Alterations in the Timing of Huperzine A Cerebral Pharmacodynamics in the Acute Traumatic Brain Injury Setting

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 gamma-aminobutyric acid (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. Anesthetized adult rats were exposed to FPI or sham injury. Ninety minutes post-TBI, rats were injected with HupA or saline (0.6mg/kg, intraperitoneally). TBI resulted in reduced cortical inhibition 90min 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). The median time to maximum HupA inhibition in sham and TBI groups were 46.4 and 76.5min, respectively (p=0.03). This was consistent with a quadratic trend comparison that projects HupA-mediated cortical inhibition to last longer in injured rats (p=0.007). We show that 1) cortical GABA-mediated inhibition, as measured by ppTMS, decreases acutely post-TBI, 2) HupA restores lost post-TBI GABA-mediated inhibition, and 3) HupA-mediated enhancement of cortical inhibition is delayed post-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, and 2) GABAR dysfunction and increased AChE activity post-TBI.