title: Astrocyte-mediated inflammation in cortical spreading depression.
abstract: Background Cortical spreading depression (CSD) related diseases such as migraine, cerebrovascular diseases, and epilepsy have been associated with reactive astrocytosis, yet the mechanisms of these tissue changes remain unclear. CSD-induced inflammatory response has been proposed to play a role in some neurological disorders and thus may also contribute to reactive astrocytosis. Methods Using ex vivo brain slices and in vitro astrocytic cultures, we aimed to characterize CSD related changes in astrocytes and markers of inflammation by immunocyto- and immunohistochemistry. CSD was induced by application of KCl (3 mol/l) on neocortical tissues. The application of KCl was repeated weekly over the course of four weeks. Results CSD induced an increase in the mean number and volume of astrocytes in rat brain tissue when compared to controls, whereas no changes in neuronal numbers and volumes were seen. These cell-type specific changes, suggestive of reactive astrocytosis, were paralleled by an increased expression of protein markers indicative of astrocytes and neuroinflammation in ex vivo brain slices of animals undergoing CSD when compared to sham-treated controls. Cultured astrocytes showed an increased expression of the immune modulatory enzyme indoleamine 2,3-dioxygenase and an elevated expression of the pro-inflammatory markers, IL-6, IL-1β, and TNFα in addition to increased levels of toll like receptors (TLR3 and TLR4) and astrocytic markers after induction of CSD. Conclusion These findings indicate that CSD related reactive astrocytosis is linked to an upregulation of inflammatory markers. Targeting inflammation with already approved and available immunomodulatory treatments may thus represent a strategy to combat or ameliorate CSD-related disease.
authors.affiliation: 1 Shefa Neuroscience Research Center, Khatam-Alanbia Hospital, Tehran, Iran.|2 Department of Virology, Golestan University of Medical Sciences, Gorgan, Iran.
authors.forename: Amir
authors.initials: A
authors.lastname: Ghaemi
authors.affiliation: 1 Shefa Neuroscience Research Center, Khatam-Alanbia Hospital, Tehran, Iran.
authors.forename: Leila
authors.initials: L
authors.lastname: Alizadeh
authors.affiliation: 1 Shefa Neuroscience Research Center, Khatam-Alanbia Hospital, Tehran, Iran.
authors.forename: Shahnaz
authors.initials: S
authors.lastname: Babaei
authors.affiliation: 1 Shefa Neuroscience Research Center, Khatam-Alanbia Hospital, Tehran, Iran.
authors.forename: Maryam
authors.initials: M
authors.lastname: Jafarian
authors.affiliation: 3 Department of Neurosurgery, WestfälischeWilhelms-Universität Münster, Germany.
authors.forename: Maryam
authors.initials: M
authors.lastname: Khaleghi Ghadiri
authors.affiliation: 4 Department of Neurology, WestfälischeWilhelms-Universität Münster, Germany.
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
authors.affiliation: 4 Department of Neurology, WestfälischeWilhelms-Universität Münster, Germany.
authors.forename: Stjepana
authors.initials: S
authors.lastname: Kovac
authors.affiliation: 1 Shefa Neuroscience Research Center, Khatam-Alanbia Hospital, Tehran, Iran.|3 Department of Neurosurgery, WestfälischeWilhelms-Universität Münster, Germany.|4 Department of Neurology, WestfälischeWilhelms-Universität Münster, Germany.|5 Department of Neuroscience, Mashhad University of Medical Sciences, Mashhad, Iran.|6 Epilepsy Research Center, Westfälische Wilhelms-Universität Münster, Germany.
authors.forename: Ali
authors.initials: A
authors.lastname: Gorji
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D018929:Cell Culture Techniques; D013181:Cortical Spreading Depression / Q000502:physiology*; D007249:Inflammation / Q000473:pathology*; D008297:Male; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar
keywords: Brain; glia; neuromodulation; spreading depolarization; subarachnoid hemorrhage