title: Methamphetamine exerts toxic effects on subventricular zone stem/progenitor cells and inhibits neuronal differentiation.
abstract: Methamphetamine (METH) is a potent and widely consumed psychostimulant drug that causes brain functional and structural abnormalities. However, there is little information regarding METH impact on adult neurogenic niches and, indeed, nothing is known about its consequences on the subventricular zone (SVZ). Thus, this work aims to clarify the effect of METH on SVZ stem/progenitor cells dynamics and neurogenesis. For that purpose, SVZ neurospheres were obtained from early postnatal mice and treated with increasing concentrations of METH (1  μM to 500  μM). Exposure to 100, 250, or 500  μM METH for 24  h triggered cell death both by necrosis and apoptosis, as assessed by propidium iodide uptake, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and quantification of the proapoptotic caspase-3 activity. Furthermore, we showed that METH inhibited SVZ progenitor cells proliferation as it decreased BrdU incorporation. Interestingly, at non-toxic concentrations (1 and 10  μM), METH decreased neuronal differentiation and maturation, which were evaluated by quantification of the number of neuronal nuclei-positive neurons and measurements of phospho-c-Jun-NH(2)-terminal kinase signal in growing axons, respectively. Altogether, our data demonstrate that METH has a negative impact on SVZ stem/progenitor cells, inducing cell death and inhibiting neurogenesis, effects that in vivo may challenge the cell replacement capacities displayed by endogenous populations of brain stem/progenitor cells.
authors: Neuroprotection and Neurogenesis in Brain Repair Group, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors: Ana Rita
authors: AR
authors: Bento
authors: Sofia
authors: S
authors: Baptista
authors: João O
authors: JO
authors: Malva
authors: Ana Paula
authors: AP
authors: Silva
authors: Fabienne
authors: F
authors: Agasse
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine / Q000494:pharmacology; D016923:Cell Death; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation; D002478:Cells, Cultured; D020287:In Situ Nick-End Labeling; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013566:Sympathomimetics / Q000633:toxicity*
chemical_list: D013566:Sympathomimetics; D008694:Methamphetamine; D001973:Bromodeoxyuridine