title: Long-lasting neuronal loss following experimental focal cerebral ischemia is not affected by combined administration of tissue plasminogen activator and hyperbaric oxygen.
abstract: Acute focal cerebral ischemia and consecutive energy failure are accompanied by neuronal death in regions with impaired cerebral blood flow. Several translational attempts of potential neuroprotective agents have failed, hence extended perspectives are required regarding the regional differences of neuronal impairment and glial involvement by using clinically relevant stroke models. This study aimed on neuronal loss following experimental focal cerebral ischemia, considering tissue plasminogen activator (tPA) as established treatment in stroke and hyperbaric oxygenation (HBO) as potential neuroprotective co-treatment. Wistar rats were subjected to embolic middle cerebral artery occlusion and underwent either treatment with tPA only, combined tPA+HBO, or no treatment. Neuronal impairment was assessed by Neuronal Nuclei (NeuN) staining in 4 ischemia-related areas and at 4 different time points after stroke induction (24hours, 7, 14 and 28 days). Additionally, spatial relationships between neuronal loss and gliosis were revealed by triple fluorescence staining of neurons, astrocytes and microglia, comparing the ipsi- and contra-lesional hemisphere. Analyzing the ischemic injury in general, a shell-like distribution of neuronal damage was observed, starting in the ischemic core and diminishing over the general ischemic area to the ischemic border zone and the primary non-affected area. This pattern remained detectable up to 4weeks after ischemia induction. Surprisingly, tPA and tPA+HBO did not markedly affect the post-ischemic course of neuronal impairment. Further studies are needed to investigate the effects of treatment with tPA or potential neuroprotective agents on neuronal integrity, with emphasis on the separation of intact neurons from those undergoing apoptosis or necrosis.
authors.affiliation: Department of Neurology, University of Leipzig, Liebigstr. 20, 04103 Leipzig, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Hobohm
authors.forename: Félix
authors.initials: F
authors.lastname: Laignel
authors.forename: Johannes
authors.initials: J
authors.lastname: Kacza
authors.forename: Lea
authors.initials: L
authors.lastname: Küppers-Tiedt
authors.forename: Marita
authors.initials: M
authors.lastname: Heindl
authors.forename: Dietmar
authors.initials: D
authors.lastname: Schneider
authors.forename: Jens
authors.initials: J
authors.lastname: Grosche
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Härtig
authors.forename: Dominik
authors.initials: D
authors.lastname: Michalski
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000150:complications / Q000473:pathology / Q000628:therapy; D016923:Cell Death; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D006931:Hyperbaric Oxygenation; D007150:Immunohistochemistry; D008297:Male; D009410:Nerve Degeneration / Q000473:pathology / Q000628:therapy*; D009474:Neurons / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000473:pathology / Q000628:therapy*; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator