Intranasal deferoxamine can improve memory in healthy C57 mice, suggesting a partially non-disease-specific pathway of functional neurologic improvement.

INTRODUCTION: Intranasal deferoxamine (IN DFO) has been shown to decrease memory loss and have beneficial impacts across several models of neurologic disease and injury, including rodent models of Alzheimer's and Parkinson's disease. METHODS: In order to assess the mechanism of DFO, determine its ability to improve memory from baseline in the absence of a diseased state, and assess targeting ability of intranasal delivery, we treated healthy mice with IN DFO (2.4 mg) or intraperitoneal (IP) DFO and compared behavioral and biochemical changes with saline-treated controls. Mice were treated 5 days/week for 4 weeks and subjected to behavioral tests 30 min after dosing. RESULTS: We found that IN DFO, but not IP DFO, significantly enhanced working memory in the radial arm water maze, suggesting that IN administration is more efficacious as a targeted delivery route to the brain. Moreover, the ability of DFO to improve memory from baseline in healthy mice suggests a non-disease-specific mechanism of memory improvement. IN DFO treatment was accompanied by decreased GSK-3ß activity and increased HIF-1α activity. CONCLUSIONS: These pathways are suspected in DFO's ability to improve memory and perhaps represent a component of the common mechanism through which DFO enacts beneficial change in models of neurologic disease and injury.

Focal middle cerebral artery ischemia in rats via a transfemoral approach using a custom designed microwire.

OBJECTIVES: The aim of this study was to develop a reliable and repeatable method of inducing focal middle cerebral artery occlusion (MCAo) in rats without ligation of the external carotid artery (ECA), while reducing the risk of subarachnoid hemorrhage. METHODS: We prototyped microwires with different diameters (0.0120 inch, 0.0115 inch, 0.0110 inch), materials, and construction methods (coil-on-core, extruded polymer jacket-on-core). Under fluoroscopic guidance and using femoral artery access, the microwires were navigated into the internal carotid artery of male Wistar rats (n=50, weight 376±64 g) to induce MCAo for 1 or 2 h. We performed neurological assessments at baseline, and at 3, 24, 72, and 168 h after MCAo. MRI measurements were performed on a 9.4 T scanner at 1 and 7 days post-injury. RESULTS: The 0.0115 inch microwire with polymer jacket-on-core provided the most successful outcome. At 1 and 7 days post-injury, we observed similar infarction volumes for 1 and 2 h MCAo in the MRI study. Infarcted lesion volumes in both MCAo groups were significantly reduced at 7 days compared with 1 day post-injury. The trend in longitudinal changes for the scores of different neurological assessments was confirmed to be significant after the injury, but both groups showed a similar trend of neurological deficits over the course of the study. CONCLUSIONS: We have developed a reliable and repeatable MCAo method in rats, allowing for precise occlusion of the MCA under direct fluoroscopic visualization without alteration of the cerebral hemodynamics associated with ECA ligation. The custom designed microwire can also be sized for targeted focal ischemia in larger animals.