Inhibition of the microglial response is essential for the neuroprotective effects of Rho-kinase inhibitors on MPTP-induced dopaminergic cell death
Several recent studies have shown that activation of the RhoA/Rho-associated kinase (ROCK) pathway is involved in the MPTP-induced dopaminergic cell degeneration and possibly in Parkinson's disease. ROCK inhibitors have been suggested as candidate neuroprotective drugs for Parkinson's dise...
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| creator | Borrajo, Ana Rodriguez-Perez, Ana I. Villar-Cheda, Begoña Guerra, Maria J. Labandeira-Garcia, Jose L. |
| description | Several recent studies have shown that activation of the RhoA/Rho-associated kinase (ROCK) pathway is involved in the MPTP-induced dopaminergic cell degeneration and possibly in Parkinson's disease. ROCK inhibitors have been suggested as candidate neuroprotective drugs for Parkinson's disease. However, the mechanism responsible for the increased survival of dopaminergic neurons after treatment with ROCK inhibitors is not clear. We exposed primary (neuron-glia) mesencephalic cultures, cultures of the MES 23.5 dopaminergic neuron cell line and primary mesencephalic cultures lacking microglial cells to the dopaminergic neurotoxin MPP+ and the ROCK inhibitor Y-27632 in order to study the effects of ROCK inhibition on dopaminergic cell loss and the length of neurites of surviving dopaminergic neurons. In primary (neuron-glia) cultures, simultaneous treatment with MPP+ and the ROCK inhibitor significantly reduced the loss of dopaminergic neurons. In the absence of microglia, treatment with the ROCK inhibitor did not induce a significant reduction in the dopaminergic cell loss. Treatment with the ROCK inhibitor induced a significant decrease in axonal retraction in primary cultures with and without microglia and in cultures of the MES 23.5 neuron cell line. In conclusion, inhibition of microglial ROCK is essential for the neuroprotective effects of ROCK inhibitors against cell death induced by the dopaminergic neurotoxin MPP+. In addition, ROCK inhibition induced a direct effect against axonal retraction in surviving neurons. However, the latter effect was not sufficient to cause a significant increase in the survival of dopaminergic neurons after treatment with MPP+.
•Rho-kinase (ROCK) inhibitors may provide neuroprotection against Parkinson's disease.•ROCK inhibitors are currently used in clinical practice to treat vascular diseases.•Inhibition of microglial Rho-kinase activity is essential for survival of neurons.•Direct effect of inhibitors on neurons decreases axonal retraction in surviving cells. |
| doi_str_mv | 10.1016/j.neuropharm.2014.05.021 |
| format | Article |
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•Rho-kinase (ROCK) inhibitors may provide neuroprotection against Parkinson's disease.•ROCK inhibitors are currently used in clinical practice to treat vascular diseases.•Inhibition of microglial Rho-kinase activity is essential for survival of neurons.•Direct effect of inhibitors on neurons decreases axonal retraction in surviving cells.</description><identifier>ISSN: 0028-3908</identifier><identifier>EISSN: 1873-7064</identifier><identifier>DOI: 10.1016/j.neuropharm.2014.05.021</identifier><identifier>PMID: 24878243</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Amides - pharmacology ; Animals ; Axons - drug effects ; Axons - pathology ; Axons - physiology ; Cell Culture Techniques ; Cell Death - drug effects ; Cell Death - physiology ; Cell Line, Tumor ; Cells, Cultured ; Dopamine ; Dopaminergic Neurons - drug effects ; Dopaminergic Neurons - pathology ; Dopaminergic Neurons - physiology ; Mesencephalon - drug effects ; Mesencephalon - pathology ; Mesencephalon - physiopathology ; Microglia ; Microglia - drug effects ; Microglia - enzymology ; MPTP Poisoning - drug therapy ; MPTP Poisoning - pathology ; MPTP Poisoning - physiopathology ; Neurites - drug effects ; Neurites - pathology ; Neurites - physiology ; Neuroinflammation ; Neuroprotection ; Neuroprotective Agents - pharmacology ; Parkinson ; Pyridines - pharmacology ; Rats ; Rho ; rho-Associated Kinases - antagonists & inhibitors ; rho-Associated Kinases - metabolism</subject><ispartof>Neuropharmacology, 2014-10, Vol.85, p.1-8</ispartof><rights>2014 Elsevier Ltd</rights><rights>Copyright © 2014 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c473t-fec5d526787520bdae1e60a87c739c09d0fa3485826ac41bbed07b4129a27e533</citedby><cites>FETCH-LOGICAL-c473t-fec5d526787520bdae1e60a87c739c09d0fa3485826ac41bbed07b4129a27e533</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.neuropharm.2014.05.021$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24878243$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Borrajo, Ana</creatorcontrib><creatorcontrib>Rodriguez-Perez, Ana I.</creatorcontrib><creatorcontrib>Villar-Cheda, Begoña</creatorcontrib><creatorcontrib>Guerra, Maria J.</creatorcontrib><creatorcontrib>Labandeira-Garcia, Jose L.</creatorcontrib><title>Inhibition of the microglial response is essential for the neuroprotective effects of Rho-kinase inhibitors on MPTP-induced dopaminergic cell death</title><title>Neuropharmacology</title><addtitle>Neuropharmacology</addtitle><description>Several recent studies have shown that activation of the RhoA/Rho-associated kinase (ROCK) pathway is involved in the MPTP-induced dopaminergic cell degeneration and possibly in Parkinson's disease. ROCK inhibitors have been suggested as candidate neuroprotective drugs for Parkinson's disease. However, the mechanism responsible for the increased survival of dopaminergic neurons after treatment with ROCK inhibitors is not clear. We exposed primary (neuron-glia) mesencephalic cultures, cultures of the MES 23.5 dopaminergic neuron cell line and primary mesencephalic cultures lacking microglial cells to the dopaminergic neurotoxin MPP+ and the ROCK inhibitor Y-27632 in order to study the effects of ROCK inhibition on dopaminergic cell loss and the length of neurites of surviving dopaminergic neurons. In primary (neuron-glia) cultures, simultaneous treatment with MPP+ and the ROCK inhibitor significantly reduced the loss of dopaminergic neurons. In the absence of microglia, treatment with the ROCK inhibitor did not induce a significant reduction in the dopaminergic cell loss. Treatment with the ROCK inhibitor induced a significant decrease in axonal retraction in primary cultures with and without microglia and in cultures of the MES 23.5 neuron cell line. In conclusion, inhibition of microglial ROCK is essential for the neuroprotective effects of ROCK inhibitors against cell death induced by the dopaminergic neurotoxin MPP+. In addition, ROCK inhibition induced a direct effect against axonal retraction in surviving neurons. However, the latter effect was not sufficient to cause a significant increase in the survival of dopaminergic neurons after treatment with MPP+.
•Rho-kinase (ROCK) inhibitors may provide neuroprotection against Parkinson's disease.•ROCK inhibitors are currently used in clinical practice to treat vascular diseases.•Inhibition of microglial Rho-kinase activity is essential for survival of neurons.•Direct effect of inhibitors on neurons decreases axonal retraction in surviving cells.</description><subject>Amides - pharmacology</subject><subject>Animals</subject><subject>Axons - drug effects</subject><subject>Axons - pathology</subject><subject>Axons - physiology</subject><subject>Cell Culture Techniques</subject><subject>Cell Death - drug effects</subject><subject>Cell Death - physiology</subject><subject>Cell Line, Tumor</subject><subject>Cells, Cultured</subject><subject>Dopamine</subject><subject>Dopaminergic Neurons - drug effects</subject><subject>Dopaminergic Neurons - pathology</subject><subject>Dopaminergic Neurons - physiology</subject><subject>Mesencephalon - drug effects</subject><subject>Mesencephalon - pathology</subject><subject>Mesencephalon - physiopathology</subject><subject>Microglia</subject><subject>Microglia - drug effects</subject><subject>Microglia - enzymology</subject><subject>MPTP Poisoning - drug therapy</subject><subject>MPTP Poisoning - pathology</subject><subject>MPTP Poisoning - physiopathology</subject><subject>Neurites - drug effects</subject><subject>Neurites - pathology</subject><subject>Neurites - physiology</subject><subject>Neuroinflammation</subject><subject>Neuroprotection</subject><subject>Neuroprotective Agents - pharmacology</subject><subject>Parkinson</subject><subject>Pyridines - pharmacology</subject><subject>Rats</subject><subject>Rho</subject><subject>rho-Associated Kinases - antagonists & inhibitors</subject><subject>rho-Associated Kinases - metabolism</subject><issn>0028-3908</issn><issn>1873-7064</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1u1TAQhS0EopeWV0Beskk6dn7su4QK2kpFVKhdW449aXxJ7IudVOI5eGGcpsCSlS37mzkz5xBCGZQMWHt-KD0uMRwHHaeSA6tLaErg7AXZMSmqQkBbvyQ7AC6Lag_yhLxJ6QAAtWTyNTnhtRSS19WO_Lr2g-vc7IKnoafzgHRyJoaH0emRRkzH4BNSlyimhH5eX_sQn8BthhhmNLN7RIp9n29p7fNtCMV35_VaugmEmD88_XJ7d1s4bxeDltpw1JPzGB-coQbHkVrU83BGXvV6TPj2-Twl958_3V1cFTdfL68vPtwUphbVXGSxxja8FVI0HDqrkWELWgojqr2BvYVeV7VsJG-1qVnXoQXR1YzvNRfYVNUpeb_1zTv8WDDNanJpHUN7DEtSrGkh09m1jMoNzdakFLFXx-gmHX8qBmqNRB3Uv0jUGomCRuVIcum7Z5Wlm9D-LfyTQQY-bgDmXR8dRpWMQ58NcjH7qWxw_1f5DX12pcs</recordid><startdate>20141001</startdate><enddate>20141001</enddate><creator>Borrajo, Ana</creator><creator>Rodriguez-Perez, Ana I.</creator><creator>Villar-Cheda, Begoña</creator><creator>Guerra, Maria J.</creator><creator>Labandeira-Garcia, Jose L.</creator><general>Elsevier Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope></search><sort><creationdate>20141001</creationdate><title>Inhibition of the microglial response is essential for the neuroprotective effects of Rho-kinase inhibitors on MPTP-induced dopaminergic cell death</title><author>Borrajo, Ana ; Rodriguez-Perez, Ana I. ; Villar-Cheda, Begoña ; Guerra, Maria J. ; Labandeira-Garcia, Jose L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c473t-fec5d526787520bdae1e60a87c739c09d0fa3485826ac41bbed07b4129a27e533</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Amides - pharmacology</topic><topic>Animals</topic><topic>Axons - drug effects</topic><topic>Axons - pathology</topic><topic>Axons - physiology</topic><topic>Cell Culture Techniques</topic><topic>Cell Death - drug effects</topic><topic>Cell Death - physiology</topic><topic>Cell Line, Tumor</topic><topic>Cells, Cultured</topic><topic>Dopamine</topic><topic>Dopaminergic Neurons - drug effects</topic><topic>Dopaminergic Neurons - pathology</topic><topic>Dopaminergic Neurons - physiology</topic><topic>Mesencephalon - drug effects</topic><topic>Mesencephalon - pathology</topic><topic>Mesencephalon - physiopathology</topic><topic>Microglia</topic><topic>Microglia - drug effects</topic><topic>Microglia - enzymology</topic><topic>MPTP Poisoning - drug therapy</topic><topic>MPTP Poisoning - pathology</topic><topic>MPTP Poisoning - physiopathology</topic><topic>Neurites - drug effects</topic><topic>Neurites - pathology</topic><topic>Neurites - physiology</topic><topic>Neuroinflammation</topic><topic>Neuroprotection</topic><topic>Neuroprotective Agents - pharmacology</topic><topic>Parkinson</topic><topic>Pyridines - pharmacology</topic><topic>Rats</topic><topic>Rho</topic><topic>rho-Associated Kinases - antagonists & inhibitors</topic><topic>rho-Associated Kinases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Borrajo, Ana</creatorcontrib><creatorcontrib>Rodriguez-Perez, Ana I.</creatorcontrib><creatorcontrib>Villar-Cheda, Begoña</creatorcontrib><creatorcontrib>Guerra, Maria J.</creatorcontrib><creatorcontrib>Labandeira-Garcia, Jose L.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><jtitle>Neuropharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Borrajo, Ana</au><au>Rodriguez-Perez, Ana I.</au><au>Villar-Cheda, Begoña</au><au>Guerra, Maria J.</au><au>Labandeira-Garcia, Jose L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of the microglial response is essential for the neuroprotective effects of Rho-kinase inhibitors on MPTP-induced dopaminergic cell death</atitle><jtitle>Neuropharmacology</jtitle><addtitle>Neuropharmacology</addtitle><date>2014-10-01</date><risdate>2014</risdate><volume>85</volume><spage>1</spage><epage>8</epage><pages>1-8</pages><issn>0028-3908</issn><eissn>1873-7064</eissn><abstract>Several recent studies have shown that activation of the RhoA/Rho-associated kinase (ROCK) pathway is involved in the MPTP-induced dopaminergic cell degeneration and possibly in Parkinson's disease. ROCK inhibitors have been suggested as candidate neuroprotective drugs for Parkinson's disease. However, the mechanism responsible for the increased survival of dopaminergic neurons after treatment with ROCK inhibitors is not clear. We exposed primary (neuron-glia) mesencephalic cultures, cultures of the MES 23.5 dopaminergic neuron cell line and primary mesencephalic cultures lacking microglial cells to the dopaminergic neurotoxin MPP+ and the ROCK inhibitor Y-27632 in order to study the effects of ROCK inhibition on dopaminergic cell loss and the length of neurites of surviving dopaminergic neurons. In primary (neuron-glia) cultures, simultaneous treatment with MPP+ and the ROCK inhibitor significantly reduced the loss of dopaminergic neurons. In the absence of microglia, treatment with the ROCK inhibitor did not induce a significant reduction in the dopaminergic cell loss. Treatment with the ROCK inhibitor induced a significant decrease in axonal retraction in primary cultures with and without microglia and in cultures of the MES 23.5 neuron cell line. In conclusion, inhibition of microglial ROCK is essential for the neuroprotective effects of ROCK inhibitors against cell death induced by the dopaminergic neurotoxin MPP+. In addition, ROCK inhibition induced a direct effect against axonal retraction in surviving neurons. However, the latter effect was not sufficient to cause a significant increase in the survival of dopaminergic neurons after treatment with MPP+.
•Rho-kinase (ROCK) inhibitors may provide neuroprotection against Parkinson's disease.•ROCK inhibitors are currently used in clinical practice to treat vascular diseases.•Inhibition of microglial Rho-kinase activity is essential for survival of neurons.•Direct effect of inhibitors on neurons decreases axonal retraction in surviving cells.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>24878243</pmid><doi>10.1016/j.neuropharm.2014.05.021</doi><tpages>8</tpages></addata></record> |
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| subjects | Amides - pharmacology Animals Axons - drug effects Axons - pathology Axons - physiology Cell Culture Techniques Cell Death - drug effects Cell Death - physiology Cell Line, Tumor Cells, Cultured Dopamine Dopaminergic Neurons - drug effects Dopaminergic Neurons - pathology Dopaminergic Neurons - physiology Mesencephalon - drug effects Mesencephalon - pathology Mesencephalon - physiopathology Microglia Microglia - drug effects Microglia - enzymology MPTP Poisoning - drug therapy MPTP Poisoning - pathology MPTP Poisoning - physiopathology Neurites - drug effects Neurites - pathology Neurites - physiology Neuroinflammation Neuroprotection Neuroprotective Agents - pharmacology Parkinson Pyridines - pharmacology Rats Rho rho-Associated Kinases - antagonists & inhibitors rho-Associated Kinases - metabolism |
| title | Inhibition of the microglial response is essential for the neuroprotective effects of Rho-kinase inhibitors on MPTP-induced dopaminergic cell death |
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