Medial ganglionic eminence-derived neural stem cell grafts ease spontaneous seizures and restore GDNF expression in a rat model of chronic temporal lobe epilepsy

Ben Waldau, Bharathi Hattiangady, Ramkumar Kuruba, Ashok K. Shetty

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Nearly 30% of patients with mesial temporal lobe epilepsy (TLE) are resistant to treatment with antiepileptic drugs. Neural stem cell (NSC) grafting into the hippocampus could offer an alternative therapy to hippocampal resection in these patients. As TLE is associated with reduced numbers of inhibitory gamma-amino butyric acid (GABA)-ergic interneurons and astrocytes expressing the anticonvulsant glial-derived neurotrophic factor (GDNF) in the hippocampus, we tested the hypothesis that grafting of NSCs that are capable of adding new GABA-ergic interneurons and GDNF-expressing astrocytes into the epileptic hippocampus restrains spontaneous recurrent motor seizures (SRMS) in chronic TLE. We grafted NSCs expanded in vitro from embryonic medial ganglionic eminence (MGE) into hippocampi of adult rats exhibiting chronic TLE with cognitive impairments. NSC grafting reduced frequencies of SRMS by 43% and stage V seizures by 90%. The duration of individual SRMS and the total time spent in seizures were reduced by 51 and 74%, respectively. Grafting did not improve the cognitive function however. Graft-derived cells (equivalent to ∼28% of injected cells) were observed in various layers of the epileptic hippocampus where they differentiated into NeuN+ neurons (13%), S-100β+ astrocytes (57%), and NG2+ oligodendrocyte-progenitors (3%). Furthermore, among graft-derived cells, 10% expressed GABA and 50% expressed GDNF. Additionally, NSC grafting restored GDNF in a vast majority of the hippocampal astrocytes but had no effect on neurogenesis. Thus, MGE-NSC therapy is efficacious for diminishing SRMS in chronic TLE. Addition of new GABA-ergic neurons and GDNF+ cells, and restoration of GDNF in the hippocampal astrocytes may underlie the therapeutic effect of MGE-NSC grafts.

Original languageEnglish (US)
Pages (from-to)1153-1164
Number of pages12
JournalStem Cells
Volume28
Issue number7
DOIs
StatePublished - Jul 2010
Externally publishedYes

Fingerprint

Median Eminence
Neural Stem Cells
Temporal Lobe Epilepsy
Nerve Growth Factors
Neuroglia
Seizures
Astrocytes
Butyric Acid
Hippocampus
Transplants
Interneurons
Anticonvulsants
Neurons
Neurogenesis
Oligodendroglia
Therapeutic Uses
Complementary Therapies
Cell- and Tissue-Based Therapy
Cognition

Keywords

  • Chronic epilepsy
  • Glial-derived neurotrophic factor
  • Hippocampal neurogenesis
  • Learning and memory
  • Medial ganglionic eminence
  • Neural stem cell therapy
  • Spontaneous seizures

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

Cite this

Medial ganglionic eminence-derived neural stem cell grafts ease spontaneous seizures and restore GDNF expression in a rat model of chronic temporal lobe epilepsy. / Waldau, Ben; Hattiangady, Bharathi; Kuruba, Ramkumar; Shetty, Ashok K.

In: Stem Cells, Vol. 28, No. 7, 07.2010, p. 1153-1164.

Research output: Contribution to journalArticle

@article{224074db0fa24939aeaba1ead5e6f390,
title = "Medial ganglionic eminence-derived neural stem cell grafts ease spontaneous seizures and restore GDNF expression in a rat model of chronic temporal lobe epilepsy",
abstract = "Nearly 30{\%} of patients with mesial temporal lobe epilepsy (TLE) are resistant to treatment with antiepileptic drugs. Neural stem cell (NSC) grafting into the hippocampus could offer an alternative therapy to hippocampal resection in these patients. As TLE is associated with reduced numbers of inhibitory gamma-amino butyric acid (GABA)-ergic interneurons and astrocytes expressing the anticonvulsant glial-derived neurotrophic factor (GDNF) in the hippocampus, we tested the hypothesis that grafting of NSCs that are capable of adding new GABA-ergic interneurons and GDNF-expressing astrocytes into the epileptic hippocampus restrains spontaneous recurrent motor seizures (SRMS) in chronic TLE. We grafted NSCs expanded in vitro from embryonic medial ganglionic eminence (MGE) into hippocampi of adult rats exhibiting chronic TLE with cognitive impairments. NSC grafting reduced frequencies of SRMS by 43{\%} and stage V seizures by 90{\%}. The duration of individual SRMS and the total time spent in seizures were reduced by 51 and 74{\%}, respectively. Grafting did not improve the cognitive function however. Graft-derived cells (equivalent to ∼28{\%} of injected cells) were observed in various layers of the epileptic hippocampus where they differentiated into NeuN+ neurons (13{\%}), S-100β+ astrocytes (57{\%}), and NG2+ oligodendrocyte-progenitors (3{\%}). Furthermore, among graft-derived cells, 10{\%} expressed GABA and 50{\%} expressed GDNF. Additionally, NSC grafting restored GDNF in a vast majority of the hippocampal astrocytes but had no effect on neurogenesis. Thus, MGE-NSC therapy is efficacious for diminishing SRMS in chronic TLE. Addition of new GABA-ergic neurons and GDNF+ cells, and restoration of GDNF in the hippocampal astrocytes may underlie the therapeutic effect of MGE-NSC grafts.",
keywords = "Chronic epilepsy, Glial-derived neurotrophic factor, Hippocampal neurogenesis, Learning and memory, Medial ganglionic eminence, Neural stem cell therapy, Spontaneous seizures",
author = "Ben Waldau and Bharathi Hattiangady and Ramkumar Kuruba and Shetty, {Ashok K.}",
year = "2010",
month = "7",
doi = "10.1002/stem.446",
language = "English (US)",
volume = "28",
pages = "1153--1164",
journal = "Stem Cells",
issn = "1066-5099",
publisher = "AlphaMed Press",
number = "7",

}

TY - JOUR

T1 - Medial ganglionic eminence-derived neural stem cell grafts ease spontaneous seizures and restore GDNF expression in a rat model of chronic temporal lobe epilepsy

AU - Waldau, Ben

AU - Hattiangady, Bharathi

AU - Kuruba, Ramkumar

AU - Shetty, Ashok K.

PY - 2010/7

Y1 - 2010/7

N2 - Nearly 30% of patients with mesial temporal lobe epilepsy (TLE) are resistant to treatment with antiepileptic drugs. Neural stem cell (NSC) grafting into the hippocampus could offer an alternative therapy to hippocampal resection in these patients. As TLE is associated with reduced numbers of inhibitory gamma-amino butyric acid (GABA)-ergic interneurons and astrocytes expressing the anticonvulsant glial-derived neurotrophic factor (GDNF) in the hippocampus, we tested the hypothesis that grafting of NSCs that are capable of adding new GABA-ergic interneurons and GDNF-expressing astrocytes into the epileptic hippocampus restrains spontaneous recurrent motor seizures (SRMS) in chronic TLE. We grafted NSCs expanded in vitro from embryonic medial ganglionic eminence (MGE) into hippocampi of adult rats exhibiting chronic TLE with cognitive impairments. NSC grafting reduced frequencies of SRMS by 43% and stage V seizures by 90%. The duration of individual SRMS and the total time spent in seizures were reduced by 51 and 74%, respectively. Grafting did not improve the cognitive function however. Graft-derived cells (equivalent to ∼28% of injected cells) were observed in various layers of the epileptic hippocampus where they differentiated into NeuN+ neurons (13%), S-100β+ astrocytes (57%), and NG2+ oligodendrocyte-progenitors (3%). Furthermore, among graft-derived cells, 10% expressed GABA and 50% expressed GDNF. Additionally, NSC grafting restored GDNF in a vast majority of the hippocampal astrocytes but had no effect on neurogenesis. Thus, MGE-NSC therapy is efficacious for diminishing SRMS in chronic TLE. Addition of new GABA-ergic neurons and GDNF+ cells, and restoration of GDNF in the hippocampal astrocytes may underlie the therapeutic effect of MGE-NSC grafts.

AB - Nearly 30% of patients with mesial temporal lobe epilepsy (TLE) are resistant to treatment with antiepileptic drugs. Neural stem cell (NSC) grafting into the hippocampus could offer an alternative therapy to hippocampal resection in these patients. As TLE is associated with reduced numbers of inhibitory gamma-amino butyric acid (GABA)-ergic interneurons and astrocytes expressing the anticonvulsant glial-derived neurotrophic factor (GDNF) in the hippocampus, we tested the hypothesis that grafting of NSCs that are capable of adding new GABA-ergic interneurons and GDNF-expressing astrocytes into the epileptic hippocampus restrains spontaneous recurrent motor seizures (SRMS) in chronic TLE. We grafted NSCs expanded in vitro from embryonic medial ganglionic eminence (MGE) into hippocampi of adult rats exhibiting chronic TLE with cognitive impairments. NSC grafting reduced frequencies of SRMS by 43% and stage V seizures by 90%. The duration of individual SRMS and the total time spent in seizures were reduced by 51 and 74%, respectively. Grafting did not improve the cognitive function however. Graft-derived cells (equivalent to ∼28% of injected cells) were observed in various layers of the epileptic hippocampus where they differentiated into NeuN+ neurons (13%), S-100β+ astrocytes (57%), and NG2+ oligodendrocyte-progenitors (3%). Furthermore, among graft-derived cells, 10% expressed GABA and 50% expressed GDNF. Additionally, NSC grafting restored GDNF in a vast majority of the hippocampal astrocytes but had no effect on neurogenesis. Thus, MGE-NSC therapy is efficacious for diminishing SRMS in chronic TLE. Addition of new GABA-ergic neurons and GDNF+ cells, and restoration of GDNF in the hippocampal astrocytes may underlie the therapeutic effect of MGE-NSC grafts.

KW - Chronic epilepsy

KW - Glial-derived neurotrophic factor

KW - Hippocampal neurogenesis

KW - Learning and memory

KW - Medial ganglionic eminence

KW - Neural stem cell therapy

KW - Spontaneous seizures

UR - http://www.scopus.com/inward/record.url?scp=77954824190&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954824190&partnerID=8YFLogxK

U2 - 10.1002/stem.446

DO - 10.1002/stem.446

M3 - Article

C2 - 20506409

AN - SCOPUS:77954824190

VL - 28

SP - 1153

EP - 1164

JO - Stem Cells

JF - Stem Cells

SN - 1066-5099

IS - 7

ER -