TIME-COURSE AND TREATMENT RESPONSE WITH SNX-111, AN N-TYPE CALCIUM-CHANNEL BLOCKER, IN A RODENT MODEL OF FOCAL CEREBRAL-ISCHEMIA USING DIFFUSION-WEIGHTED MRI
Ma. Yenari et al., TIME-COURSE AND TREATMENT RESPONSE WITH SNX-111, AN N-TYPE CALCIUM-CHANNEL BLOCKER, IN A RODENT MODEL OF FOCAL CEREBRAL-ISCHEMIA USING DIFFUSION-WEIGHTED MRI, Brain research, 739(1-2), 1996, pp. 36-45
Diffusion-weighted magnetic resonance imaging (DWI) is capable of noni
nvasively imaging acute cerebral ischemia. We demonstrate the utility
of this technique by evaluating SNX-111, a novel N-type calcium channe
l blocker with potential neuroprotective properties in a rodent model
of transient focal ischemia. Twenty-four Sprague-Dawley rats weighting
between 310-350 g underwent occlusion of the middle cerebral artery (
MCAO) for 105 min followed by 22.5 h of reperfusion. Thirty minutes fo
llowing MCAO, animals were randomized to receive SNX-111 5 mg/kg intra
venously over 1 h vs. placebo. DW1 and T2-weighted MRIs (T2W) were per
formed at 0.5, 1.5 and 24 h after the onset of ischemia. Area fraction
s of increased signal intensity on the DWI and T2W images were measure
d. DWI area fractions at 1.5 and 24 h were also normalized to the init
ial, pre-treatment scans. Apparent diffusion coefficients (ADC) were c
alculated from fitted maps. Tri-phenyl tetrazolium chloride (TTC) stai
ning was performed on brains at 24 h and infarct area fractions were m
easured. SNX-111 treated animals showed significantly improved 1.5-h D
WI scan ratios compared to controls (ratios of 1.06 +/- 0.25 vs. 2.98
+/- 0.78 SNX vs. controls respectively, P < 0.05). A trend toward impr
oved DWI ratios was seen by 24 h in the SNX-111 group (2.5 +/- 0.75 vs
. 4.12 +/- 1.5, N.S.) DWI, T2W and TTC area functions at 24 h also sho
wed trends favoring a neuroprotective effect of SNX-111. Bright areas
on DWI corresponded to ADC decreases of about 30% compared to the non-
ischemic hemisphere. These decreases were the same in both treatment g
roups and at each time point. DWI, T2W and TTC area fractions at 24 h
were strongly correlated (r = 0.98, DWI and TTC; r = 0.99, T2W and TTC
; r = 0.97, T2W and DWI, P < 0.0001). We conclude that in this ischemi
c model, SNX-111 provides early neuroprotection and that serial DWI is
a useful way of demonstrating this.