J M Schilling1,2, A Kassan1,2, C Mandyam1,3, M L Pearn1,2, A Voong1,2, G G Grogman1,2, V B Risbrough4, I R Niesman5, H H Patel1,2, P M Patel1,2, B P Head1,2. 1. Department of Anesthesiology, Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. 2. Department of Anesthesiology, School of Medicine, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA. 3. Skaggs School of Pharmacy and Pharmaceutical Sciences, School of Medicine, University of California, San Diego, La Jolla, CA, USA. 4. Departments of Psychiatry and Anesthesiology, University of California, San Diego, La Jolla, CA, USA. 5. Department of Cellular & Molecular Medicine-Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA.
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. 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.
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. 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.
Authors: Matthew L Pearn; Yue Hu; Ingrid R Niesman; Hemal H Patel; John C Drummond; David M Roth; Katerina Akassoglou; Piyush M Patel; Brian P Head Journal: Anesthesiology Date: 2012-02 Impact factor: 7.892
Authors: Brian P Lemkuil; Brian P Head; Matthew L Pearn; Hemal H Patel; John C Drummond; Piyush M Patel Journal: Anesthesiology Date: 2011-01 Impact factor: 7.892
Authors: Brian P Head; Jason N Peart; Mathivadhani Panneerselvam; Takaakira Yokoyama; Matthew L Pearn; Ingrid R Niesman; Jacqueline A Bonds; Jan M Schilling; Atsushi Miyanohara; John Headrick; Sameh S Ali; David M Roth; Piyush M Patel; Hemal H Patel Journal: PLoS One Date: 2010-12-23 Impact factor: 3.240
Authors: M L Pearn; J M Schilling; M Jian; J Egawa; C Wu; C D Mandyam; M J Fannon-Pavlich; U Nguyen; J Bertoglio; M Kodama; S K Mahata; C DerMardirossian; B P Lemkuil; R Han; W C Mobley; H H Patel; P M Patel; B P Head Journal: Br J Anaesth Date: 2018-02-15 Impact factor: 9.166
Authors: Gregory A Chinn; Jennifer M Sasaki Russell; Nicole A Yabut; Deenu Maharjan; Jeffrey W Sall Journal: Anesthesiology Date: 2020-10-01 Impact factor: 7.892