ArticleAnesthesiology2020
Androgenic Modulation of the Chloride Transporter NKCC1 Contributes to Age-dependent Isoflurane Neurotoxicity in Male Rats.
Article in Anesthesiology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 31 citations in OpenAlex.
- Bioengineered human brain organoids and organ-on-chip platforms for exposure-aware assessment of developmental neurotoxicity induced by general anesthetics and sedatives.Frontiers in bioengineering and biotechnology · 2026Review
- Neonatal sevoflurane exposure enhances stress-related neurological susceptibility via NKCC1 modulation.Scientific reports · 2025Article
- Neonatal Diazepam Exposure Decreases Dendritic Arborization and Spine Density of Cortical Pyramidal Neurons in Rats.Journal of neurosurgical anesthesiology · 2025Article
- Anesthetics in pathological cerebrovascular conditions.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2025Review
- Metabolic Dysfunction in Idiopathic Intracranial Hypertension: Current Theories and Updates.Aging and disease · 2024Review
- Article
- Isoflurane-induced neuroinflammation and NKCC1/KCC2 dysregulation result in long-term cognitive disorder in neonatal mice.BMC anesthesiology · 2024Article
- Modelling idiopathic intracranial hypertension in rats: contributions of high fat diet and testosterone to intracranial pressure and cerebrospinal fluid production.Fluids and barriers of the CNS · 2023Article
- Amide Proton Transfer-Weighted Magnetic Resonance Imaging for Detecting Severity and Predicting Outcome after Traumatic Brain Injury in Rats.Neurotrauma reports · 2022Article
- Testosterone attenuates sevoflurane-induced tau phosphorylation and cognitive impairment in neonatal male mice.British journal of anaesthesia · 2021Article
- The potential role of stress and sex steroids in heritable effects of sevoflurane†.Biology of reproduction · 2021Review
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Authors and funding
5 authors at 1 institution in 1 country.
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Abstract
backgroundCognitive deficits after perinatal anesthetic exposure are well established outcomes in animal models. This vulnerability is sex-dependent and associated with expression levels of the chloride transporters NKCC1 and KCC2. The hypothesis was that androgen signaling, NKCC1 function, and the age of isoflurane exposure are critical for the manifestation of anesthetic neurotoxicity in male rats.
methodsFlutamide, an androgen receptor antagonist, was administered to male rats on postnatal days 2, 4, and 6 before 6 h of isoflurane on postnatal day 7 (ntotal = 26). Spatial and recognition memory were subsequently tested in adulthood. NKCC1 and KCC2 protein levels were measured from cortical lysates by Western blot on postnatal day 7 (ntotal = 20). Bumetanide, an NKCC1 antagonist, was injected immediately before isoflurane exposure (postnatal day 7) to study the effect of NKCC1 inhibition (ntotal = 48). To determine whether male rats remain vulnerable to anesthetic neurotoxicity as juveniles, postnatal day 14 animals were exposed to isoflurane and assessed as adults (ntotal = 30).
resultsFlutamide-treated male rats exposed to isoflurane successfully navigated the spatial (Barnes maze probe trial F[1, 151] = 78; P < 0.001; mean goal exploration ± SD, 6.4 ± 3.9 s) and recognition memory tasks (mean discrimination index ± SD, 0.09 ± 0.14; P = 0.003), unlike isoflurane-exposed controls. Flutamide changed expression patterns of NKCC1 (mean density ± SD: control, 1.49 ± 0.69; flutamide, 0.47 ± 0.11; P < 0.001) and KCC2 (median density [25th percentile, 75th percentile]: control, 0.23 [0.13, 0.49]; flutamide, 1.47 [1.18,1.62]; P < 0.001). Inhibiting NKCC1 with bumetanide was protective for spatial memory (probe trial F[1, 162] = 6.6; P = 0.011; mean goal time, 4.6 [7.4] s). Delaying isoflurane exposure until postnatal day 14 in males preserved spatial memory (probe trial F[1, 140] = 28; P < 0.001; mean goal time, 6.1 [7.0] s).
conclusionsVulnerability to isoflurane neurotoxicity is abolished by blocking the androgen receptor, disrupting the function of NKCC1, or delaying the time of exposure to at least 2 weeks of age in male rats. These results support a dynamic role for androgens and chloride transporter proteins in perinatal anesthetic neurotoxicity. EDITOR’S PERSPECTIVE:
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