Introduction: We studied the pharmacokinetics and pharmacology of intravenously administered CNB-001, a pleiotropic anti-inflammatory molecule with neurotrophic properties in two rabbit neuro-ischemia models.
Hypothesis: In vitro, we have found that CNB-001 can significantly reduce cell death mediated by glutamate, iodoacetic acid, ATP depletion, oxidative stress (glutathione depletion) and oxygen-glucose depletion. We tested the hypothesis that CNB-001 would attenuate ischemia-induced behavioral deficits in vivo.
Methods: Abiding by RIGOR guidelines, the study was randomized and the neuro-examiners were naive (blinded) to treatment. CNB-001 (10mg/kg) was administered IV 45 minutes prior to balloon of occlusion of the infrarenal aorta, which reliably produces spinal cord ischemia (SCI) depending upon the occlusion time. Using TARLOV scores and quantal analysis, we quantified the ischemia duration (P50 in minutes) producing SCI in 50% of study rabbits. Second, using a rabbit embolic stroke model (RSCEM), CNB-001(1-25mg/kg) was applied IV 1 hour post-ischemia and behavioral function measured. We calculated the effective stroke clot dose (P50 in mg) producing neurological deficits in 50% of embolized rabbits. Control groups and positive-control drugs were also studied in parallel in both rabbit ischemia models. All behavioral endpoints were measured 2days after ischemia.
Results: Pharmacokinetic analysis of CNB-001 in normal male rabbits indicated that the t1/2 was 3.37 ± 0.52 hours and clearance rate was 44.2 ml/min/kg in rabbits. In the SCI model, CNB-001 (10mg/kg) significantly increased P50 values to 19.38 ± 2.03 min (n=16) from 13.58 ± 0.90min (n=14; p<0.05); the positive control, memantine (IV 10mg/kg) increased P50 to 22.52 ± 2.98 min (n=23; P<0.05). In the RSCEM, 10mg/kg CNB-001 significantly improved behavior: P50 2.15 ± 0.09 mg (n=18, p<0.05) compared to vehicle 1.11± 0.08 mg (n=20), when the drug was administered 1 hour after embolization; tPA (IV 3.3mg/kg) also increased P50 2.69 ± 0.29mg (n=20).
Conclusions: CNB-001 can be provided to patients prior to cardiaovascular surgery to reduce the probability of SCI. Moreover, CNB-001 can reduce behavioral deficits associated with brain ischemia when given after an embolic stroke.