TY - JOUR
T1 - Soluble epoxide hydrolase inhibition attenuates MPTP-induced neurotoxicity in the nigrostriatal dopaminergic system
T2 - Involvement of α-synuclein aggregation and er stress
AU - Huang, Hui Ju
AU - Wang, Yi Ting
AU - Lin, Hui Ching
AU - Lee, Yi Hsuan
AU - Lin, Anya Maan Yuh
N1 - Publisher Copyright:
© Springer Science+Business Media, LLC 2017.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - Soluble epoxide hydrolase (sEH) is widely expressed in the mammalian brain and possesses dual enzymatic activities, including C-terminal epoxide hydrolase (C-EH) which degrades epoxyeicosatrienoic acid (EET), a beneficial arachidonic acid metabolite. In the present study, the neuroprotective effect of sEH inhibition on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurodegeneration of nigrostriatal dopaminergic system was investigated using genetic and pharmacological approaches. MPTP (15 mg/kg) was intraperitoneally injected in sEH knockout (KO) mice and C57BL/6J mice as wild-type (WT) mice. Compared with the MPTP-treated WT mice, MPTP-induced reductions in striatal dopamine content and nigral tyrosine hydroxylase level (TH, a biomarker of dopaminergic neurons) were less significant in the treated sEH mice. Furthermore, MPTP-induced HO-1 elevation (a redoxregulated protein), α-synuclein aggregation, and caspase 12 activation (a hallmark of ER stress) were less prominent in sEH KO mice than in WT mice. These data indicate that sEH KO mice are more resistant to MPTP-induced neurotoxicity. The pharmacological effect of N-[1-(1-oxopropyl)-4-piperidinyl]- N0-[4-(trifluoromethoxy)phenyl)-urea (TPPU, an sEH inhibitor) on MPTP-induced neurotoxicity was investigated in WT mice. TPPU (1 mg/kg, i.p.) attenuated MPTP-induced reduction in striatal dopamine content, TH-positive cell numbers, TH, and pro-caspase 9 protein levels (an initiator caspase of apoptosis) in mouse SN. Moreover, TPPU reduced MPTP-induced HO-1 elevation, α-synuclein aggregation and caspase 12 activation, indicating that TPPU is effective in attenuating MPTP-induced oxidative stress, apoptosis, protein aggregation, and ER stress. In conclusion, our study suggests that sEH is a potential target for developing therapies for parkinsonism. Furthermore, sEH inhibitors may be of clinical significance for treating CNS neurodegenerative diseases.
AB - Soluble epoxide hydrolase (sEH) is widely expressed in the mammalian brain and possesses dual enzymatic activities, including C-terminal epoxide hydrolase (C-EH) which degrades epoxyeicosatrienoic acid (EET), a beneficial arachidonic acid metabolite. In the present study, the neuroprotective effect of sEH inhibition on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurodegeneration of nigrostriatal dopaminergic system was investigated using genetic and pharmacological approaches. MPTP (15 mg/kg) was intraperitoneally injected in sEH knockout (KO) mice and C57BL/6J mice as wild-type (WT) mice. Compared with the MPTP-treated WT mice, MPTP-induced reductions in striatal dopamine content and nigral tyrosine hydroxylase level (TH, a biomarker of dopaminergic neurons) were less significant in the treated sEH mice. Furthermore, MPTP-induced HO-1 elevation (a redoxregulated protein), α-synuclein aggregation, and caspase 12 activation (a hallmark of ER stress) were less prominent in sEH KO mice than in WT mice. These data indicate that sEH KO mice are more resistant to MPTP-induced neurotoxicity. The pharmacological effect of N-[1-(1-oxopropyl)-4-piperidinyl]- N0-[4-(trifluoromethoxy)phenyl)-urea (TPPU, an sEH inhibitor) on MPTP-induced neurotoxicity was investigated in WT mice. TPPU (1 mg/kg, i.p.) attenuated MPTP-induced reduction in striatal dopamine content, TH-positive cell numbers, TH, and pro-caspase 9 protein levels (an initiator caspase of apoptosis) in mouse SN. Moreover, TPPU reduced MPTP-induced HO-1 elevation, α-synuclein aggregation and caspase 12 activation, indicating that TPPU is effective in attenuating MPTP-induced oxidative stress, apoptosis, protein aggregation, and ER stress. In conclusion, our study suggests that sEH is a potential target for developing therapies for parkinsonism. Furthermore, sEH inhibitors may be of clinical significance for treating CNS neurodegenerative diseases.
KW - ER stress
KW - Oxidative stress
KW - Parkinsonism
KW - Soluble epoxide hydroxylase
KW - TPPU
KW - sEH KOmice
KW - α-Synuclein aggregation
UR - http://www.scopus.com/inward/record.url?scp=85027731385&partnerID=8YFLogxK
U2 - 10.1007/s12035-017-0726-9
DO - 10.1007/s12035-017-0726-9
M3 - Article
C2 - 28822080
AN - SCOPUS:85027731385
SN - 0893-7648
VL - 55
SP - 138
EP - 144
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 1
ER -