High-Dose MK-801 Attenuated Early TTC-Defined Cortical Injury Even under the Conditions of Suppressed Rapamycin-Sensitive pS6 Signaling during Early Cerebral Ischemia–Reperfusion
Experimental study demonstrates MK-801 attenuates cortical injury in ischemic rats despite mTORC1 suppression, suggesting neuroprotection independent of downstream pS6 signaling.
Key Points
To determine whether NMDA receptor antagonism by MK-801 protects against early cerebral ischemia–reperfusion injury under conditions of suppressed mTORC1 activity.
Rats received rapamycin (20 mg/kg, i.p.) for two days before undergoing 90 minutes of transient middle cerebral artery occlusion (MCAO), followed by MK-801 (5 mg/kg, i.v.) administered 15 minutes post-occlusion.
Blood–brain barrier permeability, plasma volume, and TTC-defined cortical infarct size were measured after two hours of reperfusion; Western blots in non-ischemic rats assessed pS6, pAkt, mBDNF, proBDNF, and MMP-2.
MK-801 reduced cortical infarct size from 8.4% ± 2.1% to 4.7% ± 1.5% in the control group and from 12.2% ± 2.3% to 6.7% ± 2.0% in the rapamycin-pretreated group.
Blood–brain barrier permeability remained unchanged across groups, but MK-801 treatment produced the largest average plasma volume.
MK-801 elevated pS6 in non-ischemic brains (an effect abolished by rapamycin) and increased proBDNF without altering mBDNF, neither of which depended on rapamycin pretreatment.