title: Differential neuroprotective properties of endogenous and exogenous erythropoietin in a mouse model of traumatic brain injury.
abstract: Both heat acclimation (HA) and post-injury treatment with recombinant human erythropoietin (Epo, rhEpo, exogenous Epo) are neuroprotective against traumatic brain injury (TBI). Our previous data demonstrated that HA-induced neuroprotection includes improved functional recovery and reduced cerebral edema formation. Additionally, in earlier Western-blot analyses, we found that HA mice display increased expression of the specific erythropoietin receptor (EpoR) and of hypoxia-inducible factor-1 alpha (HIF-1 alpha), the inducible subunit of the transcription factor, which regulates Epo gene expression, but not of Epo itself. In light of this, the aim of the current study was threefold: (1) to assess Epo expression in the trauma area and hippocampus following HA, rhEpo administration, or combined HA-rhEpo treatment, using immunohistochemical methods that offer enhanced anatomical resolution; (2) to examine the effects of endogenous and exogenous Epo on edema formation in normothermic (NT) mice; and (3) to evaluate the effects of exogenous Epo administration on neuroprotective outcome measures in HA animals. HA induced enhanced expression of endogenous Epo in the trauma area and the hippocampus. Treatment with anti-Epo antibody given to NT mice increased edema formation, whereas rhEpo induced no beneficial effect. Cognitive performance testing and immunohistochemical findings reinforced HA and rhEpo as separate protective interventions but showed no advantage to combining the two strategies. We therefore suggest that HA-induced neuroprotection is shaped by pre-existing mediators but cannot be modified by post-injury treatment aimed at increasing the levels of neuroprotective agents.
authors.affiliation: Department of Pharmacology, The Hebrew University, Jerusalem, Israel.
authors.forename: Na'ama A
authors.initials: NA
authors.lastname: Shein
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Grigoriadis
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Alexandrovich
authors.forename: Constantina
authors.initials: C
authors.lastname: Simeonidou
authors.forename: Evangelia
authors.initials: E
authors.lastname: Spandou
authors.forename: Jeanna
authors.initials: J
authors.lastname: Tsenter
authors.forename: Ido
authors.initials: I
authors.lastname: Yatsiv
authors.forename: Michal
authors.initials: M
authors.lastname: Horowitz
authors.forename: Esther
authors.initials: E
authors.lastname: Shohami
mesh_terms: D000064:Acclimatization; D000818:Animals; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology; D003071:Cognition / Q000502:physiology; D004921:Erythropoietin / Q000096:biosynthesis / Q000494:pharmacology* / Q000502:physiology* / Q000627:therapeutic use; D005452:Fluoresceins; D005456:Fluorescent Dyes; D006624:Hippocampus / Q000473:pathology; D006358:Hot Temperature; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy; D008297:Male; D051379:Mice; D009410:Nerve Degeneration / Q000473:pathology; D018696:Neuroprotective Agents; D009930:Organic Chemicals; D021641:Recognition, Psychology / Q000502:physiology; D011994:Recombinant Proteins
chemical_list: D005452:Fluoresceins; D005456:Fluorescent Dyes; D018696:Neuroprotective Agents; D009930:Organic Chemicals; D011994:Recombinant Proteins; C435731:fluoro jade; D004921:Erythropoietin