Gaba Drugs For Motor Recovery After Stroke

Abstract

Clinical reports describe a rare but striking recovery of brain function post stroke after taking the non-benzodiazepine ‘Z-drug’ zolpidem. The underlying mechanism for this is still unknown. This body of work investigates the relationship of Z-drugs and stroke and serves three purposes. Firstly, it furthers our understanding of the particular GABAA receptor subtypes Z-drugs modulate. Benzodiazepines bind between the α-γ2 subunit interfaces (where α is α1, α2, α3, or α5). An analogous binding site is present when γ2 is substituted for γ1 or γ3 but has limited and conflicting pharmacological information. Using concatenated GABAA pentamers expressed in Xenopus laevis oocytes, we observe that zaleplon and eszopiclone modulate γ3 receptors with comparable efficacy potency to γ2, zolpidem does not, and no drug tested modulates γ1 receptors. Supporting this, Z-drug binding within neural tissue was assessed via a competitive autoradiography assay using mice with a γ2F77I mutation that prevents Z-drug binding to the γ2 subunit. This study showed zaleplon and eszopiclone, but not zolpidem displaced flumazenil on γ3 receptors. However, there were no observed differences in zaleplon related neural firing activity measured through c-Fos immunoreactivity. Second, this work explores how stroke may alter the expression levels of benzodiazepine-sensitive GABAA receptors. Because the zolpidem effect is observed months to years after initial injury in humans, we investigated expression three weeks post stroke in mice. The radioligand [3H]-flumazenil's total binding density was assessed via autoradiography. We observed no binding density differences indicating that 3-weeks post-stroke, there are no major increases or decreases in expression levels of benzodiazepine-sensitive GABAA receptors. Finally, this dissertation shows that zolpidem treatment in the late phase of recovery in mice after a photothrombotic cortical stroke does not affect motor recovery speed, highlighting a significant difference between reported observations in the clinic and animal stroke models.