Testing Different Combinations of Acoustic Pressure and Doses of Quinolinic Acid for Induction of Focal Neuron Loss in Mice Using Transcranial Low-Intensity Focused Ultrasound.

The goal of this study was to test different combinations of acoustic pressure and doses of quinolinic acid (QA) for producing a focal neuronal lesion in the murine hippocampus without causing unwanted damage to adjacent brain structures. Sixty male CD-1 mice were divided into 12 groups that underwent magnetic resonance-guided focused ultrasound at high (0.67 MPa), medium (0.5 MPa) and low (0.33 MPa) acoustic peak negative pressures and received QA at high (0.012 mmol), medium (0.006 mmol) and low (0.003 mmol) dosages. Neuronal loss occurred only when magnetic resonance-guided focused ultrasound with adequate acoustic power (0.67 or 0.5 MPa) was combined with QA. The animals subjected to the highest acoustic power had larger lesions than those treated with medium acoustic power, but two mice had evidence of bleeding. When the intermediate acoustic power was used, medium and high dosages of QA produced lesions larger than those produced by the low dosage.

Perihematomal Cellular Injury Is Reduced by Trans-sodium Crocetinate in a Model of Intracerebral Hemorrhage.

The carotenoid compound trans-sodium crocetinate (TSC) has been shown to increase oxygenation in various tissues, including the brain. Notably, TSC can enhance oxygenation under conditions of reduced blood flow, thus attenuating the depth of an ischemic challenge. This study examined the impact of TSC on neuronal loss in an animal model of intracerebral hemorrhage (ICH). Utilizing a rat model of collagenase injection, TSC was shown to reduce perihematomal cellular loss after ICH, as assessed by Fluoro-Jade B staining in tissue sections. This is the first evidence demonstrating that TSC is capable of limiting hemorrhagic injury to neurons in the brain. The finding supports the concept that TSC may represent a candidate therapeutic for early intervention regardless of whether a stroke is hemorrhagic or ischemic in nature.

Metabolic reflow as a therapy for ischemic brain injury.

Ischemic neuronal damage is a common feature of occlusive strokes, hemorrhagic strokes, and traumatic brain injury. In addition, ischemia can be an anticipated or unanticipated complication of a variety of surgical procedures. Most therapeutic strategies for managing ischemic injury seek to re-establish blood flow, suppress neural metabolism, and/or limit specific cellular injury cascades. An alternative therapeutic approach is to enhance the delivery of metabolic substrates to ischemic tissue. This strategy is typified by efforts to increase tissue oxygenation by elevating the levels of circulating oxygen. Our studies are examining a complementary approach in which the delivery of metabolic substrates is enhanced by facilitating the diffusion of oxygen and glucose from the vasculature into neural tissue during ischemia. This is achieved by increasing the diffusivity of small molecules in aqueous solutions, such as plasma and interstitial fluid. The carotenoid compound, trans-sodium crocetinate (TSC) is capable of increasing oxygen and glucose diffusivity, and our studies demonstrate that TSC increases cerebral tissue oxygenation in the penumbra of a focal ischemic event. In addition, TSC treatment reduces the volume of cerebral infarction in rodent models of both permanent and temporary focal ischemia. This strategy of "metabolic reflow" thus blunts the metabolic challenge in partially-perfused tissue and reduces ischemic neural injury.