Treatment of TBI remains a major unmet medical need, with 2.5 million new cases of traumatic brain injury (TBI) each year in Europe and 1.5 million in the USA. This single-center proof-of-concept preclinical study tested the hypothesis that pharmacologic neurostimulation with proconvulsants, either atipamezole, a selective α-adrenoceptor antagonist, or the cannabinoid receptor 1 antagonist SR141716A, as monotherapy would improve functional recovery after TBI. A total of 404 adult Sprague-Dawley male rats were randomized into two groups: sham-injured or lateral fluid-percussion-induced TBI. The rats were treated with atipamezole (started at 30min or 7 d after TBI) or SR141716A (2min or 30min post-TBI) for up to 9 wk. Total follow-up time was 14 wk after treatment initiation. Outcome measures included motor (composite neuroscore, beam-walking) and cognitive performance (Morris water-maze), seizure susceptibility, spontaneous seizures, and cortical and hippocampal pathology. All injured rats exhibited similar impairment in the neuroscore and beam-walking tests at 2 d post-TBI. Atipamezole treatment initiated at either 30min or 7 d post-TBI and continued for 9 wk via subcutaneous osmotic minipumps improved performance in both the neuroscore and beam-walking tests, but not in the Morris water-maze spatial learning and memory test. Atipamezole treatment initiated at 7 d post-TBI also reduced seizure susceptibility in the pentylenetetrazol test 14 wk after treatment initiation, although it did not prevent the development of epilepsy. SR141716A administered as a single dose at 2min post-TBI or initiated at 30min post-TBI and continued for 9 wk had no recovery-enhancing or antiepileptogenic effects. Mechanistic studies to assess the α-adrenoceptor subtype specificity of the disease-modifying effects of atipametzole revealed that genetic ablation of α-noradrenergic receptor function in Adra2A mice carrying an N79P point mutation had antiepileptogenic effects after TBI. On the other hand, blockade of α-adrenoceptors using the receptor subtype-specific antagonist ORM-12741 had no favorable effects on the post-TBI outcome. Finally, to assess whether regulation of the post-injury inflammatory response by atipametzole in glial cells contributed to a favorable outcome, we investigated the effect of atipamezole on spontaneous and/or lipopolysaccharide-stimulated astroglial or microglial cytokine release in vitro. We observed no effect. Our data demonstrate that a 9-wk administration of α2A-noradrenergic antagonist, atipamezole, is recovery-enhancing after TBI.
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Sleep disturbances commonly occur after traumatic brain injury (TBI) and may predispose patients to epileptic seizures. We hypothesized that unprovoked seizure occurrence post-TBI depends on the sleep-wake cycle, and that the electrographic characteristics of a given sleep stage provide biomarkers for post-traumatic epilepsy (PTE). We show, in a rat lateral fluid percussion model, that 92% of spontaneous generalized seizures occur during the transition from stage III to rapid eye movement sleep. Moreover, a reduction in spindle duration and dominant frequency during the transition stage present as specific and sensitive noninvasive biomarkers for experimentally induced PTE with generalized electrographic seizures.
Severe traumatic brain injury (TBI) induces seizures or status epilepticus (SE) in 20-30% of patients during the acute phase. We hypothesized that severe TBI induced with lateral fluid-percussion injury (FPI) triggers post-impact SE. Adult Sprague-Dawley male rats were anesthetized with isoflurane and randomized into the sham-operated experimental control or lateral FPI-induced severe TBI groups. Electrodes were implanted right after impact or sham-operation, then videoelectroencephalogram (EEG) monitoring was started. In addition, video-EEG was recorded from naïve rats. During the first 72 h post-TBI, injured rats had seizures that were intermingled with other epileptiform EEG patterns typical to nonconvulsive SE, including occipital intermittent rhythmic delta activity, lateralized or generalized periodic discharges, spike-and-wave complexes, poly-spikes, poly-spike-and-wave complexes, generalized continuous spiking, burst suppression, or suppression. Almost all (98%) of the electrographic seizures were recorded during 0-72 h post-TBI (23.2-17.4 seizures/rat). Mean latency from the impact to the first electrographic seizure was 18.4-15.1 h. Mean seizure duration was 86-57 sec. Analysis of high-resolution videos indicated that only 41% of electrographic seizures associated with behavioral abnormalities, which were typically subtle (Racine scale 1-2). Fifty-nine percent of electrographic seizures did not show any behavioral manifestations. In most of the rats, epileptiform EEG patterns began to decay spontaneously on Days 5-6 after TBI. Interestingly, also a few sham-operated and naïve rats had post-operation seizures, which were not associated with EEG background patterns typical to non-convulsive SE seen in TBI rats. To summarize, our data show that lateral FPI-induced TBI results in non-convulsive SE with subtle behavioral manifestations; this explains why it has remained undiagnosed until now. The lateral FPI model provides a novel platform for assessing the mechanisms of acute symptomatic non-convulsive SE and for testing treatments to prevent post-injury SE in a clinically relevant context.
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