Abstracts

Rationale: Traumatic brain injury (TBI) may affect the pharmacodynamics of centrally acting drugs. Paired-pulse transcranial magnetic stimulation (ppTMS) is a safe and noninvasive measure of cortical GABA-mediated cortical inhibition. Huperzine A (HupA) is a naturally-occurring acetylcholinesterase inhibitor with newly discovered potent GABA-mediated antiepileptic capacity, which is reliably detected by ppTMS. To test whether TBI alters cerebral HupA pharmacodynamics, we exposed rats to fluid percussion injury (FPI), and tested whether ppTMS metrics of cortical inhibition differ in magnitude and temporal pattern in injured rats.   Methods: Anesthetized adult rats were exposed to FPI or sham injury. 90 minutes after TBI, rats were injected with HupA or saline (0.6 mg/kg, i.p.). Cortical inhibition was measured by 15 pulse pairs immediately before the injection at baseline, and then every 15 minutes for 90 minutes post-injection. Log transform of the test:conditioning ratio of the motor evoked potential (MEP) amplitudes were compared across treatment conditions. Repeated Measures ANOVA was used to compare saline and HupA in both sham and TBI groups. Mann Whitney U test was used to compare TBI and sham groups regarding baseline cortical inhibition and time to maximum HupA effect. To compare time to maximal HupA effect, we also adopted a longitudinal model using linear mixed-effects regression model, and included linear and quadratic effects of time and their interaction with group to differentiate the trajectories of sham and TBI groups.  Results: TBI resulted in reduced cortical inhibition 90 minutes after the injury (N=18) compared to sham (N=13) controls (p=0.03). HupA enhanced cortical inhibition after both sham injury (N=6, p=0.002) and TBI (N=6, p=0.02). Time to maximal HupA effect was delayed in the TBI group. The median time to maximum HupA inhibition in sham and TBI groups were 46.4 and 76.5 minutes, respectively (p=0.03). This is consistent with a quadratic trend comparison that projects HupA-mediated cortical inhibition to last longer in injured rats (p=0.007). Conclusions: We show that (1) cortical GABA-mediated inhibition, as measured by ppTMS, decreases acutely after TBI, (2) HupA restores lost post-TBI GABA-mediated inhibition, and (3) HupA-mediated enhancement of cortical inhibition is delayed after TBI. The plausible reasons of the latter include (1) low HupA volume of distribution rendering HupA confined in the intravascular compartment, therefore vulnerable to reduced post-TBI cerebral perfusion (2) GABAR dysfunction following TBI. We anticipate that these and analogous experiments will enable improved dosing of neuropsychiatric medications, especially GABAergic antiepileptic drugs, after brain injury. Funding: This study was funded by Translational Research Program at Boston Children's Hospital.