Farzaneh A Sorond1, Can Ozan Tan2, Sarah LaRose2, Andrew D Monk2, Raina Fichorova2, Stanthia Ryan2, Lewis A Lipsitz2. 1. From the Stroke Division, Department of Neurology (F.A.S., S.L.R., A.D.M.) and Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology (R.F., S.R.), Brigham and Women's Hospital, Boston, MA; Cardiovascular Research Laboratory, Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Boston, MA (C.O.T.); Department of Medicine, Hebrew SeniorLife Institute for Aging Research, Boston, MA (L.A.L.); Division of Gerontology, Beth Israel Deaconess Medical Center, Boston, MA (L.A.L.); and Department of Neurology, Physical Medicine and Rehabilitation, Obstetrics and Gynecology, and Medicine, Harvard Medical School, Boston, MA (F.A.S., C.O.T., R.F., L.A.L.). fsorond@partners.org. 2. From the Stroke Division, Department of Neurology (F.A.S., S.L.R., A.D.M.) and Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology (R.F., S.R.), Brigham and Women's Hospital, Boston, MA; Cardiovascular Research Laboratory, Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Boston, MA (C.O.T.); Department of Medicine, Hebrew SeniorLife Institute for Aging Research, Boston, MA (L.A.L.); Division of Gerontology, Beth Israel Deaconess Medical Center, Boston, MA (L.A.L.); and Department of Neurology, Physical Medicine and Rehabilitation, Obstetrics and Gynecology, and Medicine, Harvard Medical School, Boston, MA (F.A.S., C.O.T., R.F., L.A.L.).
Abstract
BACKGROUND AND PURPOSE: Iron chelation therapy is emerging as a novel neuroprotective strategy. The mechanisms of neuroprotection are diverse and include both neuronal and vascular pathways. We sought to examine the effect of iron chelation on cerebrovascular function in healthy aging and to explore whether hypoxia-inducible transcription factor-1 activation may be temporally correlated with vascular changes. METHODS: We assessed cerebrovascular function (autoregulation, vasoreactivity, and neurovascular coupling) and serum concentrations of vascular endothelial growth factor and erythropoietin, as representative measures of hypoxia-inducible transcription factor-1 activation, during 6 hours of deferoxamine infusion in 24 young and 24 older healthy volunteers in a randomized, blinded, placebo-controlled cross-over study design. Cerebrovascular function was assessed using the transcranial Doppler ultrasound. Vascular endothelial growth factor and erythropoietin serum protein assays were conducted using the Meso Scale Discovery platform. RESULTS: Deferoxamine elicited a strong age- and time-dependent increase in the plasma concentrations of erythropoietin and vascular endothelial growth factor, which persisted ≤3 hours post infusion (age effect P=0.04; treatment×time P<0.01). Deferoxamine infusion also resulted in a significant time- and age-dependent improvement in cerebral vasoreactivity (treatment×time P<0.01; age P<0.01) and cerebral autoregulation (gain: age×time×treatment P=0.04). CONCLUSIONS: Deferoxamine infusion improved cerebrovascular function, particularly in older individuals. The temporal association between improved cerebrovascular function and increased serum vascular endothelial growth factor and erythropoietin concentrations is supportive of shared hypoxia-inducible transcription factor-1-regulated pathways. Therefore, pharmacological activation of hypoxia-inducible transcription factor-1 to enhance cerebrovascular function may be a promising neuroprotective strategy in acute and chronic ischemic syndromes, especially in elderly patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT013655104.
BACKGROUND AND PURPOSE: Iron chelation therapy is emerging as a novel neuroprotective strategy. The mechanisms of neuroprotection are diverse and include both neuronal and vascular pathways. We sought to examine the effect of iron chelation on cerebrovascular function in healthy aging and to explore whether hypoxia-inducible transcription factor-1 activation may be temporally correlated with vascular changes. METHODS: We assessed cerebrovascular function (autoregulation, vasoreactivity, and neurovascular coupling) and serum concentrations of vascular endothelial growth factor and erythropoietin, as representative measures of hypoxia-inducible transcription factor-1 activation, during 6 hours of deferoxamine infusion in 24 young and 24 older healthy volunteers in a randomized, blinded, placebo-controlled cross-over study design. Cerebrovascular function was assessed using the transcranial Doppler ultrasound. Vascular endothelial growth factor and erythropoietin serum protein assays were conducted using the Meso Scale Discovery platform. RESULTS: Deferoxamine elicited a strong age- and time-dependent increase in the plasma concentrations of erythropoietin and vascular endothelial growth factor, which persisted ≤3 hours post infusion (age effect P=0.04; treatment×time P<0.01). Deferoxamine infusion also resulted in a significant time- and age-dependent improvement in cerebral vasoreactivity (treatment×time P<0.01; age P<0.01) and cerebral autoregulation (gain: age×time×treatment P=0.04). CONCLUSIONS: Deferoxamine infusion improved cerebrovascular function, particularly in older individuals. The temporal association between improved cerebrovascular function and increased serum vascular endothelial growth factor and erythropoietin concentrations is supportive of shared hypoxia-inducible transcription factor-1-regulated pathways. Therefore, pharmacological activation of hypoxia-inducible transcription factor-1 to enhance cerebrovascular function may be a promising neuroprotective strategy in acute and chronic ischemic syndromes, especially in elderly patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT013655104.
Authors: Malee S Fernando; Julie E Simpson; Fiona Matthews; Carol Brayne; Claire E Lewis; Robert Barber; Raj N Kalaria; Gill Forster; Filomena Esteves; Stephen B Wharton; Pamela J Shaw; John T O'Brien; Paul G Ince Journal: Stroke Date: 2006-04-20 Impact factor: 7.914
Authors: Farzaneh A Sorond; Dan K Kiely; Andrew Galica; Nicola Moscufo; Jorge M Serrador; Ike Iloputaife; Svetlana Egorova; Elisa Dell'Oglio; Dominik S Meier; Elizabeth Newton; William P Milberg; Charles R G Guttmann; Lewis A Lipsitz Journal: Ann Neurol Date: 2011-06-14 Impact factor: 10.422
Authors: Oscar L Lopez; William E Klunk; Chester Mathis; Rhaven L Coleman; Julie Price; James T Becker; Howard J Aizenstein; Beth Snitz; Ann Cohen; Milos Ikonomovic; Eric McDade; Steven T DeKosky; Lisa Weissfeld; Lewis H Kuller Journal: Neurology Date: 2014-10-10 Impact factor: 9.910
Authors: Azizah J Jor'dan; Victoria N Poole; Ikechukwu Iloputaife; William Milberg; Brad Manor; Michael Esterman; Lewis A Lipsitz Journal: J Gerontol A Biol Sci Med Sci Date: 2017-11-09 Impact factor: 6.053
Authors: Jared M Fine; Jacob Kosyakovsky; Amanda M Baillargeon; Julian V Tokarev; Jacob M Cooner; Aleta L Svitak; Katherine A Faltesek; William H Frey; Leah R Hanson Journal: Brain Behav Date: 2020-01-20 Impact factor: 2.708