title: Midkine Is a Novel Regulator of Amphetamine-Induced Striatal Gliosis and Cognitive Impairment: Evidence for a Stimulus-Dependent Regulation of Neuroinflammation by Midkine.
abstract: Midkine (MK) is a cytokine that modulates amphetamine-induced striatal astrogliosis, suggesting a possible role of MK in neuroinflammation induced by amphetamine. To test this hypothesis, we studied astrogliosis and microglial response induced by amphetamine (10 mg/kg i.p. four times, every 2 h) in different brain areas of MK-/- mice and wild type (WT) mice. We found that amphetamine-induced microgliosis and astrocytosis are enhanced in the striatum of MK-/- mice in a region-specific manner. Surprisingly, LPS-induced astrogliosis in the striatum was blocked in MK-/- mice. Since striatal neuroinflammation induced by amphetamine-type stimulants correlates with the cognitive deficits induced by these drugs, we also tested the long-term effects of periadolescent amphetamine treatment (3 mg/kg i.p. daily for 10 days) in a memory task in MK-/- and WT mice. Significant deficits in the Y-maze test were only observed in amphetamine-pretreated MK-/- mice. The data demonstrate for the first time that MK is a novel modulator of neuroinflammation depending on the inflammatory stimulus and the brain area considered. The data indicate that MK limits amphetamine-induced striatal neuroinflammation. In addition, our data demonstrate that periadolescent amphetamine treatment in mice results in transient disruption of learning and memory processes in absence of endogenous MK.
authors.affiliation: Pharmacology Lab, Department of Pharmaceutical and Health Sciences, Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Vicente-Rodríguez
authors.affiliation: Pharmacology Lab, Department of Pharmaceutical and Health Sciences, Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain.
authors.forename: Rosalía
authors.initials: R
authors.lastname: Fernández-Calle
authors.affiliation: Pharmacology Lab, Department of Pharmaceutical and Health Sciences, Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Gramage
authors.affiliation: Pharmacology Lab, Department of Pharmaceutical and Health Sciences, Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Pérez-García
authors.affiliation: Biochemistry and Molecular Biology Lab, Department of Chemistry and Biochemistry, Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain.
authors.forename: María P
authors.initials: MP
authors.lastname: Ramos
authors.affiliation: Pharmacology Lab, Department of Pharmaceutical and Health Sciences, Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain.
authors.forename: Gonzalo
authors.identifier: 0000-0002-1578-3744
authors.initials: G
authors.lastname: Herradón
mesh_terms: D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003072:Cognition Disorders / Q000139:chemically induced / Q000378:metabolism*; D060825:Cognitive Dysfunction / Q000139:chemically induced; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D005911:Gliosis / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D018782:Maze Learning; D051379:Mice; D018345:Mice, Knockout; D000078792:Midkine
chemical_list: D000662:Amphetamines; D000697:Central Nervous System Stimulants; D036341:Intercellular Signaling Peptides and Proteins; C582105:Mdk protein, mouse; D000078792:Midkine