Persistent neuronal apoptosis and synaptic loss induced by multiple but not single exposure of propofol contribute to long-term cognitive dysfunction in neonatal rats

Abstract

-Propofol can induce acute neuronal apoptosis or long-term cognitive dysfunction when exposed at early age in rodents, but it is unclear how the neurotoxicity including neuronal apoptosis and synaptic loss will change in a dynamic manner with brain development after multiple or single exposure of propofol, and the role of neuronal apoptosis and synaptic loss in propofol-induced long-term cognitive impairment needs to be elucidated. In this study, we investigated dynamic changes of neuronal apoptosis, neuronal density, synaptic density in hippocampal CA1 region and the prelimbic cortex (PrL), and longterm cognitive function after multiple or single exposure of propofol in neonatal rats. Results showed that single exposure of propofol only induced great neuronal apoptosis and deficit at postnatal day 9(P9); while multiple exposures of propofol could induce significant neuronal apoptosis, neuronal deficit and synaptic loss at P9, P14, P21, or P35 compared with intact, and spatial learning and memory impairment from P36 to P41. Results suggest that single exposure of propofol only induces transient neuronal apoptosis and deficit, while multiple exposures of propofol induce persistent neuronal apoptosis, neuronal deficit, synaptic loss, and long-term cognitive impairment. Furthermore, persistent neuronal deficit and disturbances in synapse formation but not transient neuronal apoptosis may contribute to long-term cognitive impairment.

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

“…In our study, we observed that the number of TUNEL-positive neurons in the hippocampus increased in the adult rats that had been treated with propofol at young age. 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.…”

“…More recently, studies confirmed that repeated exposure to propofol induced long-term neurotoxicity in neonatal rats 9,31. In our previous study, Dex preconditioning attenuated the propofol-induced formation of acute lesions in hippocam-pal neurons in postnatal 7-day-old rats by upregulating the phosphorylation of Akt and GSK3β 28.…”

“…The decreased levels of PSD 95 and the structural damages may be associated with the impairment of spatial learning and memory functions. Although the mechanisms underlying the action of propofol in downregulating PSD 95 expression are unclear, they may be associated with that propofol induced neuronal apoptosis and inhibited the synapse formation 31. It is known that activation of NMDA receptor can promote calcium influx and activate the CaMK-II and F-actin to induce the phosphorylation and structural reorganization of PSD 45,48,49.…”

MicroRNA‑433 inhibits cell growth and induces apoptosis in human cervical cancer through PI3K/AKT signaling by targeting FAK

“…In addition, it invades the mesenchyme and transfers to other sites to develop invasive carcinoma. This process forms a continuous lesion, which frequently occurs over 10 years (14). Early identification and timely treatment can substantially improve the survival rate of patients with cervical squamous carcinoma (15).…”

KIF17 mediates the learning and memory impairment in offspring induced by maternal exposure to propofol during middle pregnancy

“…Propofol is able to induce neuronal apoptosis in young rats and cause brain dysfunction by activating the γ-aminobutyric acid receptor (27,28). Neonatal or juvenile exposure to propofol has been reported to cause learning and memory impairments in adult rats by inducing neurodegeneration and a reduction in the expression of neurotransmitters and brain-derived neurotrophic factor (BDNF) (29)(30)(31)(32)(33). In addition, prolonged exposure to propofol in aged rats also causes long-term learning and memory impairment (34,35).…”