Background General anesthetics induce apoptotic neurodegeneration in the developing mammalian brain. General anesthesia (GA) also causes significant disturbances in mitochondrial morphogenesis during intense synaptogenesis. Mitochondria are dynamic organelles that undergo remodeling via fusion and fission. The fine balance between these two opposing processes determines mitochondrial morphometric properties, allowing for their regeneration and enabling normal functioning. As mitochondria are exquisitely sensitive to anesthesia-induced damage, we examined how GA affects mitochondrial fusion/fission. Methods Seven-day-old rat pups received anesthesia containing a sedative dose of midazolam followed by a combined nitrous oxide and isoflurane anesthesia for 6 h. Results GA causes 30% upregulation of reactive oxygen species (n = 3–5 pups/group), accompanied by a 2-fold downregulation of an important scavenging enzyme, superoxide dismutase (n = 6 pups/group). Reactive oxygen species upregulation is associated with impaired mitochondrial fission/fusion balance, leading to excessive mitochondrial fission. The imbalance between fission and fusion is due to acute sequestration of the main fission protein, dynamin-related protein 1, from the cytoplasm to mitochondria, and its oligomerization on the outer mitochondrial membrane. These are necessary steps in the formation of the ring-like structures that are required for mitochondrial fission. The fission is further promoted by GA-induced 40% downregulation of cytosolic mitofusin-2, a protein necessary for maintaining the opposing process, mitochondrial fusion (n = 6 pups/group). Conclusions Early exposure to GA causes acute reactive oxygen species upregulation and disturbs the fine balance between mitochondrial fission and fusion, leading to excessive fission and disturbed mitochondrial morphogenesis. These effects may play a causal role in GA-induced developmental neuroapoptosis.

Background: More than 4 million children are exposed annually to sedatives and general anaesthetics (GAs) in the USA alone. Recent data suggest that common GAs can be detrimental to brain development causing neurodegeneration and long-term cognitive impairments. Challenged by a recent US Food and Drug Administration (FDA) warning about potentially neurotoxic effects of GAs in children, there is an urgent need to develop safer GAs. Methods: Postnatal Day 7 (P7) rat pups of both sexes were exposed to six (repeated every 2 h) injections of equipotent hypnotic doses of ketamine or the neuroactive steroid (3b,5b,17b)-3-hydroxyandrostane-17-carbonitrile (3b-OH) for 12 h. Loss of righting reflex was used to assess hypnotic properties and therapeutic index; quantitative caspase-3 immunohistochemistry was used to assess developmental neuroapoptosis; patch-clamp recordings in acute brain slices were used to assess the effects of 3b-OH on neuronal excitability and synaptic transmission. Cognitive abilities of rats exposed to ketamine, 3b-OH, or vehicle at P7 were assessed in young adulthood using the radial arm maze. Results: The neuroactive steroid 3b-OH has a therapeutic index similar to ketamine, a commonly used clinical GA. We report that 3b-OH is safe and, unlike ketamine, does not cause neuroapoptosis or impair cognitive development when administered to P7 rat pups. Interestingly, 3b-OH blocks T-type calcium channels and presynaptically dampens synaptic transmission at hypnotically-relevant brain concentrations, but it lacks a direct effect on g-aminobutyric acid A or glutamate-gated ion channels.

Background Early postnatal exposure to general anesthesia (GA) may be detrimental to brain development, resulting in long-term cognitive impairments. Older literature suggests that in utero exposure of rodents to GA causes cognitive impairments in the first-generation as well as in the second-generation offspring never exposed to GA. Thus, the authors hypothesize that transient exposure to GA during critical stages of synaptogenesis causes epigenetic changes in chromatin with deleterious effects on transcription of target genes crucial for proper synapse formation and cognitive development. They focus on the effects of GA on histone acetyltransferase activity of cAMP-responsive element-binding protein and the histone-3 acetylation status in the promoters of the target genes brain-derived neurotrophic factor and cellular Finkel-Biskis-Jinkins murine sarcoma virus osteosarcoma oncogene (c-Fos) known to regulate the development of neuronal morphology and function. Methods Seven-day-old rat pups were exposed to a sedative dose of midazolam followed by combined nitrous oxide and isoflurane anesthesia for 6 h. Hippocampal neurons and organotypic hippocampal slices were cultured in vitro and exposed to GA for 24 h. Results GA caused epigenetic modulations manifested as histone-3 hypoacetylation (decrease of 25 to 30%, n = 7 to 9) and fragmentation of cAMP-responsive element-binding protein (two-fold increase, n = 6) with 25% decrease in its histone acetyltransferase activity, which resulted in down-regulated transcription of brain-derived neurotrophic factor (0.2- to 0.4-fold, n = 7 to 8) and cellular Finkel-Biskis-Jinkins murine sarcoma virus osteosarcoma oncogene (about 0.2-fold, n = 10 to 12). Reversal of histone hypoacetylation with sodium butyrate blocked GA-induced morphological and functional impairments of neuronal development and synaptic communication. Conclusion Long-term impairments of neuronal development and synaptic communication could be caused by GA-induced epigenetic phenomena.

The present study aimed to evaluate the analgesic effect of the antioxidant nanoparticle fullerol in a mouse radiculopathy and a dorsal root ganglion (DRG) culture models. Intervertebral disc degeneration causes significant hyperalgesia and nerve inflammation. Pain sensitization and inflammatory reaction were counteracted by fullerol when disc material was bathed in 10 or 100µM of fullerol prior to implantation. Immunohistochemistry showed similar massive IBA1 positive macrophage infiltration surrounding implanted disc material among groups, but IL-1β and IL-6 expression was decreased in fullerol treated group. In the DRG explant culture, after treatment with TNF-α, the expression of IL-1β, NLRP3, and caspase 1 was significantly increased but this was reversed by the addition of fullerol. In addition, fullerol also decreased the expression of substance P and CGRP in the cultured DRGs. Nanoparticle fullerol effectively counteracts pain sensitization and the inflammatory cascade caused by disc degeneration.

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