title: Adenosine A1 receptor knockout mice develop lethal status epilepticus after experimental traumatic brain injury.
abstract: Adenosine, acting at A1 receptors, exhibits anticonvulsant effects in experimental epilepsy--and inhibits progression to status epilepticus (SE). Seizures after traumatic brain injury (TBI) may contribute to pathophysiology. Thus, we hypothesized that endogenous adenosine, acting via A1 receptors, mediates antiepileptic benefit after experimental TBI. We subjected A1-receptor knockout (ko) mice, heterozygotes, and wild-type (wt) littermates (n=115) to controlled cortical impact (CCI). We used four outcome protocols in male mice: (1) observation for seizures, SE, and mortality in the initial 2 h, (2) assessment of seizure score (electroencephalogram (EEG)) in the initial 2 h, (3) assessment of mortality at 24 h across injury levels, and (4) serial assessment of arterial blood pressure, heart rate, blood gases, and hematocrit. Lastly, to assess the influence of gender on this observation, we observed female mice for seizures, SE, and mortality in the initial 2 h. Seizure activity was noted in 83% of male ko mice in the initial 2 h, but was seen in no heterozygotes and only 33% of wt (P<0.05). Seizures in wt were brief (1 to 2 secs). In contrast, SE involving lethal sustained (>1 h) tonic clonic activity was uniquely seen in ko mice after CCI (50% incidence in males), (P<0.05). Seizure score was twofold higher in ko mice after CCI versus either heterozygote or wt (P<0.05). An injury-intensity dose-response for 24 h mortality was seen in ko mice (P<0.05). Physiologic parameters were similar between genotypes. Seizures were seen in 100% of female ko mice after CCI versus 14% of heterozygotes and 25% wt (P<0.05) and SE was restricted to the ko mice (83% incidence). Our data suggest a critical endogenous anticonvulsant action of adenosine at A1 receptors early after experimental TBI.
authors.affiliation: Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA. kochanekpm@ccm.upmc.edu
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Vagni
authors.forename: Keri L
authors.initials: KL
authors.lastname: Janesko
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Washington
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Crumrine
authors.forename: Robert H
authors.initials: RH
authors.lastname: Garman
authors.forename: Larry W
authors.initials: LW
authors.lastname: Jenkins
authors.forename: Robert S B
authors.initials: RS
authors.lastname: Clark
authors.forename: Gregg E
authors.initials: GE
authors.lastname: Homanics
authors.forename: C Edward
authors.initials: CE
authors.lastname: Dixon
authors.forename: Jurgen
authors.initials: J
authors.lastname: Schnermann
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000150:complications*; D004569:Electroencephalography; D004834:Epilepsy, Post-Traumatic / Q000209:etiology* / Q000401:mortality; D005260:Female; D005838:Genotype; D006403:Hematologic Tests; D006439:Hemodynamics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D043682:Receptor, Adenosine A1 / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D012737:Sex Factors; D016896:Treatment Outcome
chemical_list: D043682:Receptor, Adenosine A1