title: Pentylentetrazole-induced loss of blood-brain barrier integrity involves excess nitric oxide generation by neuronal nitric oxide synthase.
abstract: Dysfunction of the blood-brain barrier (BBB) is one of the major pathophysiological consequences of epilepsy. The increase in the permeability caused by BBB failure is thought to contribute to the development of epileptic outcomes. We developed a method by which the BBB permeability can be demonstrated by gadolinium-enhanced T1 weighted imaging (GdET1WI). The present study examined the changes in the BBB permeability in mice with generalized convulsive seizures (GCS) induced by acute pentylentetrazole (PTZ) injection. At 15min after PTZ-induced GCS, the BBB temporarily leaks BBB-impermeable contrast agent into the parenchyma of the diencephalon, hippocampus and cerebral cortex in mice, and the loss of BBB integrity was gradually recovered by 24h. The temporary BBB failure is a critical link to the glutamatergic activities that occur following the injection of PTZ. PTZ activates the glutamatergic pathway via the NMDA receptor, then nitric oxide (NO) is generated by NMDA receptor-coupled neuronal NO synthase (nNOS). To examine the influence of nNOS-derived NO induced by PTZ on the increases of the BBB permeability, GdET1WI was performed using conventional nNOS gene-deficient mice with or without PTZ injection. The failure of the BBB induced by PTZ was completely protected by nNOS deficiency in the brain. These results suggest that nNOS-derived excess NO in the glutamatergic pathway plays a key role in the failure of the BBB during PTZ-induced GCS. The levels of NO synthetized by nNOS in the brain may represent an important target for the future development of drugs to protect the BBB.
authors.affiliation: Department of Neuropsychiatry, School of Medicine, Kagawa University, Kita, Kagawa 761-0793, Japan.
authors.forename: Sonoko
authors.initials: S
authors.lastname: Danjo
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ishihara
authors.forename: Masatomo
authors.initials: M
authors.lastname: Watanabe
authors.forename: Yu
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Kouichi
authors.initials: K
authors.lastname: Itoh
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D010433:Pentylenetetrazole / Q000494:pharmacology*; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism
chemical_list: D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D010433:Pentylenetetrazole
keywords: (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine maleate; (E)-(±)-2-amino-4-methyl-5-phospho no-3-pentenoic acid ethyl ester; 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide; AEDs; AMPA; BBB; Blood–brain barrier; CBF; CBZ; CGP39551; CNS; CSM; DETC; DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; DMSO; GABA; Gd; Gd-HP-DO3A; GdET1WI; Generalized convulsive seizures; MK-801; MRI; N,N-diethyldithiocarbamate Na; N-methyl-d-aspartate; NBQX; NMDA; NO; Nitric oxide; PTZ; Pentylenetetrazole; SI; TBARS; VPA; antiepileptic drugs; blood–brain barrier; carbamazepine; central nervous system; cerebral blood flow; cerebral smooth muscle; dimethyl sulfoxide; gadolinium; gadolinium-1,4,7-tris(carbonylmethyl)-10-(2′-hydroxypropyl)-1,4,7,10-tetraazacyclo-dodecane; gadolinium-enhanced T1 weighted image; gamma-aminobutyric acid; magnetic resonance imaging; nNOS; neuronal nitric oxide synthase; nitric oxide; pentylentetrazole; signal intensities; thiobarbituric acid-reactive substance; valproic acid