COG1410, a novel apolipoprotein E-based peptide, improves functional recovery in a murine model of traumatic brain injury.
Traumatic brain injury (TBI) is a silent epidemic affecting approximately 1.4 million Americans annually, at an estimated annual cost of $60 billion in the United States alone. Despite an increased understanding of the pathophysiology of closed head injury, there remains no pharmacological intervention proven to improve functional outcomes in this setting. Currently, the existing standard of care for TBI consists primarily of supportive measures. Apolipoprotein E (apoE) is the primary apolipoprotein synthesized in the brain in response to injury, where it modulates several components of the neuroinflammatory cascade associated with TBI. We have previously demonstrated that COG133, an apoE mimetic peptide, improved functional outcomes and attenuated neuronal death when administered as a single intravenous injection at 30 min post-TBI in mice. Using the principles of rational drug design, we developed a more potent analog, COG1410, which expands the therapeutic window for the treatment of TBI by a factor of four, from 30 min to 2 h. Mice that received a single intravenous injection of COG1410 at 120 min post-TBI exhibited significant improvement on a short term test of vestibulomotor function and on a long term test of spatial learning and memory. This was associated with a significant attenuation of microglial activation and neuronal death in the hippocampus, the neuroanatomical substrate for learning and memory. Rationally derived apoE mimetic peptides have been demonstrated to exert neuroprotective and anti-inflammatory effects in vitro and in clinically relevant models of brain injury. This represents a novel therapeutic strategy in the treatment of TBI.
Laskowitz
Daniel T
DT
Division of Neurology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
McKenna
Suzanne E
SE
Song
Pingping
P
Wang
Haichen
H
Durham
Lori
L
Yeung
Nolan
N
Christensen
Dale
D
Vitek
Michael P
MP
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002460:Cell Line; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D005911:Gliosis / Q000188:drug therapy / Q000209:etiology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007275:Injections, Intravenous; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors; D016896:Treatment Outcome
D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E; C524548:COG1410; D018696:Neuroprotective Agents; D010455:Peptides