Flufenamic acid improves survival and neurologic outcome after
successful cardiopulmonary resuscitation in mice
Abstract
Background Brain injury is the main cause of high mortality and
disability after successful cardiopulmonary resuscitation (CPR) from
sudden cardiac arrest (CA). Transient receptor potential M4 (TRPM4)
channel is a novel target for ameliorating blood-brain barrier (BBB)
disruption and neuroinflammation. Herein, we tested whether flufenamic
acid (FFA), which is reported to block TRPM4 with high potency, confers
neuroprotection against brain injury secondary to CA/CPR and whether the
action is exerted by blocking the TRPM4 channel. Methods Wild-type (WT)
and Trpm4 knockout (Trpm4−/−) mice subjected to 10-min CA/CPR were
randomized to receive FFA or vehicle once daily. Post-CA/CPR brain
injuries including neurological deficits, survival rate, histological
damages, edema formation, BBB destabilization and neuroinflammation were
assessed. Results In WT mice subjected to CA/CPR, FFA was effective in
improving survival and neurologic outcome, reducing neuropathological
injuries, attenuating brain edema, lessening leakage of IgG, restoring
tight junction protein expression as well as promoting
microglia/macrophages from the pro-inflammatory subtype towards the
anti-inflammatory one. In comparison to WT mice, Trpm4−/− mice exhibited
less neurologic deficiency, lighter histological impairment, more
integrity of BBB and more anti-inflammatory microglia/macrophages
polarization. As expected, FFA did not provide a benefit of
superposition compared with vehicle in the Trpm4−/− mice after CA/CPR.
Conclusions FFA mitigates BBB breach and modifies the functional status
of microglia/macrophages, thereby improving survival and neurological
deficits following CA/CPR. The neuroprotective effects are at least
partially through interfering with the TRPM4 channel. These results
provide significant clinical potentials to improve the prognosis for CA
victims with successful resuscitation.