Glial activation links early-life seizures and long-term neurologic dysfunction: evidence using a small molecule inhibitor of proinflammatory cytokine upregulation.
OBJECTIVE
Early-life seizures increase vulnerability to subsequent neurologic insult. We tested the hypothesis that early-life seizures increase susceptibility to later neurologic injury by causing chronic glial activation. To determine the mechanisms by which glial activation may modulate neurologic injury, we examined both acute changes in proinflammatory cytokines and long-term changes in astrocyte and microglial activation and astrocyte glutamate transporters in a "two-hit" model of kainic acid (KA)-induced seizures.


METHODS
Postnatal day (P) 15 male rats were administered KA or phosphate buffered saline (PBS). On P45 animals either received a second treatment of KA or PBS. On P55, control (PBS-PBS), early-life seizure (KA-PBS), adult seizure (PBS-KA), and "two-hit" (KA-KA) groups were examined for astrocyte and microglial activation, alteration in glutamate transporters, and expression of the glial protein, clusterin.


RESULTS
P15 seizures resulted in an acute increase in hippocampal levels of IL-1beta and S100B, followed by behavioral impairment and long-term increases in GFAP and S100B. Animals in the "two-hit" group showed greater microglial activation, neurologic injury, and susceptibility to seizures compared to the adult seizure group. Glutamate transporters increased following seizures but did not differ between these two groups. Treatment with Minozac, a small molecule inhibitor of proinflammatory cytokine upregulation, following early-life seizures prevented both the long-term increase in activated glia and the associated behavioral impairment.


CONCLUSIONS
These data suggest that glial activation following early-life seizures results in increased susceptibility to seizures in adulthood, in part through priming microglia and enhanced microglial activation. Glial activation may be a novel therapeutic target in pediatric epilepsy.
Somera-Molina
Kathleen C
KC
Integrated Graduate Program, Department of PediatricsNeurologyNeonatologyCenter for Drug Discovery and Chemical BiologyDepartment of Cell and Molecular BiologyDepartment of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, Illinois, U.S.A.
Robin
Beverley
B
Integrated Graduate Program, Department of PediatricsNeurologyNeonatologyCenter for Drug Discovery and Chemical BiologyDepartment of Cell and Molecular BiologyDepartment of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, Illinois, U.S.A.
Somera
Cherie Ann
CA
Integrated Graduate Program, Department of PediatricsNeurologyNeonatologyCenter for Drug Discovery and Chemical BiologyDepartment of Cell and Molecular BiologyDepartment of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, Illinois, U.S.A.
Anderson
Christopher
C
Integrated Graduate Program, Department of PediatricsNeurologyNeonatologyCenter for Drug Discovery and Chemical BiologyDepartment of Cell and Molecular BiologyDepartment of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, Illinois, U.S.A.
Stine
Christy
C
Integrated Graduate Program, Department of PediatricsNeurologyNeonatologyCenter for Drug Discovery and Chemical BiologyDepartment of Cell and Molecular BiologyDepartment of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, Illinois, U.S.A.
Koh
Sookyong
S
Integrated Graduate Program, Department of PediatricsNeurologyNeonatologyCenter for Drug Discovery and Chemical BiologyDepartment of Cell and Molecular BiologyDepartment of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, Illinois, U.S.A.
Behanna
Heather A
HA
Integrated Graduate Program, Department of PediatricsNeurologyNeonatologyCenter for Drug Discovery and Chemical BiologyDepartment of Cell and Molecular BiologyDepartment of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, Illinois, U.S.A.
Van Eldik
Linda J
LJ
Integrated Graduate Program, Department of PediatricsNeurologyNeonatologyCenter for Drug Discovery and Chemical BiologyDepartment of Cell and Molecular BiologyDepartment of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, Illinois, U.S.A.
Watterson
D Martin
DM
Integrated Graduate Program, Department of PediatricsNeurologyNeonatologyCenter for Drug Discovery and Chemical BiologyDepartment of Cell and Molecular BiologyDepartment of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, Illinois, U.S.A.
Wainwright
Mark S
MS
Integrated Graduate Program, Department of PediatricsNeurologyNeonatologyCenter for Drug Discovery and Chemical BiologyDepartment of Cell and Molecular BiologyDepartment of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, Illinois, U.S.A.
D000367:Age Factors; D027322:Amino Acid Transport System X-AG / Q000276:immunology / Q000502:physiology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D015153:Blotting, Western; D051152:Clusterin / Q000276:immunology; D017242:Complement Factor H; D016207:Cytokines / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000276:immunology; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000276:immunology / Q000502:physiology; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology; D007608:Kainic Acid; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D009457:Neuroglia / Q000187:drug effects / Q000276:immunology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology; D012720:Severity of Illness Index; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology / Q000502:physiology
D027322:Amino Acid Transport System X-AG; C498500:Clu protein, rat; D051152:Clusterin; D016207:Cytokines; D017242:Complement Factor H; D007608:Kainic Acid