Neuroprotective Effects of Tempol and Its Acyl Esters in a Rat Partial Optic Nerve Crush Model

Abstract

 

Purpose:

 

To compare the efficacy of Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl), a superoxide dismutase mimetic, and its 4 acyl derivatives with different numbers of side-chain carbons (Tempol-C4, -C8, -C12, -C16) as retinoprotective agents in a rat model of partial optic nerve crush (PONC).

 

Methods:

 

Tempol in doses of 5.8, 29 and 116 micromole/kg (equivalent to 1, 5 and 20 mg/kg) or its acyl derivatives in doses 5.8 micromole/kg were administered intraperitoneally to Brown-Norway rats 6 hours before the calibrated partial optic nerve crush (PONC) and then once daily for 7 consecutive days. Control rats were treated with vehicle (5% ethanol in PBS, pH 7.2). RGC were retrogradely labeled with the fluorescent tracer Fluorogold 5 days after PONC. Eyes were enucleated 2 days later, RGC counting was performed on retinal wholemounts. Data are expressed as RGC counts per mm² of retina +/- SE.

 

Results:

 

In vehicle-treated animals PONC reduced RGC counts by approx. 60%. Tempol significantly attenuated RGC loss after PONC in a dose of 20 mg/kg but not in a dose of 1mg/kg. In molar doses equivalent to 1mg/kg of Tempol, Tempol-C4 and in particular Tempol-C8 showed enhanced neuroprotective effects, similar to that of unmodified Tempol in a dose of 20 mg/kg. Tempol-C12 and C-16 did not produce neuroprotection.

 

Conclusions:

 

Our results indicate that short-chain (C4- and C8-) acyl esters of Tempol are much more potent neuroprotectants than Tempol, however further increase in acyl chain length results in a loss of neuroprotective effects.  

 

Keywords: neuroprotection • apoptosis/cell death • ganglion cells