title: Effects of sevoflurane on leucine-rich repeat kinase 2-associated Drosophila model of Parkinson's disease.
abstract: Patients with Parkinson's disease (PD) often require surgery, and therefore may receive inhalation anesthesia. However, it is currently unknown whether inhalation anesthetics affect the prognosis of the disease. Leucine‑rich repeat kinase 2 (LRRK2) genetic mutations are the most common cause of familial PD, contributing to ~39% of all cases in certain populations. The aim of the present study was to determine the effects of inhaled anesthetics on PD, by observing the influence of sevoflurane on a LRRK2‑associated Drosophila model of PD. PD transgenic Drosophila overexpressing LRRK2 were generated by crossing flies expressing an LRRK2 upstream activation sequence, with tyrosine hydroxylase (TH)‑Gal4 flies. Western blot analysis successfully verified that the transgenic Drosophila overexpressed LRRK2. Three days prior to eclosion, three genotypes of Drosophila were divided into four groups, and were exposed to air, 1, 2, or 3% sevoflurane, for 5 hours. Twenty‑four hours after the exposure, the electrophysiological activities of the projection neurons (PN) in the brains of the Drosophila were recorded using a patch clamp. The locomotor activities were tested on days 5, 10, 15, 20, 25, 30, 35 and 40 following eclosion. The frequency of miniature excitatory synaptic currents (mEPSCs) obtained from the PNs of the TH‑wild type LRRK2 (TH‑WT) Drosophila brain, following exposure to air (1.60±0.05 Hz), was lower as compared with the wild type LRRK2 (WT) (2.51±0.07 Hz) and W1118 (2.41±0.10 Hz) Drosophila. After exposure to 1, 2 and 3% sevoflurane, the frequency of mEPSCs in the brains of the TH‑WT group decreased to 0.82±0.04 Hz, 0.63±0.16 Hz and 0.55±0.04 Hz, respectively. The percentage decrease of the frequency of mEPSCs, from exposure to air to 1% sevoflurane, of the TH‑WT group (48.32%±3.08%) was significantly higher, as compared with the WT (39.17%±1.42%) and W1118 (35.10%±2.66%) groups, and there was no statistical difference between the WT and W1118 groups. The transgenic TH‑WT Drosophila presented an early decrease in locomotor ability, as compared with the WT and W1118 groups. Following a 5 hour exposure to sevoflurane, the percentage decrease of the climbing abilities of the TH‑WT group, from exposure to air to 1% sevoflurane, were significantly lower, as compared with the WT and W1118 groups. In conclusion, sevoflurane had negative effects on the control W1118 flies, and also severely aggravated the prognosis of PD in the LRRK2‑associated Drosophila model, through synaptic cholinergic deficits and impairment on locomotor abilities.
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Shan
authors.affiliation: Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Song
authors.initials: S
authors.lastname: Cai
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Liting
authors.initials: L
authors.lastname: Kuang
authors.affiliation: Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Xiu
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wen
authors.affiliation: Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Huaiyu
authors.initials: H
authors.lastname: Gu
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Kangqing
authors.initials: K
authors.lastname: Xu
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism*; D015870:Gene Expression; D005838:Genotype; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D008297:Male; D008738:Methyl Ethers / Q000494:pharmacology*; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D000077149:Sevoflurane; D055366:Synaptic Potentials / Q000187:drug effects / Q000235:genetics
chemical_list: D018685:Anesthetics, Inhalation; D029721:Drosophila Proteins; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008738:Methyl Ethers; D017346:Protein Serine-Threonine Kinases; D000077149:Sevoflurane; C543697:LRRK protein, Drosophila