Propofol Neurotoxicity Is Mediated by p75 Neurotrophin Receptor Activation

Abstract

Background Propofol exposure to neurons during synaptogenesis results in apoptosis leading to cognitive dysfunction in adulthood. Previous work from our laboratory showed that isoflurane neurotoxicity occurs through p75 neurotrophin receptor (p75NTR) and subsequent cytoskeleton depolymerization. Given that isoflurane and propofol both suppress neuronal activity, we hypothesized that propofol also induces apoptosis in developing neurons through p75NTR. Methods DIV5-7 neurons were exposed to propofol (3 µM) for 6 hr and apoptosis was assessed by cleaved caspase-3 (Cl-Csp3) immunoblot and immunofluorescence microscopy. Primary neurons from p75NTR−/− mice or wild-type neurons were treated with propofol, with or without pretreatment with TAT-Pep5 (10 µM, 15 min), a specific p75NTR inhibitor. P75NTR−/− neurons were transfected for 72 h with a lentiviral vector containing the synapsin driven p75NTR gene (Syn-p75NTR) or control vector (Syn-GFP) prior to propofol. To confirm our in vitro findings, wild type mice and p75NTR−/− mice (PND5) were pre-treated with either TAT-Pep5 or TAT-ctrl followed by propofol for 6 h. Results Neurons exposed to propofol showed a significant increase in Cl-Csp3, an effect attenuated by TAT-Pep5 and hydroxyfasudil. Apoptosis was significantly attenuated in p75NTR−/− neurons. In p75NTR−/− neurons transfected with Syn-p75NTR, propofol significantly increased Cl-Csp3 in comparison to Syn-GFP transfected p75NTR−/− neurons. Wild type mice exposed to propofol exhibited increased Cl-Csp3 in the hippocampus, an effect attenuated by TAT-Pep5. By contrast, propofol did not induce apoptosis in p75NTR−/− mice. Conclusion These results demonstrate that propofol induces apoptosis in developing neurons in vivo and in vitro and implicate a role for p75NTR and the downstream effector ROCK.

Sevoflurane exposure in postnatal rats induced long-term cognitive impairment through upregulating caspase-3/cleaved-poly (ADP-ribose) polymerase pathway

“…According to the study by Lemkuil et al (30), isoflurane induced neurotoxicity in rats by activating p75 NTR -RhoA, while inhibition of the activity of RhoA reversed the neurotoxicity of isoflurane. In addition, Pearn et al (31) reported that p75 NTR and RhoA kinase activation were involved in propofol-induced apoptosis in developing neurons in vitro and in vivo. The present study added novel results regarding the roles of caspase-3 and cleaved-PARP in sevoflurane exposure-induced cognitive impairment, and highlighted the importance of caspase-3 and cleaved PARP in the pathogenesis of nervous system dysfunction.…”

Inhibiting Rho kinase 2 reduces memory dysfunction in adult rats exposed to sevoflurane at postnatal days 7–9

“…In a previous study, Lemkuil et al (11) demonstrated that isoflurane induced neurotoxicity of mouse neurons by activating p75 NTR -RhoA, and inhibiting activation of RhoA attenuated isoflurane-induced impairment. Pearn et al (12) also reported that propofol-induced apoptosis is involved in p75 NTR and RhoA kinase activation in developing neurons in vivo and in vitro. These suggested that RhoA played important roles in the neurotoxicity of anesthetics.…”

General anesthetics in children: neurotoxic or neuroprotective?

“…[12,21,22] Almost all anesthetics were involved when administered to individuals in phases where there is neural development and synaptogenesis, except for some adjuvants such as α2-agonists. [13][14][15]21] Some studies suggest that dexmedetomidine administered as a preanesthetic medication possesses a neuroprotective effect, reducing the neurotoxicity induced by propofol and isoflurane. [16,21,25] The mechanism by which local anesthetics trigger its neurotoxic effects involves induction of apoptosis, which starts with the increased conductance of the calcium channels, with an increase of the intracellular concentration of this, production of reactive oxygen species and release of cytochrome c into the cytosol, culminating with the induction of caspases formation, decrease of the expression of anti-apoptotic proteins (Bcl-2) and increased expression of pro-apoptotic proteins (BAX), inducing acceleration of programmed cell death.…”