Preconditioning induces sustained neuroprotection by downregulation of adenosine 5'-monophosphate-activated protein kinase.

Ischemic preconditioning (IPC) induces endogenous neuroprotection from a subsequent ischemic injury. IPC involves downregulation of metabolic pathways. As adenosine 5'-monophosphate-activated protein kinase (AMPK) is a critical sensor of energy balance and plays a major role in cellular metabolism, its role in IPC was investigated. A brief 3-min middle cerebral artery occlusion (MCAO) was employed to induce IPC in male mice 72 h before 90-min MCAO. Levels of AMPK and phosphorylated AMPK (pAMPK), the active form of the kinase, were assessed after IPC. A pharmacological activator or inhibitor of AMPK was used to determine the dependence of IPC on AMPK signaling. Additionally, AMPK-α2 null mice were subjected to IPC, and subsequent infarct damage was assessed. IPC induced neuroprotection, enhanced heat shock protein-70 (HSP-70), and improved behavioral outcomes. These beneficial effects occurred in parallel with a significant inhibition of pAMPK protein expression. Although both pharmacological inhibition of AMPK or IPC led to neuroprotection, IPC offered no additional protective effects when co-administered with an AMPK inhibitor. Moreover, pharmacological activation of AMPK with metformin abolished the neuroprotective effects of IPC. AMPK-α2 null mice that lack the catalytic isoform of AMPK failed to demonstrate a preconditioning response. Regulation of AMPK plays an important role in IPC-mediated neuroprotection. AMPK may be a potential therapeutic target for the treatment of cerebral ischemia.

Breakdown and reestablishment of blood-aqueous barrier with implant surgery.

Preoperative and serial postoperative anterior chamber fluorophotometry was performed after oral administration of fluorescein sodium in patients undergoing extracapsular cataract extraction combined with intraocular lens implantation. In placebo-treated eyes, the blood-aqueous barrier was reestablished at three months after surgery. The administration of topical indomethacin before and after surgery markedly decreased aqueous fluorescein concentration, and the blood-aqueous barrier was reestablished within five weeks. Because all patients were given sub-Tenon's injection of steroids immediately after surgery and intensive topical steroid therapy postoperatively, the effect of topical indomethacin was additive to or synergistic with steroids. The addition of topical indomethacin caused a small but statistically significant increase in the postoperative intraocular pressure; this effect lasted nine weeks.

Slit-lamp fluorophotometry in intraocular lens patients.

Two hundred and sixty-four patients who had unilateral implant surgery and normal contralateral unoperated eyes were studied by slit-lamp anterior segment fluorophotomety. Patients tested five weeks to six months after surgeryb averaged 22% more fluorescein in the operated than in the unoperated eye, while those tested after six months averaged only 12% more fluorescein. Patients receiving topical indomethacin demonstrated an 11% increase in fluorescein, while those taking a placebo averaged a 33% increase. Patients with cystoid macular edema averaged a 46% increase in fluorescein compared with a 17% increase in the other patients. Twenty-seven control patients with unilaterally aphakic eyes and normal contralateral unoperated eyes, tested on an average of two years after surgery, showed essentially no increase in fluorescein in the operated eye. Fluorophotometry may be a valuable clinical tool in testing the effect of drugs on the blood-aqueous barrier and to screen patients for cystoid macular edema.