title: High therapeutic potential of positive allosteric modulation of α7 nAChRs in a rat model of traumatic brain injury: proof-of-concept.
abstract: There are currently no clinically efficacious drug therapies to treat brain damage secondary to traumatic brain injury (TBI). In this proof-of-concept study, we used a controlled cortical impact model of TBI in young adult rats to explore a novel promising approach that utilizes PNU-120596, a previously reported highly selective Type-II positive allosteric modulator (α7-PAM) of α7 nicotinic acetylcholine receptors (nAChRs). α7-PAMs enhance and prolong α7 nAChR activation, but do not activate α7 nAChRs when administered without an agonist. The rational basis for the use of an α7-PAM as a post-TBI treatment is tripartite and arises from: (1) the intrinsic ability of brain injury to elevate extracellular levels of choline (a ubiquitous cell membrane-building material and a selective endogenous agonist of α7 nAChRs) due to the breakdown of cell membranes near the site and time of injury; (2) the ubiquitous expression of functional α7 nAChRs in neuronal and glial/immune brain cells; and (3) the potent neuroprotective and anti-inflammatory effects of α7 nAChR activation. Therefore, both neuroprotective and anti-inflammatory effects can be achieved post-TBI by targeting only a single player (i.e., the α7 nAChR) using α7-PAMs to enhance the activation of α7 nAChRs by injury-elevated extracellular choline. Our data support this hypothesis and demonstrate that subcutaneous administration of PNU-120596 post-TBI in young adult rats significantly reduces both brain cell damage and reactive gliosis. Therefore, our results introduce post-TBI systemic administration of α7-PAMs as a promising therapeutic intervention that could significantly restrict brain injury post-TBI and facilitate recovery of TBI patients.
authors: UT Southwestern Medical Center, Department of Surgery, Department of Neurosurgery, 5323 Harry Hines Blvd, Dallas, TX 75390-9160, United States.
authors: Joshua W
authors: JW
authors: Gatson
authors: University of West Virginia, Center for Basic and Translational Stroke Research, Department of Physiology and Pharmacology, Morgantown, WV 26506, United States.
authors: James W
authors: JW
authors: Simpkins
authors: University of North Texas Health Science Center, Department of Pharmacology and Neuroscience, 3500 Camp Bowie Blvd, Fort Worth, TX 76248, United States. Electronic address: Victor.Uteshev@unthsc.edu.
authors: Victor V
authors: VV
authors: Uteshev
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D018678:Cholinergic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D005911:Gliosis / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; D000893:Anti-Inflammatory Agents; D018678:Cholinergic Agents; D007555:Isoxazoles; D018696:Neuroprotective Agents; D010671:Phenylurea Compounds; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: Alpha7; Choline; Nicotinic; PNU-120596; PNU120596; Traumatic brain injury
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