title: NO mediates microglial response to acute spinal cord injury under ATP control in vivo.
abstract: To understand the pathomechanisms of spinal cord injuries will be a prerequisite to develop efficient therapies. By investigating acute lesions of spinal cord white matter in anesthetized mice with fluorescently labeled microglia and axons using in vivo two-photon laser-scanning microscopy (2P-LSM), we identified the messenger nitric oxide (NO) as a modulator of injury-activated microglia. Local tissue damages evoked by high-power laser pulses provoked an immediate attraction of microglial processes. Spinal superfusion with NO synthase and guanylate cyclase inhibitors blocked these extensions. Furthermore, local injection of the NO-donor spermine NONOate (SPNO) or the NO-dependent second messenger cGMP induced efficient migration of microglial cells toward the injection site. High-tissue levels of NO, achieved by uniform superfusion with SPNO and mimicking extended tissue damage, resulted in a fast conversion of the microglial shape from ramified to ameboid indicating cellular activation. When the spinal white matter was preconditioned by increased, ambient ATP (known as a microglial chemoattractant) levels, the attraction of microglial processes to local NO release was augmented, whereas it was abolished at low levels of tissue ATP. Because both signaling molecules, NO and ATP, mediate acute microglial reactions, coordinated pharmacological targeting of NO and purinergic pathways will be an effective mean to influence the innate immune processes after spinal cord injury.
authors.affiliation: Department of Neurology, Georg August University of Göttingen, Germany.
authors.forename: Payam
authors.initials: P
authors.lastname: Dibaj
authors.forename: Fabien
authors.initials: F
authors.lastname: Nadrigny
authors.forename: Heinz
authors.initials: H
authors.lastname: Steffens
authors.forename: Anja
authors.initials: A
authors.lastname: Scheller
authors.forename: Johannes
authors.initials: J
authors.lastname: Hirrlinger
authors.forename: Eike D
authors.initials: ED
authors.lastname: Schomburg
authors.forename: Clemens
authors.initials: C
authors.lastname: Neusch
authors.forename: Frank
authors.initials: F
authors.lastname: Kirchhoff
mesh_terms: D000208:Acute Disease; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D016764:Cell Polarity / Q000187:drug effects / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000503:physiopathology*
chemical_list: D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; C091861:spermine nitric oxide complex; D013096:Spermine; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D006152:Cyclic GMP