Sevoflurane - Fluoride Levels - ASD - Valproic Acid | Thyroid - Gq/11
Posted: Wed May 11, 2022 6:40 pm
Sevoflurane
Sevoflurane → 七氟烷 (“seven-fluorine ether”) → C₄H₃F₇O.
Behne M, Wilke HJ, Harder S - "Clinical pharmacokinetics of sevoflurane" Clin Pharmacokinet 36(1):13-26 (1999) doi: 10.2165/00003088-199936010-00002 PFPC Library
"Serum inorganic fluoride concentrations after sevoflurane anaesthesia have been reported to be dose dependent and reach about 10 to 20 μmol/L (after 1 to 2 MAC hours), 20 to 40 μmol/L (after 2 to 7 MAC hours) and may be as high as 20 to 90 μmol/L with prolonged exposure."
Holaday DA, Smith FR - "Clinical characteristics and biotransformation of sevoflurane in healthy human volunteers" Anesthesiology 54(2):100-6 (1981)
https://pubs.asahq.org/anesthesiology/a ... rmation-of
"After an hour of exposure arterial blood scrum inorganic fluoride concentrations averaged 22 μM and plasma nonvolatile organic fluorine concentrations averaged 9.1 mg/I, or 61.3 μM. Uptakes of sevoflurane averaged 94 (±63 SD) mmol. Following exposure 37 (±12) mmol of unaltered sevoflurane were estimated to be excreted in exhaled air and 0.90 mmol of inorganic fluoride and 163 mg, or 1.43 (±0.26) mmol of organic fluorine were excreted in the urine."
Kharasch ED - "Metabolism and toxicity of the new anesthetic agents" Acta Anaesthesiol Belg 47(1):7-14 (1996)
"Peak serum fluoride concentrations occur within one hour after sevoflurane anesthesia, are usually in the range of 20-40 microM, and decline rapidly. Fluoride concentrations have exceeded 50 microM in approximately 7% of sevoflurane patients."
https://academic.oup.com/jpp/article-ab ... 67/6163385
"The cumulative organic and inorganic fluoride excretion in the 3 days after sevoflurane anaesthesia was 1588 and 856 mumol, respectively (ratio = 1.85). The excreted half-lives for organic and inorganic fluoride were calculated to be 4028 and 2069 min, respectively. Our study showed that a hexafluoroisopropanol glucuronide is excreted in the urine, and the major part of urinary metabolites of sevoflurane, organic and inorganic fluoride, are excreted within 2 days of sevoflurane inhalation in man."
Sarner JB, Levine M, Davis PJ, Lerman J, Cook DR, Motoyama EK - "Clinical characteristics of sevoflurane in children. A comparison with halothane" Anesthesiology 82(1):38-46 (1995) doi: 10.1097/00000542-199501000-00006
https://pubmed.ncbi.nlm.nih.gov/7832332/
"The maximum serum fluoride concentration among all patients was 28 microM." = 0.53 Mg/L of fluoride.⁻ Normal serum levels are 0.02–0.1 mg/L.
Taylor B, Scott TE, Shaw J, Chockalingam N - "Renal safety of critical care sedation with sevoflurane: a systematic review and meta-analysis" J Anesth 37(5):794-805 (2023) doi: 10.1007/s00540-023-03227-y.
https://link.springer.com/article/10.10 ... 23-03227-y
"Levels of serum inorganic fluoride were significantly elevated in patients where sevoflurane was used."
Sevoflurane & Autism
Chung W, Park S, Hong J, Park S, Lee S, Heo J, Kim D, Ko Y - "Sevoflurane exposure during the neonatal period induces long-term memory impairment but not autism-like behaviors" Paediatr Anaesth 25(10):1033-45 (2015)
https://pubmed.ncbi.nlm.nih.gov/26095314/
Ju L-S, Morey TE, Gravenstein N, Setlow B, Seubert CN, Martynyuk AE - "Effects of cohabitation on neurodevelopmental outcomes in rats discordant for neonatal exposure to sevoflurane" Biol Psychiatry Glob Open Sci 4(2):100359 (2024)
doi:10.1016/j.bpsgos.2024.100359
Sun M, Fu N, Li T, Miao M, Chen WM, Wu SY, Zhang J - "Childhood anaesthesia and autism risk: population and murine study" Brain Commun 6(5):fcae325 (2024) doi: 10.1093/braincomms/fcae325
https://pmc.ncbi.nlm.nih.gov/articles/PMC11450270/
Wang HV, Forestier S, Corces VG - "Exposure to sevoflurane results in changes of transcription factor occupancy in sperm and inheritance of autism" Biol Reprod 105(3):705-719 (2021)
https://pubmed.ncbi.nlm.nih.gov/33982067/
NOTE: When Wang was informed about the fluoride/thyroid/sevoflurane aspects, she claimed "that the exposure time during pregnancy takes place several days before the thyroid is formed." She appeared entirely ignorant of the fact that the fetus is entirely dependent on the mother's thyroid hormone for the first trimester - the crucial time of thyroid hormone effects on neurodevelopment, including neural tube closure.
Zhang L, Xu L - "Fgf2 and Ptpn11 play a role in cerebral injury caused by sevoflurane anesthesia" Medicine (Baltimore) 102(45):e36108 (2023). doi: 10.1097/MD.0000000000036108
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10637467/
"Gene Expression Heatmap showed that the core genes (Fgf2, Pdgfra, Ptpn11, Slc2a1) were highly expressed in sevoflurane anesthesia brain tissue samples. CTD Analysis showed that the 4 core genes (Fgf2, Pdgfra, Ptpn11, Slc2a1) were associated with neurodegenerative diseases, brain injuries, memory disorders, cognitive disorders, neurotoxicity, drug-induced abnormalities, neurological disorders, developmental disorders, and intellectual disabilities."
Zhang W, Chen Y, Qin J, Lu J, Fan Y, Shi Z, Song X, Li C, Zhao T – "Prolonged sevoflurane exposure causes abnormal synapse development and dysregulates beta-neurexin and neuroligins in the hippocampus in neonatal rats" J Affect Disord 312:22-29 (2022). doi: 10.1016/j.jad.2022.05.115
https://www.sciencedirect.com/science/a ... 2722006358
Both β-neurexins and neuroligins, as well as the broader process of synaptogenesis in the hippocampus, are under thyroid hormone control.
Zhang L, Xu L - "Fgf2 and Ptpn11 play a role in cerebral injury caused by sevoflurane anesthesia" Medicine (Baltimore) 102(45):e36108 (2023) doi: 10.1097/MD.0000000000036108
https://journals.lww.com/md-journal/ful ... ry.65.aspx
More On Sevoflurane Effects on TH
Boztuğ N, Aydoğdu T - "Impact of Sevoflurane on Thyroid Hormone Levels" European Journal of Anaesthesiology 17:12 (2000)
Conference: European Society of Anaesthesiologists; 8th Annual Meeting with the Austrian International Congress, Vienna, Austria April 1-4, 2000
"In the recent study, while it is noticed that inhalation anaesthetics can cause 'Low T 3 Syndrome', throughout the intra- and postoperative period with sevoflurane we found an increase in the level of T3, which make us believe that it can decrease the possibility of occurrence of 'Low T3 Syndrome'..."
Huang H, Liu P, Ma D, Zhang H, Xu H, Zhou J, Zhao H, Zhao T, Li C - "Triiodothyronine attenuates neurocognitive dysfunction induced by sevoflurane in the developing brain of neonatal rats" J Affect Disord 297:455-462 (2022) doi: 10.1016/j.jad.2021.10.086
https://www.sciencedirect.com/science/a ... 272101154X
"Furthermore, sevoflurane decreased the expression of NMDA receptor subunits NR2A and NR2B, as well as PSD-95 in the hippocampus at P15 and those effects of sevoflurane were abolished by T3 administration."
Marana E, Colicci S, Meo F, Marana R, Proietti R - "Neuroendocrine stress response in gynecological laparoscopy: TIVA with propofol versus sevoflurane anesthesia" J Clin Anesth 22(4):250-5 (2010) doi: 10.1016/j.jclinane.2009.07.011
https://www.sciencedirect.com/science/a ... 8010000929
RCT; TSH levels increased while FT3 levels decreased significantly relative to basal values. In both groups, perioperative FT4 levels significantly increased compared with preoperative values.
Sevoflurane & Gq/11
Minami K, Sudo Y, Yokoyama T, Ogata J, Takeuchi M, Uezono Y - "Sevoflurane inhibits the µ-opioid receptor function expressed in Xenopus oocytes" Pharmacology 88(3-4):127-32 (2011) doi: 10.1159/000330096
https://pubmed.ncbi.nlm.nih.gov/21912198/
"Further, the mechanism of inhibition by sevoflurane would be mediated by PKC."
Nakayama T, Hayashi M, Warner DO, Jones KA - "Anesthetics inhibit membrane receptor coupling to the Gq/11 heterotrimeric G protein in airway smooth muscle" Anesthesiology 103(2):296-305 (2005). doi: 10.1097/00000542-200508000-00013. PMID: 16052112.
https://pubmed.ncbi.nlm.nih.gov/16052112/
Nakayama T, Penheiter AR, Penheiter SG, Chini EN, Thompson M, Warner DO, Jones KA - "Differential effects of volatile anesthetics on M3 muscarinic receptor coupling to the Galphaq heterotrimeric G protein" Anesthesiology 105(2):313-24 (2006). doi: 10.1097/00000542-200608000-00014
https://pubs.asahq.org/anesthesiology/a ... thetics-on
"Halothane and sevoflurane but not isoflurane inhibit acetylcholine-promoted Galphaq guanosine nucleotide exchange."
Li Z, Zhu YX, Gu LJ, Cheng Y - "Understanding autism spectrum disorders with animal models: applications, insights, and perspectives" Zool Res 42(6):800-824 (2021)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8645879/
Sadamatsu M, Kanai H, Xu X, Liu Y, Kato N - "Review of animal models for autism: implication of thyroid hormone" Congenit Anom (Kyoto) 46(1):1-9 (2006) doi: 10.1111/j.1741-4520.2006.00094.x.
https://pubmed.ncbi.nlm.nih.gov/16643592/
Proposal to use the rat with mild and transient neonatal hypothyroidism as a novel model for autism.
Wei W, Liu A, Liu M, Li M, Wu X, Qin C, Shan Z, Zhang L - "Development of an animal model of hypothyroxinemia during pregnancy in Wistar rats" Animal Model Exp Med 7(6):926-935 (2024) doi: 10.1002/ame2.12459
https://onlinelibrary.wiley.com/doi/10.1002/ame2.12459
NOTE: PTU
"The animal model of IMH [Isolated maternal hypothyroxinemia] was developed by the administration of 1 ppm of PTU for 9 weeks, and there were autistic-like behavior changes such as anxiety, weakened social ability, and repeated stereotyping in the IMH offspring by 40 days."
Tanaka T, Masubuchi Y, Okada R, Nakajima K, Nakamura K, Masuda S, Nakahara J, Maronpot RR, Yoshida T, Koyanagi M, Hayashi SM, Shibutani M - "Ameliorating effect of postweaning exposure to antioxidant on disruption of hippocampal neurogenesis induced by developmental hypothyroidism in rats" J Toxicol Sci 44(5):357-372 (2019) doi: 10.2131/jts.44.357
NOTE: PTU
Developmental hypothyroidism as a model of autism spectrum disorders
Valproic Acid
Choi CS, Gonzales EL, Kim KC, Yang SM, Kim JW, Mabunga DF, Cheong JH, Han SH, Bahn GH, Shin CY - "The transgenerational inheritance of autism-like phenotypes in mice exposed to valproic acid during pregnancy" Sci Rep 6:36250 (2016)
https://pubmed.ncbi.nlm.nih.gov/27819277/
Nicolini C, Fahnestock M - "The valproic acid-induced rodent model of autism" Exp Neurol 299(Pt A):217-227 (2018)
https://pubmed.ncbi.nlm.nih.gov/28472621/
Valproic Acid & Gq/11
Hoshi N - "M-Current Suppression, Seizures and Lipid Metabolism: A Potential Link Between Neuronal Kv7 Channel Regulation and Dietary Therapies for Epilepsy" Front Physiol 11:513 (2020)
https://pubmed.ncbi.nlm.nih.gov/32523549/
Tokuoka SM, Saiardi A, Nurrish SJ - "The mood stabilizer valproate inhibits both inositol- and diacylglycerol-signaling pathways in Caenorhabditis elegans" Mol Biol Cell 19(5):2241-50 (2008)
https://pubmed.ncbi.nlm.nih.gov/18287529/
"VPA reduces levels of DAG and inositol-1-phosphate, but phosphatidylinositol-4,5-bisphosphate (PIP(2)) is slightly increased, suggesting that phospholipase C-mediated hydrolysis of PIP(2) to form DAG and IP(3) is defective in the presence of VPA."
Kelly E, Sharma D, Wilkinson CJ, Williams RSB - "Diacylglycerol kinase (DGKA) regulates the effect of the epilepsy and bipolar disorder treatment valproic acid in Dictyostelium discoideum" Dis Model Mech 11(9):dmm035600 (2018)
https://pubmed.ncbi.nlm.nih.gov/30135067/
"Finally, we show that VPA, lithium and novel epilepsy treatments function through DAG regulation, and the presence of DGKA is necessary for compound-specific increases in DAG levels following treatment."
Chen G, Manji HK, Wright CB, Hawver DB, Potter WZ - "Effects of valproic acid on beta-adrenergic receptors, G-proteins, and adenylyl cyclase in rat C6 glioma cells" Neuropsychopharmacology 15(3):271-80 (1996)
https://www.nature.com/articles/1380468.pdf
"..As can be seen in Figures 3 and 4, chronic incubation of C6 cells with VPA (0.5 mM) resulted in a significant decrease in the cholera toxin-catalyzed [12P]ADP-ribosylation of Gs 45, which was also apparent after 3 days of VPA incubation. Chronic incubation of C6 cells with YPA (0.5 m1v1) for 3 or more days also resulted in a significant reduction in the cholera toxin catalyzed [12P]ADP-ribosylation of Gs 52 (Figures 3 and 4). The pertussis toxin-catalyzed ['2P]ADP-ribosvlations of G(Xi/o were not altered at any time point studied."
Valproic Acid & Thyroid
Alhyan P, Aggarwal A, Chhillar N, Sharma S, Narang M, Malhotra RK - "Effect of Valproate Monotherapy on Thyroid Function Tests and Magnesium Levels in Children With Epilepsy. Cureus" 15(5):e39712 (2023) doi: 10.7759/cureus.39712
https://assets.cureus.com/uploads/origi ... y6p9m8.pdf
"Thyroid stimulating hormone (TSH) increased significantly from 2.14±1.64 µIU/ml at enrollment to 3.64±2.15 µIU/ml at six months (p<0.001), free thyroxine (FT4) decreased significantly (p<0.001)."
Attilakos A, Katsarou E, Prassouli A, Mastroyianni S, Voudris K, Fotinou A, Garoufi A - "Thyroid function in children with epilepsy treated with sodium valproate monotherapy: a prospective study" Clin Neuropharmacol 32(1):32-4 (2009)
https://pubmed.ncbi.nlm.nih.gov/18978499/
"Thyroxine and free thyroxine levels were significantly decreased, whereas TSH levels were significantly increased at 6, 12, and 24 months of VPA therapy. Triiodothyronine levels were significantly decreased only at 24 months of therapy. Thirteen children (43.3%) at 6 months, 14 children (46.6%) at 12 months, and 15 children (50%) at 24 months of treatment had TSH values greater than 5 mIU/mL. Normal serum TSH levels were restored in all 8 children examined at 3 months after withdrawal of medication."
Bentsen KD, Gram L, Veje A - "Serum thyroid hormones and blood folic acid during monotherapy with carbamazepine or valproate. A controlled study" Acta Neurol Scand 67(4):235-41 (1983)
https://pubmed.ncbi.nlm.nih.gov/6407268/
"Valproate caused a decrease in T4, FT4 and T3." [rT3 first increased (one month treatment), then decreased (3 month treatment)] -> Dose- and time-dependent Gq/11 activation
Cansu A, Serdaroğlu A, Camurdan O, Hirfanoğlu T, Bideci A, Gücüyener K - "The evaluation of thyroid functions, thyroid antibodies, and thyroid volumes in children with epilepsy during short-term administration of oxcarbazepine and valproate" Epilepsia 47(11):1855-9 (2006)
https://onlinelibrary.wiley.com/doi/10. ... 06.00821.x
(Increase in TSH)
Doneray H, Kara IS, Karakoc A, Tan H, Orbak Z - "Serum thyroid hormone profile and trace elements in children receiving valproic acid therapy: a longitudinal and controlled study" J Trace Elem Med Biol 26(4):243-7 (2012)
https://pubmed.ncbi.nlm.nih.gov/22683050/
"TSH level was significantly increased in the patient group whereas FT4 was significantly decreased."
Eirís-Puñal J, Del Río-Garma M, Del Río-Garma MC, Lojo-Rocamonde S, Novo-Rodríguez I, Castro-Gago M - "Long-term treatment of children with epilepsy with valproate or carbamazepine may cause subclinical hypothyroidism" Epilepsia 40(12):1761-6 (1999)
https://pubmed.ncbi.nlm.nih.gov/10612341/
"The increase in TSH levels was particularly marked in VPA-treated children, accounting for 26% of patients with subclinical hypothyroidism."
Fortunati N, Catalano MG, Arena K, Brignardello E, Piovesan A, Boccuzzi G - "Valproic acid induces the expression of the Na+/I- symporter and iodine uptake in poorly differentiated thyroid cancer cells" J Clin Endocrinol Metab 89(2):1006-9 (2004) doi: 10.1210/jc.2003-031407
https://pubmed.ncbi.nlm.nih.gov/14764827/
Güngör O, Özkaya AK, Temiz F - "The effect of antiepileptic drugs on thyroid hormonal function: valproic acid and phenobarbital." Acta Neurol Belg. 120(3):615-619 (2020)
https://pubmed.ncbi.nlm.nih.gov/29508221/
"When compared with the pre-treatment values, there was a statistically significant difference in the incidence of subclinical hypothyroid in the valproic acid group and no significant difference in the phenobarbital group."
Guzeva VI, Guzeva VV - "The effect of antiepileptic therapy on the level of hormones in the blood serum of girls with epilepsy" Zh Nevrol Psikhiatr Im S S Korsakova. 2014;114(4 Pt 2):23-9. Russian. PMID: 24874333.
https://pubmed.ncbi.nlm.nih.gov/24874333/
"The highest content of TSH was found in girls, aged 8-17 years, treated with valproate."
Ilić V, Bogićević D, Miljković B, Ješić M, Kovačević M, Prostran M, Vezmar Kovačević S - "Duration of valproic acid monotherapy correlates with subclinical thyroid dysfunction in children with epilepsy" Epileptic Disord 18(2):181-186 (2016) doi: 10.1684/epd.2016.0821.
https://onlinelibrary.wiley.com/doi/abs ... .2016.0821
"The valproic acid group had higher serum thyroid-stimulating hormone (p<0.001) and free triiodothyronine (p<0.05) levels compared to the control group. Serum thyroid-stimulating hormone and free triiodothyronine were above the upper limit for healthy controls in 34% and 32% of patients...Duration of valproic acid monotherapy for less than four years was a risk factor for elevated thyroid-stimulating hormone levels...One third of children with normal range serum valproic acid levels may have elevated serum thyroid-stimulating hormone and free triiodothyronine levels, especially in the first four years of treatment."
Isojärvi JI, Pakarinen AJ, Ylipalosaari PJ, Myllylä VV - "Serum hormones in male epileptic patients receiving anticonvulsant medication" Arch Neurol. 47(6):670-6 (1990)
https://pubmed.ncbi.nlm.nih.gov/2135734/
(Increased TSH, blunted TSH response to TRH stimulation)
Kim SH, Chung HR, Kim SH, Kim H, Lim BC, Chae JH, Kim KJ, Hwang YS, Hwang H - "Subclinical hypothyroidism during valproic acid therapy in children and adolescents with epilepsy" Neuropediatrics 43(3):135-9 (2012)
"Serum VPA level and daily dose of VPA were correlated with TSH level. Subclinical hypothyroidism developed frequently in children and adolescents during VPA therapy."
Lossius MI, Taubøll E, Mowinckel P, Gjerstad L - "Reversible effects of antiepileptic drugs on thyroid hormones in men and women with epilepsy: a prospective randomized double-blind withdrawal study" Epilepsy Behav 16(1):64-8 (2009) doi: 10.1016/j.yebeh.2009.07.014
https://www.sciencedirect.com/science/a ... 5009003746
"Valproate treatment of women with epilepsy increases serum FT3...serum concentrations of free triiodothyronine (FT3) decreased significantly in the withdrawal group."
Park YM, Kang SG, Lee BH, Lee HJ - "Decreased thyroid function in Korean women with bipolar disorder receiving valproic acid" Gen Hosp Psychiatry. 33(2):200.e13-5 (2011)
https://www.sciencedirect.com/science/a ... 431000246X
"Furthermore, VPA therapy is associated with increased thyroid stimulating hormone (TSH) levels, an effect that is not reversible following withdrawal of the medication in girls [10]. In contrast, VPA does not appear to exert any significant effects on thyroid function in men [5]....We report here two female patients with bipolar disorder who developed abnormal thyroid function after short-and long-term administration of VPA."
Reddy SD, Shenkeshi S, Parunandi Y, Nousheen S, Thatipelli RC - "Thyroid function in children receiving valproic acid monotherapy" Curr Med Issues J Glob Med 16(2):106-111 (2024). doi: 10.61336/cmejgm/24-02-18
(Prathima Institute of Medical Sciences, Karimnagar, and Vaagdevi Pharmacy College, Hanamkonda, India.)
https://cmegeriatricmed.co.uk/article/t ... erapy-994/
"TSH levels were increased significantly from 2.11±1.54 µIU/mL at initiation of VPA to 3.78±1.84 µIU/mL at 3 months and to 4.45±1.96 µIU/mL at 6 months (p<0.001), T4 decreased significantly (p=0.021) and T3 decreased significantly (p=0.023) at 6 months after VPA therapy. After the 6 months of VPA therapy, a total of 24 patients (16%) have developed Subclinical Hypothyroidism, and 4 patients (2.67%) have developed Overt Hypothyroidism. Conclusion: Our research indicates that valproic acid monotherapy may result in early and long-lasting changes in thyroid function, indicating the necessity of careful and early monitoring of the concentration of thyroid hormones in serum in children with epilepsy receiving VPA."
Sahu JK, Gulati S, Kabra M, Arya R, Sharma R, Gupta N, Kaleekal T, Reeta Kh, Gupta YK - "Evaluation of subclinical hypothyroidism in ambulatory children with controlled epilepsy on valproate monotherapy" J Child Neurol 27(5):594-7 (2012)
https://pubmed.ncbi.nlm.nih.gov/22114214/
"There was a significantly high (P = .012) prevalence of subclinical hypothyroidism (26%) in those receiving valproate monotherapy compared with healthy controls (7.7%)...Results of the present study suggest higher prevalence of subclinical hypothyroidism in children with controlled epilepsy on long-term valproate monotherapy."
Su QY, Wang YZ - "Effects of sodium valproate in the treatment of epilepsy on thyroid function and hemoglobin levels" Chin J Matern Child Health Res 4:412-416 (2018) (Taizhou Women’s and Children’s Hospital Affiliated to Wenzhou Medical University; Taizhou Maternal and Child Health Care Hospital; Taizhou Municipal Hospital, Zhejiang, China.) PFPC Library
After one year of sodium valproate treatment, total thyroxine (T4) levels in children with epilepsy were significantly lower than both their pre-treatment levels and those of healthy controls (q = 3.040, P < 0.05; t = –2.010, P < 0.05). Additionally, there was a positive correlation between T4 and hemoglobin (Hb) levels after one year of treatment (r = 0.27, P < 0.05). This correlation remained significant in children with blood valproate concentrations ≥ 50 μg/mL (rₛ = 0.33, P < 0.05) and in those younger than 7 years (rₛ = 0.36, P < 0.05).
Vainionpää LK, Mikkonen K, Rättyä J, Knip M, Pakarinen AJ, Myllylä VV, Isojärvi JI. - "Thyroid function in girls with epilepsy with carbamazepine, oxcarbazepine, or valproate monotherapy and after withdrawal of medication" Epilepsia 45(3):197-203 (2004)
https://onlinelibrary.wiley.com/doi/ful ... m%3Apubmed
"The VPA-treated girls with epilepsy had normal serum T4 and FT4 concentrations, but slightly increased TSH levels (3.3; SD, 1.5 mU/L; p < 0.01) compared with the control girls (2.5; SD, 1.0 mU/L)."
Yang J, Chen C, Wang Z, Zhang H - "Effects of sodium valproate on thyroid and sex hormone levels in female patients with epilepsy" J Clin Psychosom Dis. 6:11-14 (2024) (The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China.) PFPC Library
TSH and PRL levels were significantly higher, while PROG and E2 levels were significantly lower in the experimental group compared to the control group (P < 0.01). In the experimental group, TSH and T4 levels showed a negative correlation (P < 0.01), whereas T3 and FT3, T4 and FT4, and PROG and E2 levels were positively correlated (P < 0.05 or 0.01). These findings indicate that sodium valproate exerts significant effects on both thyroid and sex hormones. Therefore, thyroid and sex hormone levels in female patients receiving sodium valproate should be closely and continuously monitored, with timely interventions applied as needed to minimize adverse drug effects.
Yılmaz U, Yılmaz TS, Akıncı G, Korkmaz HA, Tekgül H - "The effect of antiepileptic drugs on thyroid function in children" Seizure 23(1):29-35 (2014)
https://pubmed.ncbi.nlm.nih.gov/24091037/
"Valproate-treated patients had decreased fT4 and increased TSH levels at months 1, 6, and 12."
Zhang YX, Shen CH, Lai QL, Fang GL, Ming WJ, Lu RY, Ding MP - "Effects of antiepileptic drug on thyroid hormones in patients with epilepsy: A meta-analysis" Seizure 35:72-9 (2016)
https://pubmed.ncbi.nlm.nih.gov/26803280/
"...and valproic acid (VPA) use was associated with decreased T4 and increased TSH."
Zhao Y, Wen SW, Qin Y, Liu Y, Gao Y, Retnakaran R, Zhang R, Zhai D - "Association between valproate treatment for acute phase schizophrenia and risk of new onset hypothyroidism" Schizophr Res 235:12-16 (2021)
https://pubmed.ncbi.nlm.nih.gov/34298238/
"Similar with lithium, valproate as adjunctive drug is associated with increased risk of new onset hypothyroidism during acute phase treatment for schizophrenia."
Valproate & rT3
Visser WE, de Rijke YB, van Toor H, Visser TJ - "Thyroid status in a large cohort of patients with mental retardation: the TOP-R (Thyroid Origin of Psychomotor Retardation) study" Clin Endocrinol (Oxf) 75(3):395-401 (2011)
https://pubmed.ncbi.nlm.nih.gov/21535074/
"Antiepileptic drugs (AEDs) use affected thyroid hormones (T4: 102·1 ± 1·2 vs 83·9 ± 1·2 nmol/l, P < 1 × 10(-24) ; FT4: 18·0 ± 0·2 vs 16·1 ± 0·2 pmol/l, P < 1 × 10(-9) ; T3: 1·72 ± 0·02 vs 1·57 ± 0·02 nmol/l, P < 1 × 10(-9) ; and rT3: 0·37 ± 0·01 vs 0·27 ± 0·01 nmol/l, P < 1 × 10(-28) in subjects without vs with AEDs).
Bentsen KD, Gram L, Veje A - "Serum thyroid hormones and blood folic acid during monotherapy with carbamazepine or valproate. A controlled study" Acta Neurol Scand 67(4):235-41 (1983)
https://pubmed.ncbi.nlm.nih.gov/6407268/
"Valproate caused a decrease in T4, FT4 and T3." [rT3 first increased (one month treatment), then decreased (3 month treatment)] -> Dose- and time-dependent Gq/11 activation
Timing: Neural Tube Closure
NOTE: The 12.5th day of gestation (E12.5) in the rat corresponds roughly to day 24–28 of human embryonic development - the end of neural-tube closure and the start of hindbrain differentiation.
Rodier PM, Ingram JL, Tisdale B, Nelson S, Romano J - "Embryological origin for autism: developmental anomalies of the cranial nerve motor nuclei" J Comp Neurol 370(2):247-261 (1996)
doi:10.1002/(SICI)1096-9861(19960624)370:2<247::AID-CNE8>3.0.CO;2-2
Rodier PM, Ingram JL, Tisdale B, Croog VJ - "Linking etiologies in humans and animal models: studies of autism" Biol Psychiatry 41(8): 819-828 (1997)
doi:10.1016/S0890-6238(97)80001-U
https://onlinelibrary.wiley.com/doi/10. ... 3.0.CO;2-2
Ingram JL, Peckham SM, Tisdale B, Rodier PM - "Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism" Neurotoxicol Teratol 22(3):319-324 (2000) doi:10.1016/S0892-0362(99)00083-5
https://linkinghub.elsevier.com/retriev ... 6299000835
Arndt TL, Stodgell CJ, Rodier PM - "The teratology of autism" Int J Dev Neurosci 23(2-3):189-199 (2005) doi:10.1016/j.ijdevneu.2004.11.001
https://onlinelibrary.wiley.com/doi/10. ... 004.11.001
https://onlinelibrary.wiley.com/doi/10. ... 004.11.001
Narita N, Kato M, Tazoe M, Miyazaki K, Narita M, Okado N - "Increased monoamine concentration in the brain and blood of fetal rats with valproate-induced autism" Brain Dev 24(7):706-710 (2002) doi:10.1016/S0387-7604(02)00062-6
https://pubmed.ncbi.nlm.nih.gov/12357053/
Schneider T, Przewłocki R - "Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism" Neuropsychopharmacology. 31(1):36-46 (2006) doi:10.1038/sj.npp.1300796
https://www.nature.com/articles/1300518
Shank3
Shank3 is one of the best-characterized genes implicated in ASD. Shank3+/ΔC mutant mice display abnormal social behaviours that mimic ASD-like symptoms. It is a thyroid hormone-regulated gene.
Martinez ME, Stohn JP, Mutina EM, Whitten RJ, Hernandez A - "Thyroid hormone elicits intergenerational epigenetic effects on adult social behavior and fetal brain expression of autism susceptibility genes" Front Neurosci 16:1055116 (2022) doi: 10.3389/fnins.2022.1055116
https://pmc.ncbi.nlm.nih.gov/articles/PMC9676973/
Navarro D, Alvarado M, Navarrete F, Giner M, Obregon MJ, Manzanares J, Berbel P - "Gestational and early postnatal hypothyroidism alters VGluT1 and VGAT bouton distribution in the neocortex and hippocampus, and behavior in rats" Front Neuroanat 9:9 (2015). doi: 10.3389/fnana.2015.00009.
https://www.frontiersin.org/journals/ne ... 00009/full
Creagh O, Torres H, Rivera K, Morales-Franqui M, Altieri-Acevedo G, Warner D - "Previous Exposure to Anesthesia and Autism Spectrum Disorder (ASD): A Puerto Rican Population-Based Sibling Cohort Study" Bol Asoc Med P R 108(2):73-80 (2016)
https://pubmed.ncbi.nlm.nih.gov/29172370/
"Children under early exposure to anesthesia in uterus, first 2 years of life, or later are not more likely to develop neither ASD nor severe form of the disorder."
He S, Zhou F, Tian G, Cui Y, Yan Y - "Effect of Anesthesia During Pregnancy, Delivery, and Childhood on Autism Spectrum Disorder: A Systematic Review and Meta-analysis" J Autism Dev Disord 54(12):4540-4554 (2024) doi: 10.1007/s10803-023-06169-2
https://pubmed.ncbi.nlm.nih.gov/37934394/
"This meta-analysis did not confirm the association between exposure to anesthesia during labour and ASD. Previous observational studies used the neurotoxicity of anesthesia to biologically explain significant associations, but in fact different controls for confounding factors led to differences in associations. The evidence for pregnancy and childhood was limited given the small number of studies in these periods."
Pikwer A, Reutfors J, Norrman S, Johansson S, Meyerson J, Jonsson F, Johansson G - "Autism after general anesthesia in early childhood: a nationwide cohort study" Minerva Anestesiol 89(1-2):22–31 (2023)
doi:10.23736/S0375-9393.22.16088-5
https://www.minervamedica.it/en/journal ... 23N01A0022
"Exposure to general anesthesia in early childhood was associated with an increased risk of autism or autism spectrum disorder. Future studies are needed to asses if general anesthesia may cause autism or if the association is due to other factors."
(No information on agents used)
Gut Dysbiosis
Fang J, Geng R, Kang SG, Huang K, Tong T - "Dietary L-proline supplementation ameliorates autism-like behaviors and modulates gut microbiota in the valproic acid-induced mouse model of autism spectrum disorder" Food Sci Hum Wellness 13(5):2889-2905 (2024) PFPC Library
Zhao Y, Ma S, Liang L, Cao S, Fan Z, He D, Shi X, Zhang Y, Liu B, Zhai M, Wu S, Kuang F, Zhang H - "Gut Microbiota-Metabolite-Brain Axis Reconstitution Reverses Sevoflurane-Induced Social and Synaptic Deficits in Neonatal Mice" Research (Wash D C) 7:0482 (2024) doi: 10.34133/research.0482
https://pmc.ncbi.nlm.nih.gov/articles/PMC11411162/
"The gut microbiota-metabolite-brain axis underlies social dysfunction caused by sevoflurane exposure in early age, and bile acid regulation may be a promising intervention to this impairment."
Han S, Bian R, Chen Y, Liang J, Zhao P, Gu Y, Zhang D - "Dysregulation of the gut microbiota contributes to sevoflurane-induced cognitive dysfunction in aged mice by activating the NLRP3 inflammasome" Molecular Neurobiology 61(12):10500-10516 (2024) doi: 10.1007/s12035-024-04229-x
https://link.springer.com/article/10.10 ... 24-04229-x
NOTE: NLRP3 is regulated by Gq/11
"Compared to those in the control group, sevoflurane significantly increased the expression of NLRP3 inflammasome-associated proteins in the gut and brain in the sevoflurane-exposed group, thus causing neuroinflammation and synaptic damage, which probiotics can mitigate (con vs. sev, P < 0.01; p+sev vs. sev, P < 0.05). "
Lin Zhixuan, Huang San, Huang Yan, Yang Xiaolin - "Effects of different sevoflurane anesthesia concentrations on the concentration of free hexafluoroisopropanol in rat blood" J Nanjing Med Univ (Nat Sci Ed) 42(7):973-977, 982 (2022) PFPC Library
Free HFIP concentration in blood rises early and then falls with prolonged anesthesia. Moderate sevoflurane concentration (≈2.3%) produces the most HFIP, while higher concentrations (≈3.5%) suppress metabolic conversion, indicating dose-dependent metabolic inhibition of sevoflurane in vivo.
Yang Xiaolin, Eger EI II, Sharma M - "Study on the metabolism of sevoflurane in mice" Sichuan Med J 33(11):1884–1886 (2012) PFPC Library
Sevoflurane can be metabolized to HFIP in both mouse liver and brain tissues, but high concentrations of sevoflurane inhibit its own biotransformation - mirroring findings in rats that show reduced HFIP accumulation at higher anesthetic doses.
Ghimenti S, Di Francesco F, Onor M, Stiegel MA, Trivella MG, Comite C, Catania N, Fuoco R, Pleil JD - "Post-operative elimination of sevoflurane anesthetic and hexafluoroisopropanol metabolite in exhaled breath: pharmacokinetic models for assessing liver function" J Breath Res 7(3):036001 (2013). doi: 10.1088/1752-7155/7/3/036001
Ni J, Sato N, Fujii K, Yuge O - "Urinary excretion of hexafluoroisopropanol glucuronide and fluoride in patients after sevoflurane anaesthesia" J Pharm Pharmacol 45(1):67-9 (1993) doi: 10.1111/j.2042-7158.1993.tb03682.x.
https://academic.oup.com/jpp/article-ab ... 67/6163385
"Our study showed that a hexafluoroisopropanol glucuronide is excreted in the urine, and the major part of urinary metabolites of sevoflurane, organic and inorganic fluoride, are excreted within 2 days of sevoflurane inhalation in man."
Keller KA, Callan C, Prokocimer P, Delgado-Herrera L, Friedman MB, Hoffman GM, Wooding WL, Cusick PK, Krasula RW - "Inhalation toxicity study of a haloalkene degradant of sevoflurane, Compound A (PIFE), in Sprague-Dawley rats" Anesthesiology 83(6):1220-32 (1995) doi: 10.1097/00000542-199512000-00013
https://pubmed.ncbi.nlm.nih.gov/8533915/
Sevoflurane is classified as PFAS
Kalmar AF, Groffen T, Vereecke H, Teunkens A, Dewinter G, Mulier H, Struys MRF, Rex S – "Volatile anaesthetics and PFAS forever chemicals: a critical gap in environmental impact assessments" Best Pract Res Clin Anaesthesiol 38(4):342-348 (2024). doi: 10.1016/j.bpa.2024.12.002
https://doi.org/10.1016/j.bpa.2024.12.002
https://www.sciencedirect.com/science/a ... 9625000023
"A median hospital performing 8 h of sevoflurane-based maintenance anaesthesia in each of its 10 operating theatres would contaminate approximately 38 million litres of local municipal water daily to the EU legal PFAS threshold."
https://link.springer.com/article/10.21 ... 1150-00001
Fluoride, Compound A (fluoromethyl-2,2-difluoro-l-[trifluoromethyl] vinyl ether), or pentafluoroisopropenyl fluoromethyl ether.
+++++++++++++++++++++++++++++++++++++
See also: Enflurane and Halothane
Related: LPS
Okano H, Takashima K, Takahashi Y, Ojiro R, Tang Q, Ozawa S, Ogawa B, Koyanagi M, Maronpot RR, Yoshida T, Shibutani M - "Ameliorating effect of continuous alpha-glycosyl isoquercitrin treatment starting from late gestation in a rat autism model induced by postnatal injection of lipopolysaccharides" Chem Biol Interact 351:109767 (2022). doi: 10.1016/j.cbi.2021.109767
https://pubmed.ncbi.nlm.nih.gov/34863679/
Sevoflurane → 七氟烷 (“seven-fluorine ether”) → C₄H₃F₇O.
Behne M, Wilke HJ, Harder S - "Clinical pharmacokinetics of sevoflurane" Clin Pharmacokinet 36(1):13-26 (1999) doi: 10.2165/00003088-199936010-00002 PFPC Library
"Serum inorganic fluoride concentrations after sevoflurane anaesthesia have been reported to be dose dependent and reach about 10 to 20 μmol/L (after 1 to 2 MAC hours), 20 to 40 μmol/L (after 2 to 7 MAC hours) and may be as high as 20 to 90 μmol/L with prolonged exposure."
Holaday DA, Smith FR - "Clinical characteristics and biotransformation of sevoflurane in healthy human volunteers" Anesthesiology 54(2):100-6 (1981)
https://pubs.asahq.org/anesthesiology/a ... rmation-of
"After an hour of exposure arterial blood scrum inorganic fluoride concentrations averaged 22 μM and plasma nonvolatile organic fluorine concentrations averaged 9.1 mg/I, or 61.3 μM. Uptakes of sevoflurane averaged 94 (±63 SD) mmol. Following exposure 37 (±12) mmol of unaltered sevoflurane were estimated to be excreted in exhaled air and 0.90 mmol of inorganic fluoride and 163 mg, or 1.43 (±0.26) mmol of organic fluorine were excreted in the urine."
Kharasch ED - "Metabolism and toxicity of the new anesthetic agents" Acta Anaesthesiol Belg 47(1):7-14 (1996)
"Peak serum fluoride concentrations occur within one hour after sevoflurane anesthesia, are usually in the range of 20-40 microM, and decline rapidly. Fluoride concentrations have exceeded 50 microM in approximately 7% of sevoflurane patients."
- SEE also: Kharasch ED, Armstrong AS, Gunn K, Artru A, Cox K, Karol MD - "Clinical sevoflurane metabolism and disposition. II. The role of cytochrome P450 2E1 in fluoride and hexafluoroisopropanol formation" Anesthesiology 82(6):1379-88 (1995) doi: 10.1097/00000542-199506000-00009
https://journals.lww.com/anesthesiology ... on_.9.aspx
https://academic.oup.com/jpp/article-ab ... 67/6163385
"The cumulative organic and inorganic fluoride excretion in the 3 days after sevoflurane anaesthesia was 1588 and 856 mumol, respectively (ratio = 1.85). The excreted half-lives for organic and inorganic fluoride were calculated to be 4028 and 2069 min, respectively. Our study showed that a hexafluoroisopropanol glucuronide is excreted in the urine, and the major part of urinary metabolites of sevoflurane, organic and inorganic fluoride, are excreted within 2 days of sevoflurane inhalation in man."
Sarner JB, Levine M, Davis PJ, Lerman J, Cook DR, Motoyama EK - "Clinical characteristics of sevoflurane in children. A comparison with halothane" Anesthesiology 82(1):38-46 (1995) doi: 10.1097/00000542-199501000-00006
https://pubmed.ncbi.nlm.nih.gov/7832332/
"The maximum serum fluoride concentration among all patients was 28 microM." = 0.53 Mg/L of fluoride.⁻ Normal serum levels are 0.02–0.1 mg/L.
Taylor B, Scott TE, Shaw J, Chockalingam N - "Renal safety of critical care sedation with sevoflurane: a systematic review and meta-analysis" J Anesth 37(5):794-805 (2023) doi: 10.1007/s00540-023-03227-y.
https://link.springer.com/article/10.10 ... 23-03227-y
"Levels of serum inorganic fluoride were significantly elevated in patients where sevoflurane was used."
Sevoflurane & Autism
Chung W, Park S, Hong J, Park S, Lee S, Heo J, Kim D, Ko Y - "Sevoflurane exposure during the neonatal period induces long-term memory impairment but not autism-like behaviors" Paediatr Anaesth 25(10):1033-45 (2015)
https://pubmed.ncbi.nlm.nih.gov/26095314/
Ju L-S, Morey TE, Gravenstein N, Setlow B, Seubert CN, Martynyuk AE - "Effects of cohabitation on neurodevelopmental outcomes in rats discordant for neonatal exposure to sevoflurane" Biol Psychiatry Glob Open Sci 4(2):100359 (2024)
doi:10.1016/j.bpsgos.2024.100359
Sun M, Fu N, Li T, Miao M, Chen WM, Wu SY, Zhang J - "Childhood anaesthesia and autism risk: population and murine study" Brain Commun 6(5):fcae325 (2024) doi: 10.1093/braincomms/fcae325
https://pmc.ncbi.nlm.nih.gov/articles/PMC11450270/
Wang HV, Forestier S, Corces VG - "Exposure to sevoflurane results in changes of transcription factor occupancy in sperm and inheritance of autism" Biol Reprod 105(3):705-719 (2021)
https://pubmed.ncbi.nlm.nih.gov/33982067/
NOTE: When Wang was informed about the fluoride/thyroid/sevoflurane aspects, she claimed "that the exposure time during pregnancy takes place several days before the thyroid is formed." She appeared entirely ignorant of the fact that the fetus is entirely dependent on the mother's thyroid hormone for the first trimester - the crucial time of thyroid hormone effects on neurodevelopment, including neural tube closure.
Zhang L, Xu L - "Fgf2 and Ptpn11 play a role in cerebral injury caused by sevoflurane anesthesia" Medicine (Baltimore) 102(45):e36108 (2023). doi: 10.1097/MD.0000000000036108
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10637467/
"Gene Expression Heatmap showed that the core genes (Fgf2, Pdgfra, Ptpn11, Slc2a1) were highly expressed in sevoflurane anesthesia brain tissue samples. CTD Analysis showed that the 4 core genes (Fgf2, Pdgfra, Ptpn11, Slc2a1) were associated with neurodegenerative diseases, brain injuries, memory disorders, cognitive disorders, neurotoxicity, drug-induced abnormalities, neurological disorders, developmental disorders, and intellectual disabilities."
- Ptpn11 --> Protein Tyrosine Phosphatase, Non-Receptor Type 11 -> regulated by thyroid hormone
Slc2a1 --> Solute Carrier Family 2 Member 1, also known as Glucose Transporter 1 (GLUT1) -> regulated by thyroid hormone
Fgf2 --> Fibroblast Growth Factor 2 -> regulated by thyroid hormone
Pdgfra --> Platelet-Derived Growth Factor Receptor Alpha -> regulated by thyroid hormone
Zhang W, Chen Y, Qin J, Lu J, Fan Y, Shi Z, Song X, Li C, Zhao T – "Prolonged sevoflurane exposure causes abnormal synapse development and dysregulates beta-neurexin and neuroligins in the hippocampus in neonatal rats" J Affect Disord 312:22-29 (2022). doi: 10.1016/j.jad.2022.05.115
https://www.sciencedirect.com/science/a ... 2722006358
Both β-neurexins and neuroligins, as well as the broader process of synaptogenesis in the hippocampus, are under thyroid hormone control.
Zhang L, Xu L - "Fgf2 and Ptpn11 play a role in cerebral injury caused by sevoflurane anesthesia" Medicine (Baltimore) 102(45):e36108 (2023) doi: 10.1097/MD.0000000000036108
https://journals.lww.com/md-journal/ful ... ry.65.aspx
More On Sevoflurane Effects on TH
Boztuğ N, Aydoğdu T - "Impact of Sevoflurane on Thyroid Hormone Levels" European Journal of Anaesthesiology 17:12 (2000)
Conference: European Society of Anaesthesiologists; 8th Annual Meeting with the Austrian International Congress, Vienna, Austria April 1-4, 2000
"In the recent study, while it is noticed that inhalation anaesthetics can cause 'Low T 3 Syndrome', throughout the intra- and postoperative period with sevoflurane we found an increase in the level of T3, which make us believe that it can decrease the possibility of occurrence of 'Low T3 Syndrome'..."
Huang H, Liu P, Ma D, Zhang H, Xu H, Zhou J, Zhao H, Zhao T, Li C - "Triiodothyronine attenuates neurocognitive dysfunction induced by sevoflurane in the developing brain of neonatal rats" J Affect Disord 297:455-462 (2022) doi: 10.1016/j.jad.2021.10.086
https://www.sciencedirect.com/science/a ... 272101154X
"Furthermore, sevoflurane decreased the expression of NMDA receptor subunits NR2A and NR2B, as well as PSD-95 in the hippocampus at P15 and those effects of sevoflurane were abolished by T3 administration."
Marana E, Colicci S, Meo F, Marana R, Proietti R - "Neuroendocrine stress response in gynecological laparoscopy: TIVA with propofol versus sevoflurane anesthesia" J Clin Anesth 22(4):250-5 (2010) doi: 10.1016/j.jclinane.2009.07.011
https://www.sciencedirect.com/science/a ... 8010000929
RCT; TSH levels increased while FT3 levels decreased significantly relative to basal values. In both groups, perioperative FT4 levels significantly increased compared with preoperative values.
Sevoflurane & Gq/11
Minami K, Sudo Y, Yokoyama T, Ogata J, Takeuchi M, Uezono Y - "Sevoflurane inhibits the µ-opioid receptor function expressed in Xenopus oocytes" Pharmacology 88(3-4):127-32 (2011) doi: 10.1159/000330096
https://pubmed.ncbi.nlm.nih.gov/21912198/
"Further, the mechanism of inhibition by sevoflurane would be mediated by PKC."
Nakayama T, Hayashi M, Warner DO, Jones KA - "Anesthetics inhibit membrane receptor coupling to the Gq/11 heterotrimeric G protein in airway smooth muscle" Anesthesiology 103(2):296-305 (2005). doi: 10.1097/00000542-200508000-00013. PMID: 16052112.
https://pubmed.ncbi.nlm.nih.gov/16052112/
Nakayama T, Penheiter AR, Penheiter SG, Chini EN, Thompson M, Warner DO, Jones KA - "Differential effects of volatile anesthetics on M3 muscarinic receptor coupling to the Galphaq heterotrimeric G protein" Anesthesiology 105(2):313-24 (2006). doi: 10.1097/00000542-200608000-00014
https://pubs.asahq.org/anesthesiology/a ... thetics-on
"Halothane and sevoflurane but not isoflurane inhibit acetylcholine-promoted Galphaq guanosine nucleotide exchange."
- Sevoflurane and VEGF (Gq/11)
Zhao J, Liu C, Jia Q - "Effects of isoflurane and sevoflurane anesthesia on microglial activation and neural stem cell proliferation and differentiation in neonatal rats and their mechanisms" Mil Med J Joint Logist 47(7):553–558 (2024) PFPC Library
(Department of Anesthesiology, Mianyang People's Hospital, Mianyang, Sichuan, China.)
Both isoflurane and sevoflurane activate microglia and suppress NSC proliferation and differentiation by modulating the VEGFR2 signaling pathway, leading to cognitive dysfunction in neonatal rats.
- Sevoflurane and SIRT
Xu X, Li C, Zou J, Liu L – "MiR-34a targets SIRT1 to reduce p53 deacetylation and promote sevoflurane inhalation anesthesia-induced neuronal autophagy and apoptosis in neonatal mice" Exp Neurol 368:114482 (2023). doi: 10.1016/j.expneurol.2023.114482
https://www.sciencedirect.com/science/a ... 862300167X
SEE: Fluoride and SIRT: viewtopic.php?p=7546#p7546
Fluoride and p53: viewtopic.php?p=7447#p7447
Li Z, Zhu YX, Gu LJ, Cheng Y - "Understanding autism spectrum disorders with animal models: applications, insights, and perspectives" Zool Res 42(6):800-824 (2021)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8645879/
Sadamatsu M, Kanai H, Xu X, Liu Y, Kato N - "Review of animal models for autism: implication of thyroid hormone" Congenit Anom (Kyoto) 46(1):1-9 (2006) doi: 10.1111/j.1741-4520.2006.00094.x.
https://pubmed.ncbi.nlm.nih.gov/16643592/
Proposal to use the rat with mild and transient neonatal hypothyroidism as a novel model for autism.
Wei W, Liu A, Liu M, Li M, Wu X, Qin C, Shan Z, Zhang L - "Development of an animal model of hypothyroxinemia during pregnancy in Wistar rats" Animal Model Exp Med 7(6):926-935 (2024) doi: 10.1002/ame2.12459
https://onlinelibrary.wiley.com/doi/10.1002/ame2.12459
NOTE: PTU
"The animal model of IMH [Isolated maternal hypothyroxinemia] was developed by the administration of 1 ppm of PTU for 9 weeks, and there were autistic-like behavior changes such as anxiety, weakened social ability, and repeated stereotyping in the IMH offspring by 40 days."
Tanaka T, Masubuchi Y, Okada R, Nakajima K, Nakamura K, Masuda S, Nakahara J, Maronpot RR, Yoshida T, Koyanagi M, Hayashi SM, Shibutani M - "Ameliorating effect of postweaning exposure to antioxidant on disruption of hippocampal neurogenesis induced by developmental hypothyroidism in rats" J Toxicol Sci 44(5):357-372 (2019) doi: 10.2131/jts.44.357
NOTE: PTU
Developmental hypothyroidism as a model of autism spectrum disorders
Valproic Acid
Choi CS, Gonzales EL, Kim KC, Yang SM, Kim JW, Mabunga DF, Cheong JH, Han SH, Bahn GH, Shin CY - "The transgenerational inheritance of autism-like phenotypes in mice exposed to valproic acid during pregnancy" Sci Rep 6:36250 (2016)
https://pubmed.ncbi.nlm.nih.gov/27819277/
Nicolini C, Fahnestock M - "The valproic acid-induced rodent model of autism" Exp Neurol 299(Pt A):217-227 (2018)
https://pubmed.ncbi.nlm.nih.gov/28472621/
- SEE also:
MHRA update on new study on risk in children born to men taking valproate
https://www.gov.uk/government/news/mhra ... -valproate
Valproic Acid & Gq/11
Hoshi N - "M-Current Suppression, Seizures and Lipid Metabolism: A Potential Link Between Neuronal Kv7 Channel Regulation and Dietary Therapies for Epilepsy" Front Physiol 11:513 (2020)
https://pubmed.ncbi.nlm.nih.gov/32523549/
Tokuoka SM, Saiardi A, Nurrish SJ - "The mood stabilizer valproate inhibits both inositol- and diacylglycerol-signaling pathways in Caenorhabditis elegans" Mol Biol Cell 19(5):2241-50 (2008)
https://pubmed.ncbi.nlm.nih.gov/18287529/
"VPA reduces levels of DAG and inositol-1-phosphate, but phosphatidylinositol-4,5-bisphosphate (PIP(2)) is slightly increased, suggesting that phospholipase C-mediated hydrolysis of PIP(2) to form DAG and IP(3) is defective in the presence of VPA."
Kelly E, Sharma D, Wilkinson CJ, Williams RSB - "Diacylglycerol kinase (DGKA) regulates the effect of the epilepsy and bipolar disorder treatment valproic acid in Dictyostelium discoideum" Dis Model Mech 11(9):dmm035600 (2018)
https://pubmed.ncbi.nlm.nih.gov/30135067/
"Finally, we show that VPA, lithium and novel epilepsy treatments function through DAG regulation, and the presence of DGKA is necessary for compound-specific increases in DAG levels following treatment."
Chen G, Manji HK, Wright CB, Hawver DB, Potter WZ - "Effects of valproic acid on beta-adrenergic receptors, G-proteins, and adenylyl cyclase in rat C6 glioma cells" Neuropsychopharmacology 15(3):271-80 (1996)
https://www.nature.com/articles/1380468.pdf
"..As can be seen in Figures 3 and 4, chronic incubation of C6 cells with VPA (0.5 mM) resulted in a significant decrease in the cholera toxin-catalyzed [12P]ADP-ribosylation of Gs 45, which was also apparent after 3 days of VPA incubation. Chronic incubation of C6 cells with YPA (0.5 m1v1) for 3 or more days also resulted in a significant reduction in the cholera toxin catalyzed [12P]ADP-ribosylation of Gs 52 (Figures 3 and 4). The pertussis toxin-catalyzed ['2P]ADP-ribosvlations of G(Xi/o were not altered at any time point studied."
Valproic Acid & Thyroid
Alhyan P, Aggarwal A, Chhillar N, Sharma S, Narang M, Malhotra RK - "Effect of Valproate Monotherapy on Thyroid Function Tests and Magnesium Levels in Children With Epilepsy. Cureus" 15(5):e39712 (2023) doi: 10.7759/cureus.39712
https://assets.cureus.com/uploads/origi ... y6p9m8.pdf
"Thyroid stimulating hormone (TSH) increased significantly from 2.14±1.64 µIU/ml at enrollment to 3.64±2.15 µIU/ml at six months (p<0.001), free thyroxine (FT4) decreased significantly (p<0.001)."
Attilakos A, Katsarou E, Prassouli A, Mastroyianni S, Voudris K, Fotinou A, Garoufi A - "Thyroid function in children with epilepsy treated with sodium valproate monotherapy: a prospective study" Clin Neuropharmacol 32(1):32-4 (2009)
https://pubmed.ncbi.nlm.nih.gov/18978499/
"Thyroxine and free thyroxine levels were significantly decreased, whereas TSH levels were significantly increased at 6, 12, and 24 months of VPA therapy. Triiodothyronine levels were significantly decreased only at 24 months of therapy. Thirteen children (43.3%) at 6 months, 14 children (46.6%) at 12 months, and 15 children (50%) at 24 months of treatment had TSH values greater than 5 mIU/mL. Normal serum TSH levels were restored in all 8 children examined at 3 months after withdrawal of medication."
Bentsen KD, Gram L, Veje A - "Serum thyroid hormones and blood folic acid during monotherapy with carbamazepine or valproate. A controlled study" Acta Neurol Scand 67(4):235-41 (1983)
https://pubmed.ncbi.nlm.nih.gov/6407268/
"Valproate caused a decrease in T4, FT4 and T3." [rT3 first increased (one month treatment), then decreased (3 month treatment)] -> Dose- and time-dependent Gq/11 activation
Cansu A, Serdaroğlu A, Camurdan O, Hirfanoğlu T, Bideci A, Gücüyener K - "The evaluation of thyroid functions, thyroid antibodies, and thyroid volumes in children with epilepsy during short-term administration of oxcarbazepine and valproate" Epilepsia 47(11):1855-9 (2006)
https://onlinelibrary.wiley.com/doi/10. ... 06.00821.x
(Increase in TSH)
Doneray H, Kara IS, Karakoc A, Tan H, Orbak Z - "Serum thyroid hormone profile and trace elements in children receiving valproic acid therapy: a longitudinal and controlled study" J Trace Elem Med Biol 26(4):243-7 (2012)
https://pubmed.ncbi.nlm.nih.gov/22683050/
"TSH level was significantly increased in the patient group whereas FT4 was significantly decreased."
Eirís-Puñal J, Del Río-Garma M, Del Río-Garma MC, Lojo-Rocamonde S, Novo-Rodríguez I, Castro-Gago M - "Long-term treatment of children with epilepsy with valproate or carbamazepine may cause subclinical hypothyroidism" Epilepsia 40(12):1761-6 (1999)
https://pubmed.ncbi.nlm.nih.gov/10612341/
"The increase in TSH levels was particularly marked in VPA-treated children, accounting for 26% of patients with subclinical hypothyroidism."
Fortunati N, Catalano MG, Arena K, Brignardello E, Piovesan A, Boccuzzi G - "Valproic acid induces the expression of the Na+/I- symporter and iodine uptake in poorly differentiated thyroid cancer cells" J Clin Endocrinol Metab 89(2):1006-9 (2004) doi: 10.1210/jc.2003-031407
https://pubmed.ncbi.nlm.nih.gov/14764827/
Güngör O, Özkaya AK, Temiz F - "The effect of antiepileptic drugs on thyroid hormonal function: valproic acid and phenobarbital." Acta Neurol Belg. 120(3):615-619 (2020)
https://pubmed.ncbi.nlm.nih.gov/29508221/
"When compared with the pre-treatment values, there was a statistically significant difference in the incidence of subclinical hypothyroid in the valproic acid group and no significant difference in the phenobarbital group."
Guzeva VI, Guzeva VV - "The effect of antiepileptic therapy on the level of hormones in the blood serum of girls with epilepsy" Zh Nevrol Psikhiatr Im S S Korsakova. 2014;114(4 Pt 2):23-9. Russian. PMID: 24874333.
https://pubmed.ncbi.nlm.nih.gov/24874333/
"The highest content of TSH was found in girls, aged 8-17 years, treated with valproate."
Ilić V, Bogićević D, Miljković B, Ješić M, Kovačević M, Prostran M, Vezmar Kovačević S - "Duration of valproic acid monotherapy correlates with subclinical thyroid dysfunction in children with epilepsy" Epileptic Disord 18(2):181-186 (2016) doi: 10.1684/epd.2016.0821.
https://onlinelibrary.wiley.com/doi/abs ... .2016.0821
"The valproic acid group had higher serum thyroid-stimulating hormone (p<0.001) and free triiodothyronine (p<0.05) levels compared to the control group. Serum thyroid-stimulating hormone and free triiodothyronine were above the upper limit for healthy controls in 34% and 32% of patients...Duration of valproic acid monotherapy for less than four years was a risk factor for elevated thyroid-stimulating hormone levels...One third of children with normal range serum valproic acid levels may have elevated serum thyroid-stimulating hormone and free triiodothyronine levels, especially in the first four years of treatment."
Isojärvi JI, Pakarinen AJ, Ylipalosaari PJ, Myllylä VV - "Serum hormones in male epileptic patients receiving anticonvulsant medication" Arch Neurol. 47(6):670-6 (1990)
https://pubmed.ncbi.nlm.nih.gov/2135734/
(Increased TSH, blunted TSH response to TRH stimulation)
Kim SH, Chung HR, Kim SH, Kim H, Lim BC, Chae JH, Kim KJ, Hwang YS, Hwang H - "Subclinical hypothyroidism during valproic acid therapy in children and adolescents with epilepsy" Neuropediatrics 43(3):135-9 (2012)
"Serum VPA level and daily dose of VPA were correlated with TSH level. Subclinical hypothyroidism developed frequently in children and adolescents during VPA therapy."
Lossius MI, Taubøll E, Mowinckel P, Gjerstad L - "Reversible effects of antiepileptic drugs on thyroid hormones in men and women with epilepsy: a prospective randomized double-blind withdrawal study" Epilepsy Behav 16(1):64-8 (2009) doi: 10.1016/j.yebeh.2009.07.014
https://www.sciencedirect.com/science/a ... 5009003746
"Valproate treatment of women with epilepsy increases serum FT3...serum concentrations of free triiodothyronine (FT3) decreased significantly in the withdrawal group."
Park YM, Kang SG, Lee BH, Lee HJ - "Decreased thyroid function in Korean women with bipolar disorder receiving valproic acid" Gen Hosp Psychiatry. 33(2):200.e13-5 (2011)
https://www.sciencedirect.com/science/a ... 431000246X
"Furthermore, VPA therapy is associated with increased thyroid stimulating hormone (TSH) levels, an effect that is not reversible following withdrawal of the medication in girls [10]. In contrast, VPA does not appear to exert any significant effects on thyroid function in men [5]....We report here two female patients with bipolar disorder who developed abnormal thyroid function after short-and long-term administration of VPA."
Reddy SD, Shenkeshi S, Parunandi Y, Nousheen S, Thatipelli RC - "Thyroid function in children receiving valproic acid monotherapy" Curr Med Issues J Glob Med 16(2):106-111 (2024). doi: 10.61336/cmejgm/24-02-18
(Prathima Institute of Medical Sciences, Karimnagar, and Vaagdevi Pharmacy College, Hanamkonda, India.)
https://cmegeriatricmed.co.uk/article/t ... erapy-994/
"TSH levels were increased significantly from 2.11±1.54 µIU/mL at initiation of VPA to 3.78±1.84 µIU/mL at 3 months and to 4.45±1.96 µIU/mL at 6 months (p<0.001), T4 decreased significantly (p=0.021) and T3 decreased significantly (p=0.023) at 6 months after VPA therapy. After the 6 months of VPA therapy, a total of 24 patients (16%) have developed Subclinical Hypothyroidism, and 4 patients (2.67%) have developed Overt Hypothyroidism. Conclusion: Our research indicates that valproic acid monotherapy may result in early and long-lasting changes in thyroid function, indicating the necessity of careful and early monitoring of the concentration of thyroid hormones in serum in children with epilepsy receiving VPA."
Sahu JK, Gulati S, Kabra M, Arya R, Sharma R, Gupta N, Kaleekal T, Reeta Kh, Gupta YK - "Evaluation of subclinical hypothyroidism in ambulatory children with controlled epilepsy on valproate monotherapy" J Child Neurol 27(5):594-7 (2012)
https://pubmed.ncbi.nlm.nih.gov/22114214/
"There was a significantly high (P = .012) prevalence of subclinical hypothyroidism (26%) in those receiving valproate monotherapy compared with healthy controls (7.7%)...Results of the present study suggest higher prevalence of subclinical hypothyroidism in children with controlled epilepsy on long-term valproate monotherapy."
Su QY, Wang YZ - "Effects of sodium valproate in the treatment of epilepsy on thyroid function and hemoglobin levels" Chin J Matern Child Health Res 4:412-416 (2018) (Taizhou Women’s and Children’s Hospital Affiliated to Wenzhou Medical University; Taizhou Maternal and Child Health Care Hospital; Taizhou Municipal Hospital, Zhejiang, China.) PFPC Library
After one year of sodium valproate treatment, total thyroxine (T4) levels in children with epilepsy were significantly lower than both their pre-treatment levels and those of healthy controls (q = 3.040, P < 0.05; t = –2.010, P < 0.05). Additionally, there was a positive correlation between T4 and hemoglobin (Hb) levels after one year of treatment (r = 0.27, P < 0.05). This correlation remained significant in children with blood valproate concentrations ≥ 50 μg/mL (rₛ = 0.33, P < 0.05) and in those younger than 7 years (rₛ = 0.36, P < 0.05).
Vainionpää LK, Mikkonen K, Rättyä J, Knip M, Pakarinen AJ, Myllylä VV, Isojärvi JI. - "Thyroid function in girls with epilepsy with carbamazepine, oxcarbazepine, or valproate monotherapy and after withdrawal of medication" Epilepsia 45(3):197-203 (2004)
https://onlinelibrary.wiley.com/doi/ful ... m%3Apubmed
"The VPA-treated girls with epilepsy had normal serum T4 and FT4 concentrations, but slightly increased TSH levels (3.3; SD, 1.5 mU/L; p < 0.01) compared with the control girls (2.5; SD, 1.0 mU/L)."
Yang J, Chen C, Wang Z, Zhang H - "Effects of sodium valproate on thyroid and sex hormone levels in female patients with epilepsy" J Clin Psychosom Dis. 6:11-14 (2024) (The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China.) PFPC Library
TSH and PRL levels were significantly higher, while PROG and E2 levels were significantly lower in the experimental group compared to the control group (P < 0.01). In the experimental group, TSH and T4 levels showed a negative correlation (P < 0.01), whereas T3 and FT3, T4 and FT4, and PROG and E2 levels were positively correlated (P < 0.05 or 0.01). These findings indicate that sodium valproate exerts significant effects on both thyroid and sex hormones. Therefore, thyroid and sex hormone levels in female patients receiving sodium valproate should be closely and continuously monitored, with timely interventions applied as needed to minimize adverse drug effects.
Yılmaz U, Yılmaz TS, Akıncı G, Korkmaz HA, Tekgül H - "The effect of antiepileptic drugs on thyroid function in children" Seizure 23(1):29-35 (2014)
https://pubmed.ncbi.nlm.nih.gov/24091037/
"Valproate-treated patients had decreased fT4 and increased TSH levels at months 1, 6, and 12."
Zhang YX, Shen CH, Lai QL, Fang GL, Ming WJ, Lu RY, Ding MP - "Effects of antiepileptic drug on thyroid hormones in patients with epilepsy: A meta-analysis" Seizure 35:72-9 (2016)
https://pubmed.ncbi.nlm.nih.gov/26803280/
"...and valproic acid (VPA) use was associated with decreased T4 and increased TSH."
Zhao Y, Wen SW, Qin Y, Liu Y, Gao Y, Retnakaran R, Zhang R, Zhai D - "Association between valproate treatment for acute phase schizophrenia and risk of new onset hypothyroidism" Schizophr Res 235:12-16 (2021)
https://pubmed.ncbi.nlm.nih.gov/34298238/
"Similar with lithium, valproate as adjunctive drug is associated with increased risk of new onset hypothyroidism during acute phase treatment for schizophrenia."
Valproate & rT3
Visser WE, de Rijke YB, van Toor H, Visser TJ - "Thyroid status in a large cohort of patients with mental retardation: the TOP-R (Thyroid Origin of Psychomotor Retardation) study" Clin Endocrinol (Oxf) 75(3):395-401 (2011)
https://pubmed.ncbi.nlm.nih.gov/21535074/
"Antiepileptic drugs (AEDs) use affected thyroid hormones (T4: 102·1 ± 1·2 vs 83·9 ± 1·2 nmol/l, P < 1 × 10(-24) ; FT4: 18·0 ± 0·2 vs 16·1 ± 0·2 pmol/l, P < 1 × 10(-9) ; T3: 1·72 ± 0·02 vs 1·57 ± 0·02 nmol/l, P < 1 × 10(-9) ; and rT3: 0·37 ± 0·01 vs 0·27 ± 0·01 nmol/l, P < 1 × 10(-28) in subjects without vs with AEDs).
Bentsen KD, Gram L, Veje A - "Serum thyroid hormones and blood folic acid during monotherapy with carbamazepine or valproate. A controlled study" Acta Neurol Scand 67(4):235-41 (1983)
https://pubmed.ncbi.nlm.nih.gov/6407268/
"Valproate caused a decrease in T4, FT4 and T3." [rT3 first increased (one month treatment), then decreased (3 month treatment)] -> Dose- and time-dependent Gq/11 activation
Timing: Neural Tube Closure
NOTE: The 12.5th day of gestation (E12.5) in the rat corresponds roughly to day 24–28 of human embryonic development - the end of neural-tube closure and the start of hindbrain differentiation.
Rodier PM, Ingram JL, Tisdale B, Nelson S, Romano J - "Embryological origin for autism: developmental anomalies of the cranial nerve motor nuclei" J Comp Neurol 370(2):247-261 (1996)
doi:10.1002/(SICI)1096-9861(19960624)370:2<247::AID-CNE8>3.0.CO;2-2
Rodier PM, Ingram JL, Tisdale B, Croog VJ - "Linking etiologies in humans and animal models: studies of autism" Biol Psychiatry 41(8): 819-828 (1997)
doi:10.1016/S0890-6238(97)80001-U
https://onlinelibrary.wiley.com/doi/10. ... 3.0.CO;2-2
Ingram JL, Peckham SM, Tisdale B, Rodier PM - "Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism" Neurotoxicol Teratol 22(3):319-324 (2000) doi:10.1016/S0892-0362(99)00083-5
https://linkinghub.elsevier.com/retriev ... 6299000835
Arndt TL, Stodgell CJ, Rodier PM - "The teratology of autism" Int J Dev Neurosci 23(2-3):189-199 (2005) doi:10.1016/j.ijdevneu.2004.11.001
https://onlinelibrary.wiley.com/doi/10. ... 004.11.001
https://onlinelibrary.wiley.com/doi/10. ... 004.11.001
Narita N, Kato M, Tazoe M, Miyazaki K, Narita M, Okado N - "Increased monoamine concentration in the brain and blood of fetal rats with valproate-induced autism" Brain Dev 24(7):706-710 (2002) doi:10.1016/S0387-7604(02)00062-6
https://pubmed.ncbi.nlm.nih.gov/12357053/
Schneider T, Przewłocki R - "Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism" Neuropsychopharmacology. 31(1):36-46 (2006) doi:10.1038/sj.npp.1300796
https://www.nature.com/articles/1300518
Shank3
Shank3 is one of the best-characterized genes implicated in ASD. Shank3+/ΔC mutant mice display abnormal social behaviours that mimic ASD-like symptoms. It is a thyroid hormone-regulated gene.
Martinez ME, Stohn JP, Mutina EM, Whitten RJ, Hernandez A - "Thyroid hormone elicits intergenerational epigenetic effects on adult social behavior and fetal brain expression of autism susceptibility genes" Front Neurosci 16:1055116 (2022) doi: 10.3389/fnins.2022.1055116
https://pmc.ncbi.nlm.nih.gov/articles/PMC9676973/
Navarro D, Alvarado M, Navarrete F, Giner M, Obregon MJ, Manzanares J, Berbel P - "Gestational and early postnatal hypothyroidism alters VGluT1 and VGAT bouton distribution in the neocortex and hippocampus, and behavior in rats" Front Neuroanat 9:9 (2015). doi: 10.3389/fnana.2015.00009.
https://www.frontiersin.org/journals/ne ... 00009/full
- Shank3 and Gq/11
Kim Y, Ko TH, Jin C, Zhang Y, Kang HR, Ma R, Li H, Choi JI, Han K - "The emerging roles of Shank3 in cardiac function and dysfunction" Front Cell Dev Biol 11:1191369 (2023) doi: 10.3389/fcell.2023.1191369
https://pmc.ncbi.nlm.nih.gov/articles/PMC10175600/
"Homer1c interacts with PLCβ1b and Shank3 in cardiomyocytes, mediating Gq-induced cardiomyocyte hypertrophy."
Grubb DR, Luo J, Yu YL, Woodcock EA - "Scaffolding protein Homer 1c mediates hypertrophic responses downstream of Gq in cardiomyocytes" FASEB J 26(2):596-603 (2012) doi: 10.1096/fj.11-190330
https://pubmed.ncbi.nlm.nih.gov/22012123/
"Gq-mediated hypertrophy involves activation of PLCβ1b scaffolded onto a Shank3/Homer complex. Signaling downstream of Homer 1c is necessary and sufficient for Gq-initiated hypertrophy."
Creagh O, Torres H, Rivera K, Morales-Franqui M, Altieri-Acevedo G, Warner D - "Previous Exposure to Anesthesia and Autism Spectrum Disorder (ASD): A Puerto Rican Population-Based Sibling Cohort Study" Bol Asoc Med P R 108(2):73-80 (2016)
https://pubmed.ncbi.nlm.nih.gov/29172370/
"Children under early exposure to anesthesia in uterus, first 2 years of life, or later are not more likely to develop neither ASD nor severe form of the disorder."
He S, Zhou F, Tian G, Cui Y, Yan Y - "Effect of Anesthesia During Pregnancy, Delivery, and Childhood on Autism Spectrum Disorder: A Systematic Review and Meta-analysis" J Autism Dev Disord 54(12):4540-4554 (2024) doi: 10.1007/s10803-023-06169-2
https://pubmed.ncbi.nlm.nih.gov/37934394/
"This meta-analysis did not confirm the association between exposure to anesthesia during labour and ASD. Previous observational studies used the neurotoxicity of anesthesia to biologically explain significant associations, but in fact different controls for confounding factors led to differences in associations. The evidence for pregnancy and childhood was limited given the small number of studies in these periods."
Pikwer A, Reutfors J, Norrman S, Johansson S, Meyerson J, Jonsson F, Johansson G - "Autism after general anesthesia in early childhood: a nationwide cohort study" Minerva Anestesiol 89(1-2):22–31 (2023)
doi:10.23736/S0375-9393.22.16088-5
https://www.minervamedica.it/en/journal ... 23N01A0022
"Exposure to general anesthesia in early childhood was associated with an increased risk of autism or autism spectrum disorder. Future studies are needed to asses if general anesthesia may cause autism or if the association is due to other factors."
(No information on agents used)
Gut Dysbiosis
Fang J, Geng R, Kang SG, Huang K, Tong T - "Dietary L-proline supplementation ameliorates autism-like behaviors and modulates gut microbiota in the valproic acid-induced mouse model of autism spectrum disorder" Food Sci Hum Wellness 13(5):2889-2905 (2024) PFPC Library
Zhao Y, Ma S, Liang L, Cao S, Fan Z, He D, Shi X, Zhang Y, Liu B, Zhai M, Wu S, Kuang F, Zhang H - "Gut Microbiota-Metabolite-Brain Axis Reconstitution Reverses Sevoflurane-Induced Social and Synaptic Deficits in Neonatal Mice" Research (Wash D C) 7:0482 (2024) doi: 10.34133/research.0482
https://pmc.ncbi.nlm.nih.gov/articles/PMC11411162/
"The gut microbiota-metabolite-brain axis underlies social dysfunction caused by sevoflurane exposure in early age, and bile acid regulation may be a promising intervention to this impairment."
Han S, Bian R, Chen Y, Liang J, Zhao P, Gu Y, Zhang D - "Dysregulation of the gut microbiota contributes to sevoflurane-induced cognitive dysfunction in aged mice by activating the NLRP3 inflammasome" Molecular Neurobiology 61(12):10500-10516 (2024) doi: 10.1007/s12035-024-04229-x
https://link.springer.com/article/10.10 ... 24-04229-x
NOTE: NLRP3 is regulated by Gq/11
"Compared to those in the control group, sevoflurane significantly increased the expression of NLRP3 inflammasome-associated proteins in the gut and brain in the sevoflurane-exposed group, thus causing neuroinflammation and synaptic damage, which probiotics can mitigate (con vs. sev, P < 0.01; p+sev vs. sev, P < 0.05). "
- SEE: Fluoride and Gut Dysbiosis: viewtopic.php?f=7&t=1850
Lin Zhixuan, Huang San, Huang Yan, Yang Xiaolin - "Effects of different sevoflurane anesthesia concentrations on the concentration of free hexafluoroisopropanol in rat blood" J Nanjing Med Univ (Nat Sci Ed) 42(7):973-977, 982 (2022) PFPC Library
Free HFIP concentration in blood rises early and then falls with prolonged anesthesia. Moderate sevoflurane concentration (≈2.3%) produces the most HFIP, while higher concentrations (≈3.5%) suppress metabolic conversion, indicating dose-dependent metabolic inhibition of sevoflurane in vivo.
Yang Xiaolin, Eger EI II, Sharma M - "Study on the metabolism of sevoflurane in mice" Sichuan Med J 33(11):1884–1886 (2012) PFPC Library
Sevoflurane can be metabolized to HFIP in both mouse liver and brain tissues, but high concentrations of sevoflurane inhibit its own biotransformation - mirroring findings in rats that show reduced HFIP accumulation at higher anesthetic doses.
Ghimenti S, Di Francesco F, Onor M, Stiegel MA, Trivella MG, Comite C, Catania N, Fuoco R, Pleil JD - "Post-operative elimination of sevoflurane anesthetic and hexafluoroisopropanol metabolite in exhaled breath: pharmacokinetic models for assessing liver function" J Breath Res 7(3):036001 (2013). doi: 10.1088/1752-7155/7/3/036001
Ni J, Sato N, Fujii K, Yuge O - "Urinary excretion of hexafluoroisopropanol glucuronide and fluoride in patients after sevoflurane anaesthesia" J Pharm Pharmacol 45(1):67-9 (1993) doi: 10.1111/j.2042-7158.1993.tb03682.x.
https://academic.oup.com/jpp/article-ab ... 67/6163385
"Our study showed that a hexafluoroisopropanol glucuronide is excreted in the urine, and the major part of urinary metabolites of sevoflurane, organic and inorganic fluoride, are excreted within 2 days of sevoflurane inhalation in man."
Keller KA, Callan C, Prokocimer P, Delgado-Herrera L, Friedman MB, Hoffman GM, Wooding WL, Cusick PK, Krasula RW - "Inhalation toxicity study of a haloalkene degradant of sevoflurane, Compound A (PIFE), in Sprague-Dawley rats" Anesthesiology 83(6):1220-32 (1995) doi: 10.1097/00000542-199512000-00013
https://pubmed.ncbi.nlm.nih.gov/8533915/
Sevoflurane is classified as PFAS
Kalmar AF, Groffen T, Vereecke H, Teunkens A, Dewinter G, Mulier H, Struys MRF, Rex S – "Volatile anaesthetics and PFAS forever chemicals: a critical gap in environmental impact assessments" Best Pract Res Clin Anaesthesiol 38(4):342-348 (2024). doi: 10.1016/j.bpa.2024.12.002
https://doi.org/10.1016/j.bpa.2024.12.002
https://www.sciencedirect.com/science/a ... 9625000023
"A median hospital performing 8 h of sevoflurane-based maintenance anaesthesia in each of its 10 operating theatres would contaminate approximately 38 million litres of local municipal water daily to the EU legal PFAS threshold."
Gentz BA, Malan TP Jr - "Renal toxicity with sevoflurane: a storm in a teacup?" Drugs 61(15):2155-62 (2001) doi: 10.2165/00003495-200161150-00001.As written earlier, the EU Drinking Water Directive limit for total PFAS is 0.5 μg/L, including TFA. Considering that most sevoflurane molecules in the atmosphere decay to TFA, one bottle of 250 ml – or 382 g – results in 218 g TFA, which, if diluted to 0.5 μg/L raises 436 million litres water, or 174 Olympic swimming pools, virtually ‘forever’ to the EU toxicity limit [20]. The global consumption of 8 million bottles [27] of sevoflurane in 2022 would, if diluted, require 3.5 × 1015 L of water, or 3,500 cubic kilometres, which corresponds to an area the size of France filled to a depth of 6.3 km.
https://link.springer.com/article/10.21 ... 1150-00001
Fluoride, Compound A (fluoromethyl-2,2-difluoro-l-[trifluoromethyl] vinyl ether), or pentafluoroisopropenyl fluoromethyl ether.
+++++++++++++++++++++++++++++++++++++
See also: Enflurane and Halothane
- Börner U, Klimek M, Schoengen H, Lynch J, Peschau C, Schicha H - "The influence of various anesthetics on the release and metabolism of thyroid hormones: results of two clinical studies" Anesth Analg 81(3):612-8 (1995) doi: 10.1097/00000539-199509000-00034
https://pubmed.ncbi.nlm.nih.gov/7653832/
"An alternative, or additional, explanation could be the effect of enflurane or its metabolites, especially fluoride, on the enzymatic metabolism of the iodothyronines. The intraoperative changes in fT, and rT, levels shown in Study A make potential inhibition of the hepatic Type I deiodinase seem quite likely. "
- Chikenji T, Mizutani M, Kitsukawa Y - "Anaesthesia, not surgical stress, induces increases in serum concentrations of reverse triiodothyronine and thyroxine during surgery" Exp Clin Endocrinol 95(2):217-23 (1990) doi: 10.1055/s-0029-1210955
https://www.thieme-connect.com/products ... 29-1210955
"T4 and rT3 increased markedly when either enflurane or halothane was given but not with the other anaesthetic agents...These results show that the increases in rT3 and T4 during and soon after surgery are due not to surgical trauma but to inhalational anaesthetics such as enflurane and halothane."
Related: LPS
Okano H, Takashima K, Takahashi Y, Ojiro R, Tang Q, Ozawa S, Ogawa B, Koyanagi M, Maronpot RR, Yoshida T, Shibutani M - "Ameliorating effect of continuous alpha-glycosyl isoquercitrin treatment starting from late gestation in a rat autism model induced by postnatal injection of lipopolysaccharides" Chem Biol Interact 351:109767 (2022). doi: 10.1016/j.cbi.2021.109767
https://pubmed.ncbi.nlm.nih.gov/34863679/