Cyclophilin D Contributes to Anesthesia Neurotoxicity in the Developing Brain

Area of Science:

• Neuroscience
• Anesthesiology
• Mitochondrial Biology

Background:

• Anesthetic sevoflurane is known to cause mitochondrial dysfunction, impaired neurogenesis, and cognitive deficits in young animals.
• The precise mechanisms underlying these sevoflurane-induced effects, particularly involving mitochondrial pathways, require further elucidation.
• Cyclophilin D (CypD) is a key regulator of the mitochondrial permeability transition pore (mPTP), suggesting a potential role in sevoflurane's actions.

Purpose of the Study:

• To investigate the role of Cyclophilin D (CypD) in sevoflurane-induced mitochondrial dysfunction, neurogenesis impairment, and cognitive deficits in young mice.
• To explore the interaction between sevoflurane, CypD, and the mitochondrial permeability transition pore (mPTP) in neural progenitor cells (NPCs) and in vivo.

Main Methods:

• Utilized wild-type (WT) and CypD knockout (KO) young mice and their corresponding neural progenitor cells (NPCs).
• Administered sevoflurane anesthesia to mice and NPCs, followed by assessments using immunohistochemistry, flow cytometry, Western blot, RT-PCR, co-immunoprecipitation, and the Morris Water Maze.
• Evaluated mitochondrial function, neurogenesis markers, cognitive performance, and the interaction of CypD with the mPTP components.

Main Results:

• Sevoflurane anesthesia induced CypD accumulation, mitochondrial dysfunction, impaired neurogenesis, and cognitive deficits in WT mice and NPCs.
• These adverse effects were significantly attenuated or absent in CypD KO mice and NPCs, indicating a CypD-dependent mechanism.
• Sevoflurane anesthesia reduced the binding between CypD and Adenine nucleotide translocator, a component of the mPTP, in WT models.

Conclusions:

• Sevoflurane anesthesia-induced mitochondrial dysfunction, neurogenesis impairment, and cognitive deficits in young mice are likely mediated by a CypD-dependent pathway.
• Targeting CypD or the mPTP may offer a strategy to mitigate the neurotoxic effects of sevoflurane anesthesia in the developing brain.
• The findings highlight the critical role of CypD in protecting against anesthetic-induced neurodevelopmental and cognitive impairments.