1. Controlled cortical impact-induced neurodegeneration decreases after administration of the novel calpain-inhibitor Gabadur.
- Author
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Dugue R, Hassen GW, Shulman A, Goodman JH, Michelson H, Serrano P, Chauhan S, and Ling DSF
- Subjects
- Animals, Brain drug effects, Brain pathology, Brain physiopathology, Brain Injuries, Traumatic complications, Brain Injuries, Traumatic pathology, Brain Injuries, Traumatic physiopathology, Calpain antagonists & inhibitors, Calpain metabolism, Disease Models, Animal, Glycoproteins chemistry, Molecular Structure, Neurodegenerative Diseases etiology, Neurodegenerative Diseases pathology, Neurodegenerative Diseases physiopathology, Neurons drug effects, Neurons pathology, Neurons physiology, Neuroprotective Agents chemistry, Pregabalin chemistry, Rats, Sprague-Dawley, Brain Injuries, Traumatic drug therapy, Glycoproteins pharmacology, Leupeptins chemistry, Neurodegenerative Diseases drug therapy, Neuroprotective Agents pharmacology, Pregabalin analogs & derivatives, Pregabalin pharmacology
- Abstract
One aspect of secondary injury in traumatic brain injury is the marked increase in intracellular calcium and resultant over-activation of the calcium-dependent neutral cysteine protease calpain. Gabadur is a novel protease inhibitor with calpain-inhibition properties formulated from the classic protease inhibitor leupeptin linked to a pregabalin carrier. This construction allows the entire compound to cross the blood-brain barrier after peripheral administration to better target the site of injury. In this study, a single intraperitoneal dose of Gabadur was administered immediately following controlled cortical impact injury in rats. Neocortical slices were examined at 48 h post-injury via Fluoro-Jade B staining, revealing an improvement in cortical neurodegeneration in Gabadur treated rats. Levels of detrimental active calpain-2 measured via western blot were also decreased in rats receiving Gabadur. This data supports the benefit of targeted protease inhibition in the treatment of traumatic brain injury., (Copyright © 2018. Published by Elsevier Inc.)
- Published
- 2018
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