title: Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation.
abstract: The neuroinflammatory response following traumatic brain injury (TBI) is known to be a key secondary injury factor that can drive ongoing neuronal injury. Despite this, treatments that have targeted aspects of the inflammatory pathway have not shown significant efficacy in clinical trials.
  
  
  
  We suggest that this may be because classical inflammation only represents part of the story, with activation of neurogenic inflammation potentially one of the key initiating inflammatory events following TBI. Indeed, evidence suggests that the transient receptor potential cation channels (TRP channels), TRPV1 and TRPA1, are polymodal receptors that are activated by a variety of stimuli associated with TBI, including mechanical shear stress, leading to the release of neuropeptides such as substance P (SP). SP augments many aspects of the classical inflammatory response via activation of microglia and astrocytes, degranulation of mast cells, and promoting leukocyte migration. Furthermore, SP may initiate the earliest changes seen in blood-brain barrier (BBB) permeability, namely the increased transcellular transport of plasma proteins via activation of caveolae. This is in line with reports that alterations in transcellular transport are seen first following TBI, prior to decreases in expression of tight-junction proteins such as claudin-5 and occludin. Indeed, the receptor for SP, the tachykinin NK1 receptor, is found in caveolae and its activation following TBI may allow influx of albumin and other plasma proteins which directly augment the inflammatory response by activating astrocytes and microglia.
  
  
  
  As such, the neurogenic inflammatory response can exacerbate classical inflammation via a positive feedback loop, with classical inflammatory mediators such as bradykinin and prostaglandins then further stimulating TRP receptors. Accordingly, complete inhibition of neuroinflammation following TBI may require the inhibition of both classical and neurogenic inflammatory pathways.
authors.affiliation: Adelaide Centre for Neuroscience Research, School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia. frances.corrigan@adelaide.edu.au.
authors.forename: Frances
authors.initials: F
authors.lastname: Corrigan
authors.affiliation: Adelaide Centre for Neuroscience Research, School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Kimberley A
authors.initials: KA
authors.lastname: Mander
authors.affiliation: Adelaide Centre for Neuroscience Research, School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Anna V
authors.initials: AV
authors.lastname: Leonard
authors.affiliation: Sansom Institute for Health Research, The University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: Vink
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology; D000070642:Brain Injuries, Traumatic / Q000150:complications* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D020078:Neurogenic Inflammation / Q000209:etiology*; D009457:Neuroglia / Q000473:pathology; D009474:Neurons / Q000473:pathology; D013373:Substance P / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000378:metabolism
chemical_list: D050051:Transient Receptor Potential Channels; D013373:Substance P
keywords: Caveolae; Neuroinflammation; Neurokinin 1 receptor; Substance P; Traumatic brain injury