Protective effects of naloxone in two-hit seizure model.
OBJECTIVE
Early life status epilepticus (SE) could enhance the vulnerability of the immature brain to a second SE in adulthood (two-hit seizure model). Naloxone has been proved to possess inflammation inhibitory effects in nervous system. This study was designed to evaluate the dose-dependent protective effects of naloxone in kainic acid (KA)-induced two-hit seizure model.


METHODS
After KA-induced SE at postnatal day 15 (P15), Sprague-Dawley rats were infused with either saline or different doses (1.92, 3.84, 5.76, and 7.68 mg/kg) of naloxone continuously for 12 h. De novo synthesis of cytokines (interleukin-1 beta [IL-1 beta], S100B) was assessed by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) at 12 h after P15 SE. Glial activation states were analyzed by western blotting of glial markers (glial fibrillary acidic protein [GFAP], S100B, Iba1) both at 12 h after P15 SE and at P45. After a second SE at P45, cognitive deteriorations were evaluated by Morris water tests and neuron injuries were evaluated by TdT-mediated dUTP nick end labeling (TUNEL) assays.


RESULTS
Naloxone reduced IL-1 beta synthesis and microglial activation most potently at a dose of 3.84 mg/kg. Attenuation of S100B synthesis and astrocyte activation were achieved most dramatically by naloxone at a dose of 5.76 mg/kg, which is equal to the most powerful dose in ameliorating cognitive injuries and neuron apoptosis after second SE.


CONCLUSIONS
Naloxone treatment immediately after early life SE could dose-dependently reduce cytokine production, glial activation, and further lower the vulnerability of immature brains to a second hit in adulthood.
Yang
Lu
L
Pediatric department of Qilu Hospital, Shandong University, Jinan, Shandong Province, China.
Li
Fuhai
F
Ge
Wei
W
Mi
Changrui
C
Wang
Rong
R
Sun
Ruopeng
R
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005904:Glial Fibrillary Acidic Protein / Q000187:drug effects; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D053583:Interleukin-1beta / Q000187:drug effects; D007608:Kainic Acid; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D009270:Naloxone / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000139:chemically induced / Q000517:prevention & control*
D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D053583:Interleukin-1beta; D009270:Naloxone; D007608:Kainic Acid