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.

Interactions of HIV and Drugs of Abuse

“…The proliferation of both adult hippocampal and striatal progenitor cells in vivo is frequently assessed by 5-bromo-2′-deoxyuridine (BrdU) incorporation (a thymidine analogue incorporated during DNA synthesis) or Ki67 antigenicity (a nuclear protein associated with cell division) (Scholzen & Gerdes, 2000) in species including rats, mice, and gerbils (Teuchert-Noodt, Dawirs, & Hildebrandt, 2000; Mao & Wang, 2001; Mandyam, Wee, Eisch, Richardson, & Koob, 2007; Yuan, Quiocho, Kim, Wee, & Mandyam, 2011). Similar effects are seen in vitro , where survival is also variably reduced (Tian, Murrin, & Zheng, 2009; Venkatesan et al, 2011; Bento, Baptista, Malva, Silva, & Agasse, 2011). These effects have been correlated to enhanced nitration and modification of function of key metabolic proteins (Venkatesan et al, 2011).…”

Methamphetamine decreases dentate gyrus stem cell self-renewal and shifts the differentiation towards neuronal fate

“…Also, METH induces long-term effects in SGZ stem/progenitor cell proliferation, as described by Schaefers et al (2009) showing that a single METH administration (50 mg/kg) to 14-day-old gerbils decreases the number of BrdU-positive cells, 45 days post-administration. In addition, our group demonstrated that 100 μM METH (48 h of exposure) reduced proliferation in SVZ cultures (Bento et al, 2011).…”

“…Additionally, our group recently verified that a nontoxic concentration of METH (1 nM for 7 days) decreased the number of mature neurons in DG-derived neurosphere cultures (Baptista et al, 2012). Concerning the subventricular zone (SVZ), we have also shown that METH decreases cell proliferation, neuronal differentiation and maturation of stem/progenitor cells (Bento et al, 2011).…”

Methamphetamine Alters the Normal Progression by Inducing Cell Cycle Arrest in Astrocytes

“…The neurotoxicity associated with MA is attributed to increased oxidative stress, dopamine dysfunction, mitochondrial dysfunction, excitotoxicity, alteration in BBB integrity, inflammatory mechanisms and defective neurogenesis [31] , [33] . In particular, MA has been shown to inhibit neurogenesis in subventricular and hippocampal progenitor cells [34] , [35] . In addition, classical fMRI study on MA demonstrated reduced striatal volumes in children with prenatal MA exposure.…”