title: Post-injury administration of the mitochondrial permeability transition pore inhibitor, NIM811, is neuroprotective and improves cognition after traumatic brain injury in rats.
abstract: Mitochondrial dysfunction is known to play a pivotal role in cell death mechanisms following traumatic brain injury (TBI). N-methyl-4-isoleucine-cyclosporin (NIM811), a non-immunosuppressive cyclosporin A (CsA) analog, inhibits the mitochondrial permeability transition pore (mPTP) and has been shown to be neuroprotective following TBI in mice. However, the translation of the neuroprotective effects of mPTP inhibitors, including CsA and NIM811, into improved cognitive end points has yet to be fully investigated. Therefore, to build upon these results, a severe unilateral controlled cortical impact model of TBI was used in the present study to establish a dose-response curve for NIM811 in rats. The findings demonstrate that the neuroprotection afforded by NIM811 is dose dependent, with the 10 mg/kg dose being the most effective dose. Once the dose response was established, we evaluated the effect of the optimal dose of NIM811 on behavior, mitochondrial bioenergetics, and mitochondrial oxidative damage following TBI. For behavioral studies, rats were administered NIM811 at 15 min and 24 h post-injury, with cognitive testing beginning 10 days post-injury. Mitochondrial studies involved a single injection of NIM811 at 15 min post-injury followed by mitochondrial isolation at 6 h post-injury. The results revealed that the optimal dose of NIM811 improves cognition, improves mitochondrial functioning, and reduces oxidative damage following TBI.
authors.affiliation: Spinal Cord & Brain Injury Research Center, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Readnower
authors.forename: Jignesh D
authors.initials: JD
authors.lastname: Pandya
authors.forename: Melanie L
authors.initials: ML
authors.lastname: McEwen
authors.forename: James R
authors.initials: JR
authors.lastname: Pauly
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Springer
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Sullivan
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000503:physiopathology; D003071:Cognition / Q000187:drug effects*; D016572:Cyclosporine / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018696:Neuroprotective Agents; D016572:Cyclosporine; C090438:(melle-4)cyclosporin