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 Res. 1996 Nov 11;739(1-2):36-45. doi: 10.1016/s0006-8993(96)00808-6.


Diffusion-weighted magnetic resonance imaging (DWI) is capable of noninvasively imaging acute cerebral ischemia. We demonstrate the utility of this technique by evaluating SNX-111, a novel N-type calcium channel blocker with potential neuroprotective properties, in a rodent model of transient focal ischemia. Twenty-four Sprague-Dawley rats weighing between 310-350 g underwent occlusion of the middle cerebral artery (MCAO) for 105 min followed by 22.5 h of reperfusion. Thirty minutes following MCAO, animals were randomized to receive SNX-111 5 mg/kg intravenously over 1 h vs. placebo. DWI and T2-weighted MRIs (T2W) were performed at 0.5, 1.5 and 24 h after the onset of ischemia. Area fractions of increased signal intensity on the DWI and T2W images were measured. DWI area fractions at 1.5 and 24 h were also normalized to the initial, pre-treatment scans. Apparent diffusion coefficients (ADC) were calculated from fitted maps. Tri-phenyl tetrazolium chloride (TTC) staining was performed on brains at 24 h and infarct area fractions were measured. SNX-111 treated animals showed significantly improved 1.5-h DWI 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 improved DWI ratios was seen by 24 h in the SNX-111 group (2.5 +/- 0.75 vs. 4.12 +/- 1.6, N.S.) DWI, T2W and TTC area fractions at 24 h also showed 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 groups 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 ischemic model, SNX-111 provides early neuroprotection and that serial DWI is a useful way of demonstrating this.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcium Channel Blockers / therapeutic use*
  • Cerebral Infarction / complications
  • Cerebral Infarction / pathology
  • Data Interpretation, Statistical*
  • Diffusion
  • Disease Models, Animal
  • Image Processing, Computer-Assisted
  • Ischemic Attack, Transient / complications
  • Ischemic Attack, Transient / diagnosis
  • Ischemic Attack, Transient / drug therapy*
  • Linear Models
  • Magnetic Resonance Imaging / methods*
  • Neuroprotective Agents / therapeutic use*
  • Peptides / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors
  • omega-Conotoxins*


  • Calcium Channel Blockers
  • Neuroprotective Agents
  • Peptides
  • omega-Conotoxins
  • ziconotide