Inhibition of p75 neurotrophin receptor does not rescue cognitive impairment in adulthood after isoflurane exposure in neonatal mice - PubMed (original) (raw)

Inhibition of p75 neurotrophin receptor does not rescue cognitive impairment in adulthood after isoflurane exposure in neonatal mice

J M Schilling et al. Br J Anaesth. 2017.

Abstract

Background: Isoflurane is widely used for anaesthesia in humans. Isoflurane exposure of rodents prior to post-natal day 7 (PND7) leads to widespread neurodegeneration in laboratory animals. Previous data from our laboratory suggest an attenuation of apoptosis with the p75 neurotrophin receptor (p75NTR) inhibitor TAT-Pep5. We hypothesized that isoflurane toxicity leads to behavioural and cognitive abnormalities and can be rescued with pre-anaesthesia administration of TAT-Pep5.

Methods: Neonatal mouse pups were pretreated with either TAT-Pep5 (25 μl, 10 μM i.p.) or a scrambled control peptide (TAT-ctrl; 25 μl, 10 μM i.p.) prior to isoflurane exposure (1.4%; 4 h) or control ( n = 15-26/group). Three to 5 months after exposure, behavioural testing and endpoint assays [brain volume (stereology) and immunoblotting] were performed.

Results: No significant difference was observed in open field, T-maze, balance beam or wire-hanging testing. The Barnes maze revealed a significant effect of isoflurane ( P = 0.019) in errors to find the escape tunnel during the day 5 probe trial, a finding indicative of impaired short-term spatial memory. No difference was found for brain volumes or protein expression. TAT-Pep5 treatment did not reverse the effects of isoflurane on neurocognitive behaviour.

Conclusion: A single isoflurane exposure to early post-natal mice caused a hippocampal-dependent memory deficit that was not prevented by pre-administration of TAT-Pep5, although TAT-Pep5, an inhibitor of p75NTR, has been shown to reduce isoflurane-induced apoptosis. These findings suggest that neuronal apoptosis is not requisite for the development of cognitive deficits in the adults attendant with neonatal anaesthetic exposure.

Keywords: behaviour; isoflurane; mouse; neurotoxicity; pharmacology.

Published by Oxford University Press on behalf of the British Journal of Anaesthesia 2017. This work is written by US Government employees and is in the public domain in the United States.

PubMed Disclaimer

Figures

Fig 1

No baseline motor deficit or potential lack of movement and spatial exploratory performance measured by the balance beam, wire-hanging test, open field, and continuous alternating T-maze paradigm were observed. (a) Timeline of experiments, (b–d) no difference between treatments was observed in the open field paradigm [(b) time (s) spent in the centre of the arena; (c) time (s) spent in the centre of the arena; (d) zone transitions between centre and periphery], (e) continuous alternating T-maze (T-CAT) (alternation:no alternation ratio; >0.6 is considered as no hippocampal deficit, <0.6 is considered as a chance level or hippocampal deficit), (f) balance beam (number of foot slips), and (g) wire-hanging test (s). Data presented as mean (

); n = 16–27 per group; *P < 0.05.

Fig 2

Decrement in contextual fear learning and spatial learning measured by the Barnes maze. This deficit could not be ameliorated with the administration of TAT-Pep5. Hippocampal-dependent memory was assessed by the Barnes maze. (a) Day 1–4, errors over time; (b) day 5, errors during the probe trial. Data are presented as mean (

); n = 15–25 per group; *P < 0.05.

Fig 3

No gross differences in brain region volumes and synaptic marker expression were found. No difference between treatments was observed in stereological assessment of the (a) prefrontal cortex and (b) hippocampus, and immunoblotting of the synaptic markers (c) PSD-95 and (d) syntaptobrevin. (e). Immunoblot image for PSD-95, Synbrev, and GAPDH. Data are presented as mean (

); n = 3–5 per group; *P < 0.05.

References

1. Honegger P, Matthieu JM. Selective toxicity of the general anesthetic propofol for GABAergic neurons in rat brain cell cultures. J Neurosci Res. 1996;45:631–636. -PubMed
1. Jevtovic-Todorovic V, Wozniak DF, Benshoff ND, Olney JW. A comparative evaluation of the neurotoxic properties of ketamine and nitrous oxide. Brain Res. 2001;895:264–267. -PubMed
1. Briner A, De Roo M, Dayer A, Muller D, Habre W, Vutskits L. Volatile anesthetics rapidly increase dendritic spine density in the rat medial prefrontal cortex during synaptogenesis. Anesthesiology. 2010;112:546–556. -PubMed
1. Head BP, Patel HH, Niesman IR, Drummond JC, Roth DM, Patel PM. Inhibition of p75 neurotrophin receptor attenuates isoflurane-mediated neuronal apoptosis in the neonatal central nervous system. Anesthesiology. 2009;110:813–825. -PMC -PubMed
1. Pearn ML, Hu Y, Niesman IR. Propofol neurotoxicity is mediated by p75 neurotrophin receptor activation. Anesthesiology. 2012;116:352–361. -PMC -PubMed

Inhibition of p75 neurotrophin receptor does not rescue cognitive impairment in adulthood after isoflurane exposure in neonatal mice - PubMed (original) (raw)