSK3β inhibitor, 1 mg/kg), or intracerebroventricularly with DMSO (5 μL) or LY294002 (a PI3K inhibitor, 25 μg/5 μL DMSO). Other rats in the experimental group were injected with the same doses of propofol, Dex and LY294002 or TDZD-8. All the rats were monitored until they were 9 weeks old. Their spatial learning and memory were tested by Morris water maze. The neuronal apoptosis, expression of PSD95, expression and phosphorylation of Akt and GSK3β and synaptic ultrastructures were determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, immunohistochemistry, Western blot and transmission electron microscopy assays, respectively.
Compared with the NS control group, young rats injected with intralipid, Dex, TDZD-8, LY294002 or DMSO alone did not show any significant change as they aged. Propofol significantly increased the escape latency time, hippocampal neuroapoptosis and synaptic ultrastructural changes but decreased the relative levels of PSD95 expression, and Akt and GSK3β phosphorylation in the developing hippocampus of the rats. The neuronal toxic effects of propofol were significantly mitigated by the pretreatment with a higher dose of Dex. The neuroprotective effect of Dex was enhanced by the treatment with TDZD-8, but was completely abrogated by the treatment with LY294002.
Our results indicated that the pretreatment of young rats with Dex attenuated the propofol-induced long-term neurotoxicity in their developing hippocampus by enhancing the PI3K/Akt signaling.