title: Neuroprotective Effects of Antidepressants via Upregulation of Neurotrophic Factors in the MPTP Model of Parkinson's Disease.
abstract: Neurotrophic factors are essential for neuronal survival, plasticity, and development and have been implicated in the action mechanism of antidepressants. In this study, we assessed the neurotrophic factor-inducing and neuroprotective properties of antidepressants. In the first part of the study, we found that fluoxetine, imipramine, and milnacipran (i.p., 20 mg/kg/day for 1 week or 3 weeks) upregulated brain-derived neurotrophic factor in the striatum and substantia nigra both at 1 week and 3 weeks. In contrast, an increase in the glial-derived neurotrophic factor was more obvious at 3 weeks after the antidepressants treatment. Specifically, it was found that fluoxetine and imipramine are more potent in raising the levels of neurotrophic factors than milnacipran. Furthermore, antidepressants elevated the phosphorylation of extracellular signal-regulated-protein kinase (ERK1/2) and the serine/threonine kinase Akt. In the second part of the study, we compared the neuroprotective effects of fluoxetine, imipramine, and milnacipran in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. Pretreament with fluoxetine, imipramine or milnacipran for 3 weeks reduced MPTP-induced dopaminergic neurodegeneration and microglial activation in the nigrostriatal pathway. Neurochemical analysis by HPLC exhibited that antidepressants attenuated the depletion of striatal dopamine. In consistent, beam test showed that behavioral impairment was ameliorated by antidepressants. Neuroprotective effects were more prominent in the fluoxetine or imipramine treatment group than in milnacipran treatment group. Finally, we found that neuroprotection of the antidepressants against 1-methyl-4-phenylpyridinium neurotoxicity in SH-SY5Y cells was attenuated by ERK or Akt inhibitor. These results indicate that neuroprotection by antidepressants might be associated with the induction of neurotrophic factors, and antidepressant could be a potential therapeutic intervention for treatment of Parkinson's disease.
authors.affiliation: College of Pharmacy, Yeungnam University, 280 Daehak-ro, Gyeongsan, Gyeongbuk, 38541, Republic of Korea.
authors.forename: Sina
authors.initials: S
authors.lastname: Shadfar
authors.affiliation: College of Pharmacy, Keimyung University, 1095 Dalgubeol-daero, Daegu, 42601, Republic of Korea.
authors.forename: Yu-Gyeong
authors.initials: YG
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Yeungnam University, 280 Daehak-ro, Gyeongsan, Gyeongbuk, 38541, Republic of Korea.
authors.forename: Nikita
authors.initials: N
authors.lastname: Katila
authors.affiliation: College of Pharmacy, Yeungnam University, 280 Daehak-ro, Gyeongsan, Gyeongbuk, 38541, Republic of Korea.
authors.forename: Sabita
authors.initials: S
authors.lastname: Neupane
authors.affiliation: College of Pharmacy, Yeungnam University, 280 Daehak-ro, Gyeongsan, Gyeongbuk, 38541, Republic of Korea.
authors.forename: Uttam
authors.initials: U
authors.lastname: Ojha
authors.affiliation: College of Pharmacy, Yeungnam University, 280 Daehak-ro, Gyeongsan, Gyeongbuk, 38541, Republic of Korea.
authors.forename: Sunil
authors.initials: S
authors.lastname: Bhurtel
authors.affiliation: College of Pharmacy, Yeungnam University, 280 Daehak-ro, Gyeongsan, Gyeongbuk, 38541, Republic of Korea.
authors.forename: Sunil
authors.initials: S
authors.lastname: Srivastav
authors.affiliation: College of Pharmacy, Keimyung University, 1095 Dalgubeol-daero, Daegu, 42601, Republic of Korea.
authors.forename: Gil-Saeng
authors.initials: GS
authors.lastname: Jeong
authors.affiliation: College of Pharmacy, Yeungnam University, 280 Daehak-ro, Gyeongsan, Gyeongbuk, 38541, Republic of Korea.
authors.forename: Pil-Hoon
authors.initials: PH
authors.lastname: Park
authors.affiliation: College of Pharmacy, Chungbuk National University, 1 Chungdae-ro, Seowon-gu, Cheongju, Chungbuk, 28644, Republic of Korea.
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
authors.affiliation: College of Pharmacy, Yeungnam University, 280 Daehak-ro, Gyeongsan, Gyeongbuk, 38541, Republic of Korea. dychoi@yu.ac.kr.
authors.forename: Dong-Young
authors.initials: DY
authors.lastname: Choi
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009414:Nerve Growth Factors / Q000378:metabolism*; D000066829:Neuroprotection / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000928:Antidepressive Agents; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D051057:Proto-Oncogene Proteins c-akt
keywords: Antidepressants; BDNF; GDNF; MPTP; Parkinson’s disease