The History of Neurosurgical Management of Ischemic Stroke

Stroke remains a major public health issue and the second leading cause of death worldwide. The Hippocratic Corpus used the word apoplexy to describe a person collapsing while retaining pulse and respiration. This is believed to be the first written description of stroke. The theories of what caused stroke evolved over the years. When autopsies were performed stroke was attributed to emboli and thrombi formation. Carotid endarterectomies (CEA) were then performed for the treatment of stroke. Originally CEA were seen with skepticism but the North American Symptomatic Carotid Endarterectomy trial (NASCET) and the European Carotid Surgery trial (ECS) helped restore their efficacy in the management of ischemic stroke. A milestone in the management of ischemic stroke was the use of intravenous tissue plasminogen activator (tPA). Secondary to the limitations of the use of tPA other avenues were sought which included intraarterial recombinant prourokinase and mechanical thrombectomy. The field of mechanical thrombectomy continues to be rapidly changing and evolving. Various randomized controlled trials and meta-analysis have been conducted in order to evaluate who will benefit from mechanical thrombectomies, the timing, the best device to use and the role of combining this intervention with the administration of intravenous tPA

Unsaturated glycoceramides as molecular carriers for mucosal drug delivery of GLP-1

The incretin hormone Glucagon-like peptide 1 (GLP-1) requires delivery by injection for the treatment of Type 2 diabetes mellitus. Here, we test if the properties of glycosphingolipid trafficking in epithelial cells can be applied to convert GLP-1 into a molecule suitable for mucosal absorption. GLP-1 was coupled to the extracellular oligosaccharide domain of GM1 species containing ceramides with different fatty acids and with minimal loss of incretin bioactivity. When applied to apical surfaces of polarized epithelial cells in monolayer culture, only GLP-1 coupled to GM1-ceramides with short-or cis-unsaturated fatty acids trafficked efficiently across the cell to the basolateral membrane by transcytosis. In vivo studies showed mucosal absorption after nasal administration. The results substantiate our recently reported dependence on ceramide structure for trafficking the GM1 across polarized epithelial cells and support the idea that specific glycosphingolipids can be harnessed as molecular vehicles for mucosal delivery of therapeutic peptides

Lipid sorting by ceramide structure from plasma membrane to ER for the cholera toxin receptor ganglioside GM1.

The glycosphingolipid GM1 binds cholera toxin (CT) on host cells and carries it retrograde from the plasma membrane (PM) through endosomes, the trans-Golgi (TGN), and the endoplasmic reticulum (ER) to induce toxicity. To elucidate how a membrane lipid can specify trafficking in these pathways, we synthesized GM1 isoforms with alternate ceramide domains and imaged their trafficking in live cells. Only GM1 with unsaturated acyl chains sorted efficiently from PM to TGN and ER. Toxin binding, which effectively crosslinks GM1 lipids, was dispensable, but membrane cholesterol and the lipid raft-associated proteins actin and flotillin were required. The results implicate a protein-dependent mechanism of lipid sorting by ceramide structure and provide a molecular explanation for the diversity and specificity of retrograde trafficking by CT in host cells