Disease-modifying effect of atipamezole in a model of post-traumatic epilepsy

Abstract

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.

Postinjury weight rather than cognitive or behavioral impairment predicts development of posttraumatic epilepsy after lateral fluid‐percussion injury in rats

“…4,5 In the present study, the lateral FPI-induced impact force varied between 3.09 and 3.43 atm in the TBI+ and 3.03-3.44 in TBI− groups, suggesting that there could be some variability in the severity of TBI. We detected no relationship between the impact force and epileptogenesis, however, in accordance with our previous studies 13,18 . Moreover, the range of impact forces does not correlate with the severity of the cortical lesion area or T2 signal enhancement in magnetic resonance imaging.…”

“…Our findings revealed no association between acute seizure-like behavior and development of PTE, consistent with our previous study. 18 In the present study, the average body weight reduction during the first postinjury week was 12% in the TBI− group and 15% in the TBI+ group. It is well known that animals with lateral FPI lose weight, which apparently relates to brain injury-induced loss of consciousness and motor impairment, but also to nonconvulsive status epilepticus, which can last for 3-4 days.…”

“…32,33 In correlation with the present study, acute postimpact seizure-like behaviors have been reported to occur immediately after the impact in 20% to 30% of animals, and last for approximately 30 seconds. 13,18,33 It is important to differentiate these "immediate post-impact seizure-like behaviors" from postinjury seizures. We recently demonstrated that almost all animals with lateral FPI develop postinjury nonconvulsive status epilepticus, which is associated with both immediate (<24 hours) electrographic seizures, typically occurring within a few hours after impact, and early (<7 days) electrographic seizures, most of which are nonconvulsive and occur during D1-D4 after TBI.…”

“…The power calculation was based on our previous data indicating that approximately 25% of rats with severe lateral fluid-percussion-induced (FPI) traumatic brain injury (TBI) will have at least one spontaneous seizure (ie, epilepsy) during the 1-month video-electroencephalography (video-EEG) monitoring at the sixth post-TBI month. 13,18,46 Furthermore, the biomarker was expected to have an area under the curve > 0.700 in the receiver-operating characteristic (ROC) analysis. Consequently, we needed at least 22 rats with epilepsy.…”

“…FPI triggers epileptogenesis in approximately 25% to 50% of rats over a 12-month follow-up. [13][14][15][16][17][18] It is well-documented that lateral FPI also results in poor performance in spatial memory, depression, and anxiety tests, [19][20][21][22] which persists for months after FPI. 21 As observed in humans with severe TBI, structural lesions after FPI-induced TBI are progressive and widely distributed, including in the cerebral cortex, thalamus, hippocampus, and amygdala, and their connections.…”