台北榮民總醫院醫院評鑑 臺北榮民總醫院耳鼻喉頭頸醫學部 Taipei Veterans General Hospital Otorhinolaryngology-Head & Neck Surgery Soluble Epoxide Hydrolase Inhibition Modulates Gene Expression of Antioxidant Enzymes in Olfactory Bulb after Ischemic Stroke 葉建甫 林永煬 臺北榮民總醫院 耳鼻喉頭頸醫學部 鼻頭頸科 國立陽明大學耳鼻喉科 臺北榮民總醫院 重症醫學部 1

Olfactory dysfunction & ischemic stroke Introduction Olfactory dysfunction & ischemic stroke Cause Head trauma URI CRS Neurological diseases After ischemic stroke 28.2% hyposmia 15.4% anosmia Murphy, C., et al., JAMA, (2002) 288: 2307-12. Wehling et al. BMC Neurology (2015) 15:199

Olfactory dysfunction & ischemic stroke Introduction Olfactory dysfunction & ischemic stroke In tMCAO mice, microglial activation was first seen in the OB and then the ischemic lesion. Excessive microglial activation aggravates olfactory dysfunction. Ischemic stroke → olfactory dysfunction Brain 2009: 132; 940–954 Biochimica et Biophysica Acta 1842 (2014) 2193–2203

Neuroinflammation: activation of microglia Inflammation leads to activation of microglia, the brain’s resident immune cells. (Masahito Kawabori et al., 2015) (Lee, et al., 2014)

Olfactory dysfunction Introduction Olfactory dysfunction

Neuroinflammation: role of sEH Introduction Neuroinflammation: role of sEH Inhibition of soluble epoxide hydrolase (sEH) in MCAO rats induces a neuroprotective phenotype in activated microglia and increases antioxidant. (Yeh, et al., unpublished) Anti-oxidant sEH

Animal model MCAO AUDA (sEH inhibitor) Control Materials & Methods Wistar-Kyoto (WKY) rat, male, 10wk, 200-300g Middle cerebral artery occlusion (MCAO) Intraperitoneal injection Expose bil. CCA→ MCAO → 90 min bil. CCAO MCAO AUDA (sEH inhibitor) 20 mg/kg Control

Behavioral test Materials & Methods 1 days after MCAO Buried food finding test 統計資料 eNeuro 5 June 2017, 4 (3)

Reverse Transcription Quantitative Polymerase Chain Reaction (PCR) Materials & Methods Reverse Transcription Quantitative Polymerase Chain Reaction (PCR) 3 days after MCAO; Zoletil/Xylazine Total RNA extraction from ischemic cortex Reverse-transcribed to cDNA Reverse transcription quantitative PCR

Olfactory function test - Buried food finding test 台北榮民總醫院醫院評鑑 Results Olfactory function test - Buried food finding test

sEH Inhibitor attenuated M1 microglia expression 台北榮民總醫院醫院評鑑 Results sEH Inhibitor attenuated M1 microglia expression

Heme oxygenase-1 (HO-1), increased after sEH inhibitor administration 台北榮民總醫院醫院評鑑 Results Heme oxygenase-1 (HO-1), increased after sEH inhibitor administration HO-1

Olfactory marker protein (OMP) 台北榮民總醫院醫院評鑑 Results Olfactory marker protein (OMP) OMP: a marker of olfactory sensory neuron

After ischemic stroke Olfactory dysfunction M1 microglia activation 台北榮民總醫院醫院評鑑 Discussion After ischemic stroke Olfactory dysfunction M1 microglia activation Increase proinflammatory cytokine ↓ antioxidant HO-1 ↓ OMP

After sEH inhibitor administration 台北榮民總醫院醫院評鑑 Discussion After sEH inhibitor administration M1 microglia activation decreased ↓ antioxidant HO-1 increased ↓ OMP improved

台北榮民總醫院醫院評鑑 Discussion In the future Protein measurement

台北榮民總醫院醫院評鑑 Conclusion Soluble epoxide hydrolase inhibition modulates gene expression of antioxidant enzymes in olfactory bulb after ischemic stroke

台北榮民總醫院醫院評鑑 葉建甫醫師 臺北榮民總醫院 鼻頭頸科 主治醫師 陽明大學醫學系 講師 rihney@hotmail.com 放個圖