Background and Purpose: Hypoxic-ischemic brain injury, due to reduced supply of oxygen to brain, is a major cause of death and disability. There is no exclusive treatment available so far. Glycine-2-Methylproline-Glutamate (G-2MePE, NNZ 2566), an analogue of Glycine-Proline-Glutamate reduces neuronal injury after focal ischemia in adult rats. The current study investigated into the neuroprotective effects of G-2MePE after global hypoxic-ischemic brain injury in adult rats.Methods: Adult male rats received a single sub cutaneous injection of G-2MePE (1.2mg/kg) 3h post hypoxic-ischemic brain injury or the same volume of normal saline. Brains were extracted 5 days after the treatment. Tissue damage in the cortex, hippocampus and striatum was assessed. Neuronal survival, glial reactions, caspase-3 activity and TNF-α cytokine activity were also assessed.Results: The treatment with G-2MePE was associated with a significant reduction of tissue damage, improvement in neuronal survival, reduction in reactive microglia, TNF-α positive cells and caspase-3 positive cells in hippocampus and cortex but an elevation of astrocytosis.Conclusions: Neuroprotection with G-2MePE after hypoxic-ischemic brain injury in adult rats is associated with reduced neuronal necrosis, apoptosis, modulated inflammatory responses and augmented astrocytosis.
We examined the role of CCRL2 in ischemic brain injury using both in vitro and in vivo mouse stroke models. The expression of CCRL2 was enhanced at both the RNA and protein levels in cultured brain slices under ischemic conditions. Ischemia-induced cell death was reduced in brain slices derived from CCRL2 knockout (KO) mice in comparison with those from wild type (WT) mice. The infarct volume was smaller and neurological deficits were attenuated in CCRL2 KO mice when compared to WT mice subjected to a transient middle cerebral artery occlusion. Our data suggest that CCRL2 is involved in ischemia-induced brain injury in mice.
Although acute ischemic stroke has high mortality and morbidity rate but yet still has very limited treatment. In this study we have tested the concept of neuron protection by acute bioenergetic intervention or by pharmacological preconditioning with natural antioxidants. Adenosine triphosphate (ATP), pentobarbital, and suramin were encapsulated in pH-sensitive liposomes and used as bioenergy stabilizer. We induced ATP depletion model by incubating cells with media added with ATP-depleting agents for 2 hours. Treatment with bioenergy stabilizer started 10-min post inducing of ATP-depletion. The acute treatment with bioenergy stabilizer significantly increased cell viability in neuro-2a cells. In searching for a pharmacological preconditioning candidate for reducing ischemic injury, we tested cocoa-derived flavanols using bilateral common carotid artery occlusion (BCCAO). We pretreated mice with cocoa-derived flavanols (75 mg/kg) or water orally for 7 days and subjected mice for 12 minutes BCCAO. At 7 days post-ischemia, the number of surviving hippocampal CA1 neurons was significantly higher in the treated mice than in the water-treated controls. The protection from cocoa-derived flavanols was found associated with increased total antioxidant capacity in the brain. Our results indicate that for reducing acute ischemic injury bioenergetic intervention using advanced drug delivery tools is conceptually feasible, and for reducing reperfusion related secondary injury pharmacological preconditioning may provide significant protection.