title: Blood withdrawal affects iron store dynamics in primates with consequences on monoaminergic system function.
abstract: Iron homeostasis is essential for the integrity of brain monoaminergic functions and its deregulation might be involved in neurological movement disorders such as the restless legs syndrome (RLS). Although iron metabolism breakdown concomitantly appears with monoaminergic system dysfunction in iron-deficient rodents and in RLS patients, the direct consequences of peripheral iron deficiency in the central nervous system (CNS) of non-human primates have received little attention. Here, we evaluated the peripheral iron-depletion impact on brain monoamine levels in macaque monkeys. After documenting circadian variations of iron and iron-related proteins (hemoglobin, ferritin and transferrin) in both serum and cerebrospinal fluid (CSF) of normal macaques, repeated blood withdrawals (RBW) were used to reduce peripheral iron-related parameter levels. Decreased serum iron levels were paradoxically associated with increased CSF iron concentrations. Despite limited consequences on tissue monoamine contents (dopamine - DA, 3, 4-dihydroxyphenylacetic acid - DOPAC, homovanillic acid, L-3, 4-dihydroxyphenylalanine - L-DOPA, 5-8 hydroxytryptamine - 5-HT, 5-hydroxyindoleacetic acid - 5-HIAA and noradrenaline) measured with post-mortem chromatography, we found distinct and region-dependent relationships of these tissue concentrations with CSF iron and/or serum iron and/or blood hemoglobin. Additionally, striatal extracellular DA, DOPAC and 5-HIAA levels evaluated by in vivo microdialysis showed a substantial increase, suggesting an overall increase in both DA and 5-HT tones. Finally, a trending increase in general locomotor activity, measured by actimetry, was observed in the most serum iron-depleted macaques. Taken together, our data are compatible with an increase in nigrostriatal DAergic function in the event of iron deficiency and point to a specific alteration of the 5-HT/DA interaction in the CNS that is possibly involved in the etiology of RLS.
authors: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France. Electronic address: carole.hyacinthe@u-bordeaux.fr.
authors: C
authors: C
authors: Hyacinthe
authors: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France. Electronic address: deurwaer@u-bordeaux.fr.
authors: P
authors: P
authors: De Deurwaerdere
authors: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; Cynbiose, F-69280 Marcy l'Etoile, France. Electronic address: thibaud.thiollier@cynbiose.com.
authors: T
authors: T
authors: Thiollier
authors: Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China; Motac Neuroscience, Manchester, United Kingdom. Electronic address: liqin@motac.com.
authors: Q
authors: Q
authors: Li
authors: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China; Motac Neuroscience, Manchester, United Kingdom. Electronic address: erwan.bezard@u-bordeaux.fr.
authors: E
authors: E
authors: Bezard
authors: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; Département de Neurophysiologie Clinique, CHU de Bordeaux Pellegrin, F-33000 Bordeaux, France. Electronic address: imad.ghorayeb@u-bordeaux.fr.
authors: I
authors: I
authors: Ghorayeb
mesh_terms: D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D001774:Blood Chemical Analysis; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D002940:Circadian Rhythm / Q000502:physiology; D007501:Iron / Q000097:blood* / Q000134:cerebrospinal fluid*; D008252:Macaca fascicularis; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000502:physiology; D018962:Phlebotomy; D013129:Spinal Puncture
chemical_list: D015306:Biogenic Monoamines; D007501:Iron
keywords: dopamine; ferritin; iron; non-human primate; restless legs syndrome/Willis–Ekbom disease; serotonin