Neonatal Propofol Anesthesia Changes Expression of Synaptic Plasticity Proteins and Increases Stereotypic and Anxyolitic Behavior in Adult Rats

Abstract

Propofol is a general anesthetic commonly used in pediatric clinical practices. Experimental findings demonstrate that anesthetics induce widespread apoptosis and cognitive decline in a developing brain. Although anesthesia-mediated neurotoxicity is the most prominent during intense period of synaptogenesis, the effects of an early anesthesia exposure on the synapses are not well understood. The aim of this study was to examine the effects of neonatal propofol anesthesia on the expression of key proteins that participate in synaptogenesis and synaptic plasticity and to evaluate long-term neurobehavioral abnormalities in the mature adult brain. Propofol-injected 7-day-old rats were maintained under 2-, 4-, and 6-h-long anesthesia and sacrificed 0, 4, 16, and 24 h after the termination of each exposure. We showed that propofol anesthesia strongly influenced spatiotemporal expression and/or proteolytic processing of crucial presynaptic (GAP-43, synaptophysin, α-synuclein), trans-synaptic (N-cadherin), and postsynaptic (drebrin, MAP-2) proteins in the cortex and thalamus. An overall decrease of synaptophysin, α-synuclein, N-cadherin, and drebrin indicated impaired function and structure of the synaptic contacts immediately after anesthesia cessation. GAP-43 and MAP-2 adult and juvenile isoforms are upregulated following anesthesia, suggesting compensatory mechanism in the maintaining of the structural integrity and stabilization of developing axons and dendritic arbors. Neonatal propofol exposure significantly altered spontaneous motor activity (increased stereotypic/repetitive movements) and changed emotional behavior (reduced anxiety-like response) in the adulthood, 6 months later. These findings suggest that propofol anesthesia is synaptotoxic in the developing brain, disturbing synaptic dynamics and producing neuroplastic changes permanently incorporated into existing networks with long-lasting functional consequences.

Dexmedetomidine attenuates the propofol-induced long-term neurotoxicity in the developing brain of rats by enhancing the PI3K/Akt signaling pathway

“…These, together with ultrastructural changes, including decreased levels of PSD 95 expression, widening synaptic cleft and hazing postsynaptic membrane as well as impaired spatial learning and memory, indicated that administration of high doses of propofol for a short time period induced long-term neurotoxicity, structural damages and functional impairments, similar to a previous observation with similar doses of propofol administered for a longer period 31. Indeed, injection with propofol affects the expression and proteolytic processing of crucial presynaptic and postsynaptic proteins, such as GAP-43 and MAP-2, in the cortex and thalamus of the developing brain in rats, which leads to permanent impairment of neuroplasticity and emotional behaviors 41. These also support the notion that healthy neurons and their intact synaptic structure are the basis of neurological function.…”

A synthetic peptide rescues rat cortical neurons from anesthetic-induced cell death and modulation of growth and synaptic assembly

“…This may be explained by the short timeline of the experiment, with neurite lengths being observed within hours of anesthetic exposure, and not days afterwards to quantify lasting effects. For the impact of propofol on synaptogenesis, divergent results have been reported with regards to cell type and the age of animals 27,28 . Similarly, ketamine has been previously shown to either downregulate synaptic proteins in the hippocampus of the developing brain 29 , or to upregulate them in the cortex 30 .…”

Methodologic recommendations and possible interpretations of video‐EEG recordings in immature rodents used as experimental controls: A TASK1‐WG2 report of the ILAE/AES Joint Translational Task Force

“…However, some of them (e.g., pentobarbital, ketamine, fentanyl/droperidol) have also been reported to lead to increased mortality or be less effective in inducing anesthesia in 1–3 day old pups and can be associated with longer recovery times . Propofol has been reported to induce seizures in P4–6 rats, impair dendritic spines when GABA A receptor inhibition is still inefficient in newborns, as well as cause apoptosis, neuroinflammation, learning and memory deficits, sex‐specific neurodevelopmental deficits, and altered endocrine responses to stress …”