Pharmacological inhibition of PTEN attenuates cognitive deficits caused by neonatal repeated exposures to isoflurane via inhibition of NR2B-mediated tau phosphorylation in rats.
Evidence has shown that children exposed to repeated anesthesia in early childhood display long-term cognitive disabilities. However, the underlying mechanisms remain largely unclear. Our previous study has indicated the involvement of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in isoflurane-induced decrease of self-renewal capacity in hippocampal neural precursor cells. Additionally, it is demonstrated by others that PTEN inhibition could protect against cognitive impairment via reduction of tau phosphorylation in the alzheimer's disease model. Therefore, in the present in vivo study, we aimed to examine the effects of PTEN inhibition on the cognitive dysfunction and tau hyperphosphorylation caused by neonatal repeated exposures to isoflurane. Our results showed that the neonatal repeated exposures to isoflurane resulted in the activation of PTEN in the hippocampus. The treatment of PTEN inhibitor BPV (pic) restored PSD-95 synthesis, and attenuated tau phosphorylation as well as the cognitive dysfunction caused by the repeated isoflurane exposures. In addition, BPV (pic) treatment reversed the activation of NR2B-containing NMDARs induced by repeated isoflurane exposures, while in turn, the antagonism of NR2B subunit with ifenprodil alleviated tau phosphorylation, indicating a possible role of NR2B as the downstream of PTEN in mediating tau phosphorylation in the neonatal rats repeatedly exposed to isoflurane. In conclusion, our results reveal a novel role of PTEN in mediating tau phosphorylation and cognitive deficits caused by neonatal repeated exposures to isoflurane, implying that targeting on PTEN may be a potential therapeutic approach for the anesthetic-related cognitive decline in the developing brain.
Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Lei
L
Tan
Department of Anesthesiology, Shaanxi Provincial People's Hospital, Xi'an 710068, China.
Xin
X
Chen
Department of Anesthesiology, First Hospital of Xian Jiaotong University, Xi'an 710061, China.
Wei
W
Wang
Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Jianfang
J
Zhang
Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Shiyong
S
Li
Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Yilin
Y
Zhao
Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Jintao
J
Wang
Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: alluo@tjh.tjmu.edu.cn.
Ailin
A
Luo
D000818:Animals; D000831:Animals, Newborn; D060825:Cognitive Dysfunction / Q000139:chemically induced*; D000076122:Disks Large Homolog 4 Protein; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007530:Isoflurane / Q000633:toxicity*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D016704:Synapsins / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; C489131:Mapt protein, rat; D008565:Membrane Proteins; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; C494210:Snap25 protein, rat; D016704:Synapsins; D016708:Synaptophysin; D050825:Synaptosomal-Associated Protein 25; C569016:Syp protein, rat; D016875:tau Proteins; D007530:Isoflurane; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat
Developing brain; Isoflurane; NR2B-containing NMDAR; Phosphatase and tensin homolog deleted on chromosome 10; Tau phosphorylation