title: Activation of Alpha 7 Cholinergic Nicotinic Receptors Reduce Blood-Brain Barrier Permeability following Experimental Traumatic Brain Injury.
abstract: Traumatic brain injury (TBI) is a major human health concern that has the greatest impact on young men and women. The breakdown of the blood-brain barrier (BBB) is an important pathological consequence of TBI that initiates secondary processes, including infiltration of inflammatory cells, which can exacerbate brain inflammation and contribute to poor outcome. While the role of inflammation within the injured brain has been examined in some detail, the contribution of peripheral/systemic inflammation to TBI pathophysiology is largely unknown. Recent studies have implicated vagus nerve regulation of splenic cholinergic nicotinic acetylcholine receptor α7 (nAChRa7) signaling in the regulation of systemic inflammation. However, it is not known whether this mechanism plays a role in TBI-triggered inflammation and BBB breakdown. Following TBI, we observed that plasma TNF-α and IL-1β levels, as well as BBB permeability, were significantly increased in nAChRa7 null mice (Chrna7(-/-)) relative to wild-type mice. The administration of exogenous IL-1β and TNF-α to brain-injured animals worsened Evans Blue dye extravasation, suggesting that systemic inflammation contributes to TBI-triggered BBB permeability. Systemic administration of the nAChRa7 agonist PNU-282987 or the positive allosteric modulator PNU-120596 significantly attenuated TBI-triggered BBB compromise. Supporting a role for splenic nAChRa7 receptors, we demonstrate that splenic injection of the nicotinic receptor blocker α-bungarotoxin increased BBB permeability in brain-injured rats, while PNU-282987 injection decreased such permeability. These effects were not seen when α-bungarotoxin or PNU-282987 were administered to splenectomized, brain-injured rats. Together, these findings support the short-term use of nAChRa7-activating agents as a strategy to reduce TBI-triggered BBB permeability.
  
  
  CONCLUSIONS
  Breakdown of the blood-brain barrier (BBB) in response to traumatic brain injury (TBI) allows for the accumulation of circulating fluids and proinflammatory cells in the injured brain. These processes can exacerbate TBI pathology and outcome. While the role of inflammation in the injured tissue has been examined in some detail, the contribution of peripheral inflammation in BBB breakdown and ensuing pathology has not been well defined. We present experimental evidence to indicate that the stimulation of nicotinic acetylcholine α7 receptors (nAChRa7s) can reduce peripheral inflammation and BBB breakdown after TBI. These results suggest that activators of nAChRa7 may have therapeutic utility for the treatment of TBI.
authors.affiliation: Department of Neurobiology and Anatomy, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas 77030 p.dash@uth.tmc.edu.
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Dash
authors.affiliation: Department of Neurobiology and Anatomy, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas 77030.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Neurobiology and Anatomy, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas 77030.
authors.forename: Nobuhide
authors.initials: N
authors.lastname: Kobori
authors.affiliation: Department of Neurobiology and Anatomy, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas 77030.
authors.forename: John B
authors.identifier: http://orcid.org/0000-0002-3431-1961
authors.initials: JB
authors.lastname: Redell
authors.affiliation: Department of Neurobiology and Anatomy, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas 77030.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hylin
authors.affiliation: Department of Neurobiology and Anatomy, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas 77030.
authors.forename: Kimberly N
authors.initials: KN
authors.lastname: Hood
authors.affiliation: Department of Neurobiology and Anatomy, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas 77030.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Moore
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D001930:Brain Injuries / Q000097:blood* / Q000150:complications / Q000473:pathology*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000209:etiology; D004797:Enzyme-Linked Immunosorbent Assay; D053583:Interleukin-1beta / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010539:Permeability; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics / Q000378:metabolism*; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: C579166:Chrna7 protein, mouse; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; C029417:Von Willebrand antigen; D064569:alpha7 Nicotinic Acetylcholine Receptor; D014841:von Willebrand Factor; D009195:Peroxidase
keywords: blood–brain barrier breakdown; controlled cortical impact brain injury; inflammatory cytokines; secondary TBI pathology