Enhancing cognitive function in chronic TBI: The Role of α7 nicotinic acetylcholine receptor modulation.

Autor: Sangadi DK; The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA., Sangadi A; The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA., Placeres-Uray F; The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA., Titus DJ; Department of Psychiatry & Behavioral Sciences, University of Minnesota, Minneapolis, MN, USA., Johnstone T; Department of Pharmacology, College of Medicine, University of Arizona, Tucson, USA., Hogenkamp D; Department of Pharmaceutical Sciences, School of Medicine, University of California Irvine, Irvine, USA., Gee KW; Department of Pharmaceutical Sciences, School of Medicine, University of California Irvine, Irvine, USA., Atkins CM; The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA. Electronic address: catkins@miami.edu.
Jazyk: angličtina
Zdroj: Experimental neurology [Exp Neurol] 2024 Feb; Vol. 372, pp. 114647. Date of Electronic Publication: 2023 Dec 08.
DOI: 10.1016/j.expneurol.2023.114647
Abstrakt: Traumatic brain injury (TBI) results in several pathological changes within the hippocampus that result in adverse effects on learning and memory. Therapeutic strategies to enhance learning and memory after TBI are still in the early stages of clinical development. One strategy is to target the α7 nicotinic acetylcholine receptor (nAChR), which is highly expressed in the hippocampus and contributes to the formation of long-term memory. In our previous study, we found that AVL-3288, a positive allosteric modulator of the α7 nAChR, improved cognitive recovery in rats after moderate fluid-percussion injury (FPI). However, whether AVL-3288 improved cognitive recovery specifically through the α7 nAChR was not definitively determined. In this study we utilized Chrna7 knockout mice and compared their recovery to wild-type mice treated with AVL-3288 after TBI. We hypothesized that AVL-3288 treatment would improve learning and memory in wild-type mice, but not Chrna7 -/- mice after TBI. Adult male C57BL/6 wild-type and Chrna7 -/- mice received sham surgery or moderate controlled cortical impact (CCI) and recovered for 3 months. Mice were then treated with vehicle or AVL-3288 at 30 min prior to contextual fear conditioning. At 3 months after CCI, expression of α7 nAChR, choline acetyltransferase (ChAT), high-affinity choline transporter (ChT), and vesicular acetylcholine transporter (VAChT) were found to be significantly decreased in the hippocampus. Treatment of wild-type mice at 3 months after CCI with AVL-3288 significantly improved cue and contextual fear conditioning, whereas no beneficial effects were observed in Chrna7 -/- mice. Parietal cortex and hippocampal atrophy were not improved with AVL-3288 treatment in either wild-type or Chrna7 -/- mice. Our results indicate that AVL-3288 improves cognition during the chronic recovery phase of TBI through modulation of the α7 nAChR.
Competing Interests: Declaration of Competing Interest Gee, Johnstone, and Hogenkamp are patent authors on US Pat. 7,820,663 which covers composition of matter and method of use claims associated with AVL-3288.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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