Beyond Anesthetic Properties: The Effects of Isoflurane on Brain Cell Death, Neurogenesis, and Long-Term Neurocognitive Function

Abstract

Anesthetic drugs cause brain cell death and long-term neurocognitive dysfunction in neonatal rats. Recently, human data also suggest that anesthesia early in life may cause cognitive impairment. The connection between cell death and neurocognitive decline is uncertain. It is conceivable that mechanisms other than brain cell death contribute to neurocognitive outcome of neonatal anesthesia. In a series of experiments, we demonstrate that isoflurane exposure causes significant hypercarbia in postnatal day 7 rats and that exposure to isoflurane or carbon dioxide for 4 h provoked brain cell death. However, 1 h of isoflurane exposure was not sufficient to cause brain cell death. Moreover, only 4 h of isoflurane exposure, but not 1 or 2 h of exposure or 4 h of carbon dioxide, led to impaired hippocampal function,questioning the association between anesthesia-induced brain cell death and neurocognitive dysfunction. Neurogenesis both in the developing and adult dentate gyrus is important for hippocampal function, specifically learning and memory. γ-Amino-butyric-acid regulates proliferation and neuronal differentiation both in the developing and the adult brain. Inhaled anesthetics are γ-amino-butyric-acid-ergic and may therefore affect neurogenesis, which could be an alternative mechanism mediating anesthesia-induced neurocognitive decline in immature rats. Understanding the mechanism will help guide clinical trials aiming to define the scope of the problem in humans and may lead to preventive and therapeutic strategies.

Effects of Long-Duration Administration of 1% Isoflurane on Resting Cerebral Blood Flow and Default Mode Network in Macaque Monkeys

“…Also, the MAP and heart rates of monkeys in the present study were maintained in the normal ranges during the entire study of each session (although a decreasing tendency in MAP or heart rate was seen after 2 h of isoflurane exposure) (Fig. 2), in agreement with those seen in a previous study in rats under 1 minimum alveolar concentration (MAC) isoflurane for 4 h (Stratmann et al, 2010) and dogs (1.4% isoflurane from 2 to 6 h) (Brian et al, 1990).…”

“…Meanwhile, it has been reported that an increased risk for neurobehavioral disturbances correlates positively with the duration of anesthesia exposure (Block et al, 2012;Wilder et al, 2009). Animal studies have further demonstrated that spatial memory was impaired for 2 weeks after long-duration administration of isoflurane in aged rats (Culley et al, 2004) and isoflurane might cause brain cell death, neurocognitive decline in immature rats (Stratmann et al, 2010).…”

The Fas Ligand/Fas Death Receptor Pathways Contribute to Propofol-Induced Apoptosis and Neuroinflammation in the Brain of Neonatal Rats

“…Stratmann et al (2010) showed that in P7 rat brain, cell loss likely reflects severity of the treatment and cannot be causally linked to subsequent cognitive dysfunctions. Also, it needs to be determined if the absence of neuronal cell death does mean that surviving neurons are not impacted by anesthesia and function properly.…”

Dementia With Lew Body

“…136 Anesthesia induced neurodegeneration have also been reported to cause persistent hippocampal dysfunction and cognitive dysfunction. 137 Volatile anesthetics mainly isoflurane, as researched on animal, was found to produce AD like pathology like Ab oligomerization and cytotoxicity and aberrant t phosphorylation and aggregation. IV propofol may also produce same AD like pathology.…”