title: Modulation of cholinergic pathways and inflammatory mediators in blast-induced traumatic brain injury.
abstract: Cholinergic activity has been recognized as a major regulatory component of stress responses after traumatic brain injury (TBI). Centrally acting acetylcholinesterase (AChE) inhibitors are also being considered as potential therapeutic candidates against TBI mediated cognitive impairments. We have evaluated the expression of molecules involved in cholinergic and inflammatory pathways in various regions of brain after repeated blast exposures in mice. Isoflurane anesthetized C57BL/6J mice were restrained and placed in a prone position transverse to the direction of the shockwaves and exposed to three 20.6 psi blast overpressures with 1-30 min intervals. Brains were collected at the 6h time point after the last blast exposure and subjected to cDNA microarray and microRNA analysis. cDNA microarray analysis showed significant changes in the expression of cholinergic (muscarinic and nicotinic) and gammaaminobutyric acid and glutamate receptors in the midbrain region along with significant changes in multiple genes involved in inflammatory pathways in various regions of the brain. MicroRNA analysis of cerebellum revealed differential expression of miR-132 and 183, which are linked to cholinergic anti-inflammatory signaling, after blast exposure. Changes in the expression of myeloperoxidase in the cerebellum were confirmed by Western blotting. These results indicate that early pathologic progression of blast TBI involves dysregulation of cholinergic and inflammatory pathways related genes. Acute changes in molecules involved in the modulation of cholinergic and inflammatory pathways after blast TBI can cause long-term central and peripheral pathophysiological changes.
authors.affiliation: Blast-Induced Neurotrauma Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA. m.valiyaveettil@amedd.army.mil
authors.forename: Manojkumar
authors.initials: M
authors.lastname: Valiyaveettil
authors.forename: Yonas A
authors.initials: YA
authors.lastname: Alamneh
authors.forename: Stacey-Ann
authors.initials: SA
authors.lastname: Miller
authors.forename: Rasha
authors.initials: R
authors.lastname: Hammamieh
authors.forename: Peethambaran
authors.initials: P
authors.lastname: Arun
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Yanling
authors.initials: Y
authors.lastname: Wei
authors.forename: Samuel
authors.initials: S
authors.lastname: Oguntayo
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Long
authors.forename: Madhusoodana P
authors.initials: MP
authors.lastname: Nambiar
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001753:Blast Injuries / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D001930:Brain Injuries / Q000235:genetics / Q000378:metabolism*; D002531:Cerebellum / Q000293:injuries / Q000378:metabolism; D018450:Disease Progression; D058851:GPI-Linked Proteins / Q000378:metabolism; D015870:Gene Expression; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014018:Tissue Distribution
chemical_list: D058851:GPI-Linked Proteins; D018836:Inflammation Mediators; C546976:MIRN132 microRNA, mouse; D035683:MicroRNAs; C543802:Mirn183 microRNA, mouse; D000110:Acetylcholinesterase; C548245:Ache protein, mouse; D000109:Acetylcholine