PMID- 31852909 OWN - NLM STAT- MEDLINE DCOM- 20201106 LR - 20210110 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 9 IP - 1 DP - 2019 Dec 18 TI - Focused ultrasound enhanced intranasal delivery of brain derived neurotrophic factor produces neurorestorative effects in a Parkinson's disease mouse model. PG - 19402 LID - 10.1038/s41598-019-55294-5 [doi] LID - 19402 AB - Focused ultrasound-enhanced intranasal (IN + FUS) delivery is a noninvasive approach that utilizes the olfactory pathway to administer pharmacological agents directly to the brain, allowing for a more homogenous distribution in targeted locations compared to IN delivery alone. However, whether such a strategy has therapeutic values, especially in neurodegenerative disorders such as Parkinson's disease (PD), remains to be established. Herein, we evaluated whether the expression of tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine catalysis, could be enhanced by IN + FUS delivery of brain-derived neurotrophic factor (BDNF) in a toxin-based PD mouse model. Mice were put on the subacute dosing regimen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), producing bilateral degeneration of the nigrostriatal pathway consistent with early-stage PD. MPTP mice then received BDNF intranasally followed by multiple unilateral FUS-induced blood-brain barrier (BBB) openings in the left basal ganglia for three consecutive weeks. Subsequently, mice were survived for two months and were evaluated morphologically and behaviorally to determine the integrity of their nigrostriatal dopaminergic pathways. Mice receiving IN + FUS had significantly increased TH immunoreactivity in the treated hemisphere compared to the untreated hemisphere while mice receiving only FUS-induced BBB opening or no treatment at all did not show any differences. Additionally, behavioral changes were only observed in the IN + FUS treated mice, indicating improved motor control function in the treated hemisphere. These findings demonstrate the robustness of the method and potential of IN + FUS for the delivery of bioactive factors for treatment of neurodegenerative disorder. FAU - Ji, Robin AU - Ji R AUID- ORCID: 0000-0003-1361-141X AD - Department of Biomedical Engineering, Columbia University, New York, New York, USA. FAU - Smith, Morgan AU - Smith M AD - Department of Biomedical Engineering, Columbia University, New York, New York, USA. FAU - Niimi, Yusuke AU - Niimi Y AD - Department of Biomedical Engineering, Columbia University, New York, New York, USA. FAU - Karakatsani, Maria E AU - Karakatsani ME AUID- ORCID: 0000-0002-8368-1360 AD - Department of Biomedical Engineering, Columbia University, New York, New York, USA. FAU - Murillo, Maria F AU - Murillo MF AD - Department of Biomedical Engineering, Columbia University, New York, New York, USA. FAU - Jackson-Lewis, Vernice AU - Jackson-Lewis V AD - Department of Pathology & Cell Biology, Columbia University, New York, New York, USA. AD - Department of the Center for Motor Neuron Biology and Disease, Columbia University, New York, New York, USA. AD - Department of the Columbia Translational Neuroscience Initiative, Columbia University, New York, New York, USA. FAU - Przedborski, Serge AU - Przedborski S AD - Department of Pathology & Cell Biology, Columbia University, New York, New York, USA. AD - Department of Neurology, Columbia University, New York, New York, USA. AD - Department of the Center for Motor Neuron Biology and Disease, Columbia University, New York, New York, USA. AD - Department of the Columbia Translational Neuroscience Initiative, Columbia University, New York, New York, USA. FAU - Konofagou, Elisa E AU - Konofagou EE AD - Department of Biomedical Engineering, Columbia University, New York, New York, USA. ek2191@columbia.edu. AD - Department of Radiology, Columbia University, New York, New York, USA. ek2191@columbia.edu. LA - eng GR - R21 EB021103/EB/NIBIB NIH HHS/United States GR - R01 AG038961/AG/NIA NIH HHS/United States GR - R01 EB009041/EB/NIBIB NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20191218 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (Bdnf protein, mouse) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Neuroprotective Agents) RN - 9P21XSP91P (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine) RN - EC 1.14.16.2 (Tyrosine 3-Monooxygenase) RN - VTD58H1Z2X (Dopamine) SB - IM MH - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/adverse effects MH - Administration, Intranasal MH - Animals MH - Basal Ganglia/drug effects/pathology/radiation effects MH - Blood-Brain Barrier/diagnostic imaging/drug effects/radiation effects MH - Brain/drug effects/pathology/radiation effects MH - Brain-Derived Neurotrophic Factor/*pharmacology MH - Corpus Striatum/diagnostic imaging/drug effects/radiation effects MH - Disease Models, Animal MH - Dopamine/biosynthesis/*genetics MH - Humans MH - Mice MH - Neuroprotective Agents/pharmacology MH - Parkinson Disease/genetics/pathology/*therapy MH - Parkinson Disease, Secondary/chemically induced/genetics/pathology/*therapy MH - Substantia Nigra/diagnostic imaging/drug effects/radiation effects MH - Tyrosine 3-Monooxygenase/*genetics MH - Ultrasonic Waves PMC - PMC6920380 COIS- The authors declare no competing interests. EDAT- 2019/12/20 06:00 MHDA- 2020/11/11 06:00 PMCR- 2019/12/18 CRDT- 2019/12/20 06:00 PHST- 2019/08/21 00:00 [received] PHST- 2019/11/26 00:00 [accepted] PHST- 2019/12/20 06:00 [entrez] PHST- 2019/12/20 06:00 [pubmed] PHST- 2020/11/11 06:00 [medline] PHST- 2019/12/18 00:00 [pmc-release] AID - 10.1038/s41598-019-55294-5 [pii] AID - 55294 [pii] AID - 10.1038/s41598-019-55294-5 [doi] PST - epublish SO - Sci Rep. 2019 Dec 18;9(1):19402. doi: 10.1038/s41598-019-55294-5.