Protective Effects of a synthetic glycosaminoglycan mimetic (OTR4132) in a rat immunotoxic lesion model of septohippocampal cholinergic degeneration
Using a partial hippocampal cholinergic denervation model, we assessed the effects of the RGTA ® named OTR4132, a synthetic heparan-mimetic biopolymer with neuroprotective/neurotrophic properties. Long-Evans male rats were injected with the cholinergic immunotoxin 192 IgG-saporin into the medial sep...
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| Veröffentlicht in: | Glycoconjugate journal 2022-02, Vol.39 (1), p.107-130 |
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| creator | Pereira, Patricia Marques Papy-Garcia, Dulce Barritault, Denis Chiappini, Franck Jackisch, Rolf Schimchowitsch, Sarah Cassel, Jean-Christophe |
| description | Using a partial hippocampal cholinergic denervation model, we assessed the effects of the RGTA
®
named OTR4132, a synthetic heparan-mimetic biopolymer with neuroprotective/neurotrophic properties. Long-Evans male rats were injected with the cholinergic immunotoxin 192 IgG-saporin into the medial septum/diagonal band of Broca (0.37 µg); vehicle injections served as controls. Immediately after surgery, OTR4132 was injected into the lateral ventricles (0.25 µg/5 µl/rat) or intramuscularly (1.5 mg/kg). To determine whether OTR4132 reached the lesion site, some rats received intracerebroventricular (ICV) or intramuscular (I.M.) injections of fluorescent OTR4132. Rats were sacrificed at 4, 10, 20, or 60 days post-lesion (DPL). Fluorescein-labeled OTR4132 injected ICV or I.M. was found in the lesion from 4 to 20 DPL. Rats with partial hippocampal cholinergic denervation showed decreases in hippocampal acetylcholinesterase reaction products and in choline acetyltransferase-positive neurons in the medial septum. These lesions were the largest at 10 DPL and then remained stable until 60 DPL. Both hippocampal acetylcholinesterase reaction products and choline acetyltransferase-positive neurons in the medial septum effects were significantly attenuated in OTR4132-treated rats. These effects were not related to competition between OTR4132 and 192 IgG-saporin for the neurotrophin receptor P75 (p75
NTR
), as OTR4132 treatment did not alter the internalization of Cy3-labelled 192 IgG. OTR4132 was more efficient at reducing the acetylcholinesterase reaction products and choline acetyltransferase-positive neurons than a comparable heparin dose used as a comparator. Using the slice superfusion technique, we found that the lesion-induced decrease in muscarinic autoreceptor sensitivity was abolished by intramuscular OTR4132. After partial cholinergic damage, OTR4132 was able to concentrate at the brain lesion site possibly due to the disruption of the blood-brain barrier and to exert structural and functional effects that hold promises for neuroprotection/neurotrophism. |
| doi_str_mv | 10.1007/s10719-022-10047-x |
| format | Article |
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®
named OTR4132, a synthetic heparan-mimetic biopolymer with neuroprotective/neurotrophic properties. Long-Evans male rats were injected with the cholinergic immunotoxin 192 IgG-saporin into the medial septum/diagonal band of Broca (0.37 µg); vehicle injections served as controls. Immediately after surgery, OTR4132 was injected into the lateral ventricles (0.25 µg/5 µl/rat) or intramuscularly (1.5 mg/kg). To determine whether OTR4132 reached the lesion site, some rats received intracerebroventricular (ICV) or intramuscular (I.M.) injections of fluorescent OTR4132. Rats were sacrificed at 4, 10, 20, or 60 days post-lesion (DPL). Fluorescein-labeled OTR4132 injected ICV or I.M. was found in the lesion from 4 to 20 DPL. Rats with partial hippocampal cholinergic denervation showed decreases in hippocampal acetylcholinesterase reaction products and in choline acetyltransferase-positive neurons in the medial septum. These lesions were the largest at 10 DPL and then remained stable until 60 DPL. Both hippocampal acetylcholinesterase reaction products and choline acetyltransferase-positive neurons in the medial septum effects were significantly attenuated in OTR4132-treated rats. These effects were not related to competition between OTR4132 and 192 IgG-saporin for the neurotrophin receptor P75 (p75
NTR
), as OTR4132 treatment did not alter the internalization of Cy3-labelled 192 IgG. OTR4132 was more efficient at reducing the acetylcholinesterase reaction products and choline acetyltransferase-positive neurons than a comparable heparin dose used as a comparator. Using the slice superfusion technique, we found that the lesion-induced decrease in muscarinic autoreceptor sensitivity was abolished by intramuscular OTR4132. After partial cholinergic damage, OTR4132 was able to concentrate at the brain lesion site possibly due to the disruption of the blood-brain barrier and to exert structural and functional effects that hold promises for neuroprotection/neurotrophism.</description><identifier>ISSN: 0282-0080</identifier><identifier>EISSN: 1573-4986</identifier><identifier>DOI: 10.1007/s10719-022-10047-x</identifier><identifier>PMID: 35254602</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Acetylcholine receptors (muscarinic) ; Acetylcholinesterase ; Acetyltransferase ; Animals ; Biochemistry ; Biomedical and Life Sciences ; Biopolymers ; Blood-brain barrier ; Choline O-acetyltransferase ; Cholinergic Agents - pharmacology ; Denervation ; Diagonal band of Broca ; Fluorescein ; Glycosaminoglycans ; Glycosaminoglycans - pharmacology ; Heparin ; Hippocampus ; Immunoglobulin G ; Internalization ; Lesions ; Life Sciences ; Male ; Neurodegeneration ; Neurons ; Neuroprotection ; Original ; Original Article ; Pathology ; Rats ; Rats, Long-Evans ; Ribosome Inactivating Proteins, Type 1 ; Rodents ; Saporin ; Septum ; Structure-function relationships ; Ventricle (lateral)</subject><ispartof>Glycoconjugate journal, 2022-02, Vol.39 (1), p.107-130</ispartof><rights>The Author(s) 2022</rights><rights>2022. The Author(s).</rights><rights>The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c425t-8543f72cd56e10526b3c5dd322a43b0358ddfcaa4ed4c1bf29b577d54c789d153</cites><orcidid>0000-0003-0315-7444 ; 0000-0003-2225-9331 ; 0000-0002-2684-1241 ; 0000-0002-2838-4523 ; 0000-0002-4490-9086</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10719-022-10047-x$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10719-022-10047-x$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,27923,27924,41487,42556,51318</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35254602$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pereira, Patricia Marques</creatorcontrib><creatorcontrib>Papy-Garcia, Dulce</creatorcontrib><creatorcontrib>Barritault, Denis</creatorcontrib><creatorcontrib>Chiappini, Franck</creatorcontrib><creatorcontrib>Jackisch, Rolf</creatorcontrib><creatorcontrib>Schimchowitsch, Sarah</creatorcontrib><creatorcontrib>Cassel, Jean-Christophe</creatorcontrib><title>Protective Effects of a synthetic glycosaminoglycan mimetic (OTR4132) in a rat immunotoxic lesion model of septohippocampal cholinergic degeneration</title><title>Glycoconjugate journal</title><addtitle>Glycoconj J</addtitle><addtitle>Glycoconj J</addtitle><description>Using a partial hippocampal cholinergic denervation model, we assessed the effects of the RGTA
®
named OTR4132, a synthetic heparan-mimetic biopolymer with neuroprotective/neurotrophic properties. Long-Evans male rats were injected with the cholinergic immunotoxin 192 IgG-saporin into the medial septum/diagonal band of Broca (0.37 µg); vehicle injections served as controls. Immediately after surgery, OTR4132 was injected into the lateral ventricles (0.25 µg/5 µl/rat) or intramuscularly (1.5 mg/kg). To determine whether OTR4132 reached the lesion site, some rats received intracerebroventricular (ICV) or intramuscular (I.M.) injections of fluorescent OTR4132. Rats were sacrificed at 4, 10, 20, or 60 days post-lesion (DPL). Fluorescein-labeled OTR4132 injected ICV or I.M. was found in the lesion from 4 to 20 DPL. Rats with partial hippocampal cholinergic denervation showed decreases in hippocampal acetylcholinesterase reaction products and in choline acetyltransferase-positive neurons in the medial septum. These lesions were the largest at 10 DPL and then remained stable until 60 DPL. Both hippocampal acetylcholinesterase reaction products and choline acetyltransferase-positive neurons in the medial septum effects were significantly attenuated in OTR4132-treated rats. These effects were not related to competition between OTR4132 and 192 IgG-saporin for the neurotrophin receptor P75 (p75
NTR
), as OTR4132 treatment did not alter the internalization of Cy3-labelled 192 IgG. OTR4132 was more efficient at reducing the acetylcholinesterase reaction products and choline acetyltransferase-positive neurons than a comparable heparin dose used as a comparator. Using the slice superfusion technique, we found that the lesion-induced decrease in muscarinic autoreceptor sensitivity was abolished by intramuscular OTR4132. After partial cholinergic damage, OTR4132 was able to concentrate at the brain lesion site possibly due to the disruption of the blood-brain barrier and to exert structural and functional effects that hold promises for neuroprotection/neurotrophism.</description><subject>Acetylcholine receptors (muscarinic)</subject><subject>Acetylcholinesterase</subject><subject>Acetyltransferase</subject><subject>Animals</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biopolymers</subject><subject>Blood-brain barrier</subject><subject>Choline O-acetyltransferase</subject><subject>Cholinergic Agents - pharmacology</subject><subject>Denervation</subject><subject>Diagonal band of Broca</subject><subject>Fluorescein</subject><subject>Glycosaminoglycans</subject><subject>Glycosaminoglycans - pharmacology</subject><subject>Heparin</subject><subject>Hippocampus</subject><subject>Immunoglobulin G</subject><subject>Internalization</subject><subject>Lesions</subject><subject>Life Sciences</subject><subject>Male</subject><subject>Neurodegeneration</subject><subject>Neurons</subject><subject>Neuroprotection</subject><subject>Original</subject><subject>Original Article</subject><subject>Pathology</subject><subject>Rats</subject><subject>Rats, Long-Evans</subject><subject>Ribosome Inactivating Proteins, Type 1</subject><subject>Rodents</subject><subject>Saporin</subject><subject>Septum</subject><subject>Structure-function relationships</subject><subject>Ventricle 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Effects of a synthetic glycosaminoglycan mimetic (OTR4132) in a rat immunotoxic lesion model of septohippocampal cholinergic degeneration</title><author>Pereira, Patricia Marques ; Papy-Garcia, Dulce ; Barritault, Denis ; Chiappini, Franck ; Jackisch, Rolf ; Schimchowitsch, Sarah ; Cassel, Jean-Christophe</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c425t-8543f72cd56e10526b3c5dd322a43b0358ddfcaa4ed4c1bf29b577d54c789d153</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Acetylcholine receptors (muscarinic)</topic><topic>Acetylcholinesterase</topic><topic>Acetyltransferase</topic><topic>Animals</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Biopolymers</topic><topic>Blood-brain barrier</topic><topic>Choline O-acetyltransferase</topic><topic>Cholinergic Agents - pharmacology</topic><topic>Denervation</topic><topic>Diagonal band of Broca</topic><topic>Fluorescein</topic><topic>Glycosaminoglycans</topic><topic>Glycosaminoglycans - pharmacology</topic><topic>Heparin</topic><topic>Hippocampus</topic><topic>Immunoglobulin G</topic><topic>Internalization</topic><topic>Lesions</topic><topic>Life Sciences</topic><topic>Male</topic><topic>Neurodegeneration</topic><topic>Neurons</topic><topic>Neuroprotection</topic><topic>Original</topic><topic>Original Article</topic><topic>Pathology</topic><topic>Rats</topic><topic>Rats, Long-Evans</topic><topic>Ribosome Inactivating Proteins, Type 1</topic><topic>Rodents</topic><topic>Saporin</topic><topic>Septum</topic><topic>Structure-function relationships</topic><topic>Ventricle (lateral)</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pereira, Patricia Marques</creatorcontrib><creatorcontrib>Papy-Garcia, Dulce</creatorcontrib><creatorcontrib>Barritault, Denis</creatorcontrib><creatorcontrib>Chiappini, 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Jean-Christophe</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Protective Effects of a synthetic glycosaminoglycan mimetic (OTR4132) in a rat immunotoxic lesion model of septohippocampal cholinergic degeneration</atitle><jtitle>Glycoconjugate journal</jtitle><stitle>Glycoconj J</stitle><addtitle>Glycoconj J</addtitle><date>2022-02-01</date><risdate>2022</risdate><volume>39</volume><issue>1</issue><spage>107</spage><epage>130</epage><pages>107-130</pages><issn>0282-0080</issn><eissn>1573-4986</eissn><abstract>Using a partial hippocampal cholinergic denervation model, we assessed the effects of the RGTA
®
named OTR4132, a synthetic heparan-mimetic biopolymer with neuroprotective/neurotrophic properties. Long-Evans male rats were injected with the cholinergic immunotoxin 192 IgG-saporin into the medial septum/diagonal band of Broca (0.37 µg); vehicle injections served as controls. Immediately after surgery, OTR4132 was injected into the lateral ventricles (0.25 µg/5 µl/rat) or intramuscularly (1.5 mg/kg). To determine whether OTR4132 reached the lesion site, some rats received intracerebroventricular (ICV) or intramuscular (I.M.) injections of fluorescent OTR4132. Rats were sacrificed at 4, 10, 20, or 60 days post-lesion (DPL). Fluorescein-labeled OTR4132 injected ICV or I.M. was found in the lesion from 4 to 20 DPL. Rats with partial hippocampal cholinergic denervation showed decreases in hippocampal acetylcholinesterase reaction products and in choline acetyltransferase-positive neurons in the medial septum. These lesions were the largest at 10 DPL and then remained stable until 60 DPL. Both hippocampal acetylcholinesterase reaction products and choline acetyltransferase-positive neurons in the medial septum effects were significantly attenuated in OTR4132-treated rats. These effects were not related to competition between OTR4132 and 192 IgG-saporin for the neurotrophin receptor P75 (p75
NTR
), as OTR4132 treatment did not alter the internalization of Cy3-labelled 192 IgG. OTR4132 was more efficient at reducing the acetylcholinesterase reaction products and choline acetyltransferase-positive neurons than a comparable heparin dose used as a comparator. Using the slice superfusion technique, we found that the lesion-induced decrease in muscarinic autoreceptor sensitivity was abolished by intramuscular OTR4132. After partial cholinergic damage, OTR4132 was able to concentrate at the brain lesion site possibly due to the disruption of the blood-brain barrier and to exert structural and functional effects that hold promises for neuroprotection/neurotrophism.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>35254602</pmid><doi>10.1007/s10719-022-10047-x</doi><tpages>24</tpages><orcidid>https://orcid.org/0000-0003-0315-7444</orcidid><orcidid>https://orcid.org/0000-0003-2225-9331</orcidid><orcidid>https://orcid.org/0000-0002-2684-1241</orcidid><orcidid>https://orcid.org/0000-0002-2838-4523</orcidid><orcidid>https://orcid.org/0000-0002-4490-9086</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Glycoconjugate journal, 2022-02, Vol.39 (1), p.107-130 |
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| language | eng |
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| subjects | Acetylcholine receptors (muscarinic) Acetylcholinesterase Acetyltransferase Animals Biochemistry Biomedical and Life Sciences Biopolymers Blood-brain barrier Choline O-acetyltransferase Cholinergic Agents - pharmacology Denervation Diagonal band of Broca Fluorescein Glycosaminoglycans Glycosaminoglycans - pharmacology Heparin Hippocampus Immunoglobulin G Internalization Lesions Life Sciences Male Neurodegeneration Neurons Neuroprotection Original Original Article Pathology Rats Rats, Long-Evans Ribosome Inactivating Proteins, Type 1 Rodents Saporin Septum Structure-function relationships Ventricle (lateral) |
| title | Protective Effects of a synthetic glycosaminoglycan mimetic (OTR4132) in a rat immunotoxic lesion model of septohippocampal cholinergic degeneration |
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