Suppression of kindling epileptogenesis by adenosine releasing stem cell-derived brain implants

Tianfu Li; Julius A. Steinbeck; Theresa Lusardi; Philipp Koch; Jing Q. Lan; Andrew Wilz; Michaela Segschneider; Roger P. Simon; Oliver Brüstle; Detlev Boison

doi:10.1093/brain/awm057

Suppression of kindling epileptogenesis by adenosine releasing stem cell-derived brain implants

Tianfu Li, Julius A. Steinbeck, Theresa Lusardi, Philipp Koch, Jing Q. Lan, Andrew Wilz, Michaela Segschneider, Roger P. Simon, Oliver Brüstle, Detlev Boison

Knight Cancer Institute

Research output: Contribution to journal › Article › peer-review

133 Scopus citations

Abstract

Epilepsy therapy is largely symptomatic and no effective therapy is available to prevent epileptogenesis. We therefore analysed the potential of stem cell-derived brain implants and of paracrine adenosine release to suppress the progressive development of seizures in the rat kindling-model. Embryonic stem (ES) cells, engineered to release the inhibitory neuromodulator adenosine by biallelic genetic disruption of the adenosine kinase gene (Adk ^-/-), and respective wild-type (wt) cells, were differentiated into neural precursor cells (NPs) and injected into the hippocampus of rats prior to kindling. Therapeutic effects of NP-derived brain implants were compared with those of wt baby hamster kidney cells (BHK) and adenosine releasing BHK cell implants (BHK-AK2), which were previously shown to suppress seizures by paracrine adenosine release. Wild-type NP-graft recipients were characterized by an initial delay of seizure development, while recipients of adenosine releasing NPs displayed sustained protection from developing generalized seizures. In contrast, recipients of wt BHK cells failed to display any effects on kindling development, while recipients of BHK-AK2 cells were only moderately protected from seizure development. The therapeutic effect of Adk ^-/--NPs was due to graft-mediated adenosine release, since seizures could transiently be provoked after blocking adenosine A1 receptors. Histological analysis of NP-implants at day 26 revealed cell clusters within the infrahippocampal cleft as well as intrahippocampal location of graft-derived cells expressing mature neuronal markers. In contrast, BHK and BHK-AK2 cell implants only formed cell clusters within the infrahippocampal cleft. We conclude that ES cell-derived adenosine releasing brain implants are superior to paracrine adenosine release from BHK-AK2 cell implants in suppressing seizure progression in the rat kindling-model. These findings may indicate a potential antiepileptogenic function of stem cell-mediated adenosine delivery.

Original language	English (US)
Pages (from-to)	1276-1288
Number of pages	13
Journal	Brain
Volume	130
Issue number	5
DOIs	https://doi.org/10.1093/brain/awm057
State	Published - May 2007

Keywords

Adenosine
Adenosine kinase
Cell therapy
Epileptogenesis
Stem cells

ASJC Scopus subject areas

Clinical Neurology

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10.1093/brain/awm057

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@article{d0ef8c36b35e46aeb3baeb019f5b1dbf,

title = "Suppression of kindling epileptogenesis by adenosine releasing stem cell-derived brain implants",

abstract = "Epilepsy therapy is largely symptomatic and no effective therapy is available to prevent epileptogenesis. We therefore analysed the potential of stem cell-derived brain implants and of paracrine adenosine release to suppress the progressive development of seizures in the rat kindling-model. Embryonic stem (ES) cells, engineered to release the inhibitory neuromodulator adenosine by biallelic genetic disruption of the adenosine kinase gene (Adk -/-), and respective wild-type (wt) cells, were differentiated into neural precursor cells (NPs) and injected into the hippocampus of rats prior to kindling. Therapeutic effects of NP-derived brain implants were compared with those of wt baby hamster kidney cells (BHK) and adenosine releasing BHK cell implants (BHK-AK2), which were previously shown to suppress seizures by paracrine adenosine release. Wild-type NP-graft recipients were characterized by an initial delay of seizure development, while recipients of adenosine releasing NPs displayed sustained protection from developing generalized seizures. In contrast, recipients of wt BHK cells failed to display any effects on kindling development, while recipients of BHK-AK2 cells were only moderately protected from seizure development. The therapeutic effect of Adk -/--NPs was due to graft-mediated adenosine release, since seizures could transiently be provoked after blocking adenosine A1 receptors. Histological analysis of NP-implants at day 26 revealed cell clusters within the infrahippocampal cleft as well as intrahippocampal location of graft-derived cells expressing mature neuronal markers. In contrast, BHK and BHK-AK2 cell implants only formed cell clusters within the infrahippocampal cleft. We conclude that ES cell-derived adenosine releasing brain implants are superior to paracrine adenosine release from BHK-AK2 cell implants in suppressing seizure progression in the rat kindling-model. These findings may indicate a potential antiepileptogenic function of stem cell-mediated adenosine delivery.",

keywords = "Adenosine, Adenosine kinase, Cell therapy, Epileptogenesis, Stem cells",

author = "Tianfu Li and Steinbeck, {Julius A.} and Theresa Lusardi and Philipp Koch and Lan, {Jing Q.} and Andrew Wilz and Michaela Segschneider and Simon, {Roger P.} and Oliver Br{\"u}stle and Detlev Boison",

note = "Funding Information: The pMOWS-EGFP plasmid was a generous gift from Dr U. Klingm{\"u}ller (DKFZ, Heidelberg, Germany). We thank Dr D. Fedele (University of Zurich, Switzerland) for performing the adenosine assays. This work was supported by grant R01 NS047622-01A2 from the National Institutes of Health, the Good Samaritan Hospital Foundation, the Epilepsy Research Foundation through the generous support of Arlene & Arnold Goldstein Family Foundation, the Deutsche Forschungsgemeinschaft (SFB TR3, D2) and the Hertie Foundation.",

year = "2007",

month = may,

doi = "10.1093/brain/awm057",

language = "English (US)",

volume = "130",

pages = "1276--1288",

journal = "Brain",

issn = "0006-8950",

publisher = "Oxford University Press",

number = "5",

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T1 - Suppression of kindling epileptogenesis by adenosine releasing stem cell-derived brain implants

AU - Li, Tianfu

AU - Steinbeck, Julius A.

AU - Lusardi, Theresa

AU - Koch, Philipp

AU - Lan, Jing Q.

AU - Wilz, Andrew

AU - Segschneider, Michaela

AU - Simon, Roger P.

AU - Brüstle, Oliver

AU - Boison, Detlev

N1 - Funding Information: The pMOWS-EGFP plasmid was a generous gift from Dr U. Klingmüller (DKFZ, Heidelberg, Germany). We thank Dr D. Fedele (University of Zurich, Switzerland) for performing the adenosine assays. This work was supported by grant R01 NS047622-01A2 from the National Institutes of Health, the Good Samaritan Hospital Foundation, the Epilepsy Research Foundation through the generous support of Arlene & Arnold Goldstein Family Foundation, the Deutsche Forschungsgemeinschaft (SFB TR3, D2) and the Hertie Foundation.

PY - 2007/5

Y1 - 2007/5

N2 - Epilepsy therapy is largely symptomatic and no effective therapy is available to prevent epileptogenesis. We therefore analysed the potential of stem cell-derived brain implants and of paracrine adenosine release to suppress the progressive development of seizures in the rat kindling-model. Embryonic stem (ES) cells, engineered to release the inhibitory neuromodulator adenosine by biallelic genetic disruption of the adenosine kinase gene (Adk -/-), and respective wild-type (wt) cells, were differentiated into neural precursor cells (NPs) and injected into the hippocampus of rats prior to kindling. Therapeutic effects of NP-derived brain implants were compared with those of wt baby hamster kidney cells (BHK) and adenosine releasing BHK cell implants (BHK-AK2), which were previously shown to suppress seizures by paracrine adenosine release. Wild-type NP-graft recipients were characterized by an initial delay of seizure development, while recipients of adenosine releasing NPs displayed sustained protection from developing generalized seizures. In contrast, recipients of wt BHK cells failed to display any effects on kindling development, while recipients of BHK-AK2 cells were only moderately protected from seizure development. The therapeutic effect of Adk -/--NPs was due to graft-mediated adenosine release, since seizures could transiently be provoked after blocking adenosine A1 receptors. Histological analysis of NP-implants at day 26 revealed cell clusters within the infrahippocampal cleft as well as intrahippocampal location of graft-derived cells expressing mature neuronal markers. In contrast, BHK and BHK-AK2 cell implants only formed cell clusters within the infrahippocampal cleft. We conclude that ES cell-derived adenosine releasing brain implants are superior to paracrine adenosine release from BHK-AK2 cell implants in suppressing seizure progression in the rat kindling-model. These findings may indicate a potential antiepileptogenic function of stem cell-mediated adenosine delivery.

AB - Epilepsy therapy is largely symptomatic and no effective therapy is available to prevent epileptogenesis. We therefore analysed the potential of stem cell-derived brain implants and of paracrine adenosine release to suppress the progressive development of seizures in the rat kindling-model. Embryonic stem (ES) cells, engineered to release the inhibitory neuromodulator adenosine by biallelic genetic disruption of the adenosine kinase gene (Adk -/-), and respective wild-type (wt) cells, were differentiated into neural precursor cells (NPs) and injected into the hippocampus of rats prior to kindling. Therapeutic effects of NP-derived brain implants were compared with those of wt baby hamster kidney cells (BHK) and adenosine releasing BHK cell implants (BHK-AK2), which were previously shown to suppress seizures by paracrine adenosine release. Wild-type NP-graft recipients were characterized by an initial delay of seizure development, while recipients of adenosine releasing NPs displayed sustained protection from developing generalized seizures. In contrast, recipients of wt BHK cells failed to display any effects on kindling development, while recipients of BHK-AK2 cells were only moderately protected from seizure development. The therapeutic effect of Adk -/--NPs was due to graft-mediated adenosine release, since seizures could transiently be provoked after blocking adenosine A1 receptors. Histological analysis of NP-implants at day 26 revealed cell clusters within the infrahippocampal cleft as well as intrahippocampal location of graft-derived cells expressing mature neuronal markers. In contrast, BHK and BHK-AK2 cell implants only formed cell clusters within the infrahippocampal cleft. We conclude that ES cell-derived adenosine releasing brain implants are superior to paracrine adenosine release from BHK-AK2 cell implants in suppressing seizure progression in the rat kindling-model. These findings may indicate a potential antiepileptogenic function of stem cell-mediated adenosine delivery.

KW - Adenosine

KW - Adenosine kinase

KW - Cell therapy

KW - Epileptogenesis

KW - Stem cells

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JO - Brain

JF - Brain

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ER -

Suppression of kindling epileptogenesis by adenosine releasing stem cell-derived brain implants

Abstract

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