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Impairment of adult hippocampal neural progenitor proliferation by methamphetamine: role for nitrotyrosination
Arun Venkatesan, Lerna Uzasci, Zhaohui Chen, Labchan Rajbhandari, Carol Anderson, Myoung-Hwa Lee, Mario A Bianchet, Robert Cotter, Hongjun Song, Avindra Nath
Molecular Brain , 2011, DOI: 10.1186/1756-6606-4-28
Abstract: Over 35 million people internationally abuse METH, and in the United States METH abuse has reached epidemic proportions. Through mechanisms that are not yet well understood, METH abusers suffer from a variety of neurocognitive deficits, including behavioral changes, executive dysfunction, deficits in perceptual speed and information manipulation, and impairment of verbal and spatial memory. Neurocognitive deficits may persist after cessation of METH abuse, are slow to improve, and may not completely reverse [1-5]. Although METH was initially thought to selectively damage monoaminergic nerve terminals, recent studies have consistently shown that widespread neuronal cell death results [6-10]. Cell death involves not only the striatum and cortex, but the hippocampus as well [7,11]. Although the molecular mechanisms underlying METH neurotoxicity are likely multifactorial, several key findings support a significant role for both oxidative and nitrosative stress. Mice overexpressing superoxide dismutase, an antioxidant, show markedly decreased METH-induced apoptosis [12]. Suppression of nitric oxide (NO) production, through both pharmacologic and genetic means, also protects against METH-mediated neurotoxicity. In addition, METH causes increased levels of 3-nitrotyrosine adduct formation, reflective of oxidative and nitrosative stress [13,14]. Although METH-induced oxidative and nitrosative stress and toxicity have been demonstrated in neurons, little is known about whether other cells within the brain, such as NPCs, are similarly affected by METH.The brains of mammals contain several distinct populations of cells that are capable of dividing and differentiating into neurons and glial cells throughout adulthood [15,16]. Increasing evidence suggests that continued neurogenesis is important for maintenance of cognitive function [17-20]. Within the hippocampal dentate gyrus (DG), neurogenesis occurs in the subgranular zone and granule cell layer. New neurons formed here are
Methamphetamine use and malnutrition among street-involved youth
Dan Werb, Thomas Kerr, Ruth Zhang, Julio SG Montaner, Evan Wood
Harm Reduction Journal , 2010, DOI: 10.1186/1477-7517-7-5
Abstract: Over the last decade, crystal methamphetamine use has emerged as a unique and significant public health concern, and data on the prevalence of crystal methamphetamine use have shown that its use is increasing in North America, particularly among young gay men and young injection drug users [1,2]. Studies have also reported that crystal methamphetamine use is associated with a variety of physiological and neurological disorders [3], as well as with a number of risk behaviours for HIV transmission, and that these risks are heightened among street-involved youth [2]. This is of concern given that the health of street-involved youth is already often compromised by widespread unstable housing and chronic food insecurity [4].Little research, however, has been conducted on the association between patterns of drug use and food security among youth. Specifically, knowledge gaps exist concerning the potential unique impact of crystal methamphetamine use on risks of malnutrition among street-involved youth populations. We therefore sought to explore the effect of crystal methamphetamine use on the risk of experiencing malnutrition among a cohort of street-involved youth in Vancouver, Canada.We evaluated factors associated with malnutrition among participants enrolled in the At-Risk Youth Study (ARYS), a prospective cohort of street-involved youth aged 14 to 26 in Vancouver, Canada, which has been described in detail previously [5]. In brief, at baseline and semi-annually, ARYS participants complete an interviewer-administered questionnaire and provide blood samples for diagnostic testing. In the present study, Pearson's Chi-square test and multivariate analysis were used to determine factors associated with ever having experienced malnutrition among this cohort.Our primary independent variable of interest was crystal methamphetamine use, though we accounted for a wide array of socio-demographic, drug use and behavioural variables, all of which are shown in Table 1. All variabl
Systems-Scale Analysis Reveals Pathways Involved in Cellular Response to Methamphetamine  [PDF]
Lijie Sun,Hong-Mei Li,Manfredo J. Seufferheld,Kent R. Walters Jr.,Venu M. Margam,Amber Jannasch,Naomi Diaz,Catherine P. Riley,Weilin Sun,Yueh-Feng Li,William M. Muir,Jun Xie,Jing Wu,Fan Zhang,Jake Y. Chen,Eric L. Barker,Jiri Adamec,Barry R. Pittendrigh
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0018215
Abstract: Methamphetamine (METH), an abused illicit drug, disrupts many cellular processes, including energy metabolism, spermatogenesis, and maintenance of oxidative status. However, many components of the molecular underpinnings of METH toxicity have yet to be established. Network analyses of integrated proteomic, transcriptomic and metabolomic data are particularly well suited for identifying cellular responses to toxins, such as METH, which might otherwise be obscured by the numerous and dynamic changes that are induced.
Regulation of hippocampal progenitor cell survival, proliferation and dendritic development by BDNF
Se Choi, Yun Li, Luis F Parada, Sangram S Sisodia
Molecular Neurodegeneration , 2009, DOI: 10.1186/1750-1326-4-52
Abstract: We show that while the extent of cell proliferation and neuronal fate differentiation in the hippocampus of cKO mice is not different from wild-type (WT) littermates maintained in either standard or enriched conditions, reduced BDNF levels significantly impaired the survival of newborn cells in both housing conditions. In addition, while highly active enriched WT mice exhibited a robust increase in progenitor cell proliferation, highly active cKO mice showed a modest increase in cell proliferation compared to standard housed or underactive cKO mice.There results argue that while BDNF plays a role in exercise-induced cell proliferation, other factors must contribute to this phenomenon. We also show that dendritic development was impaired in cKO mice maintained in standard housing conditions, and that EE rescued this phenotype.Neurons are continuously added to the hippocampal dentate gyrus (DG) throughout life. Studies have correlated increased neurogenesis in the DG with improved performance on hippocampal learning tasks [1], suggesting that adult-generated neurons can positively impact adult hippocampal function. Adult hippocampal neurogenesis is a dynamic process that is regulated both positively and negatively, by a variety of growth factors and environmental experiences [2].Brain-derived neurotrophic factor (BDNF) is highly expressed in hippocampus [3], but the functional role of this neurotrophin in the adult hippocampus, and specifically with respect to the proliferation and survival of neural precursor cells (NPCs) in the subgranular cell layer (SGL) of the DG, is controversial. For example, studies have shown that heterozygous BDNF knockout (BDNF+/-) mice exhibit reduced [4] or enhanced cell proliferation [5] in the DG. Similarly, basal levels of cell survival were shown to be impaired in two studies [4,5], but not in another [6]. However, the interpretation of these latter series of studies is confounded by the fact that BDNF+/- mice exhibit a multiplicity o
Fragmentation Pathways of Trifluoroacetyl Derivatives of Methamphetamine, Amphetamine, and Methylenedioxyphenylalkylamine Designer Drugs by Gas Chromatography/Mass Spectrometry  [PDF]
Takeshi Kumazawa,Kenji Hara,Chika Hasegawa,Seisaku Uchigasaki,Xiao-Pen Lee,Hiroshi Seno,Osamu Suzuki,Keizo Sato
International Journal of Spectroscopy , 2011, DOI: 10.1155/2011/318148
Abstract: Methamphetamine (MA), amphetamine (AM), and the methylenedioxyphenylalkylamine designer drugs, such as 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyethylamphetamine (MDEA), N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB), 3,4-methylenedioxyamphetamine (MDA), and 3,4-(methylenedioxyphenyl)-2-butanamine (BDB), are widely abused as psychedelics. In this paper, these compounds were derivatized with trifluoroacetic (TFA) anhydride and analyzed by gas chromatography/mass spectrometry using electron ionization in positive mode. Gas chromatographic separation for TFA derivatives of all compounds was successfully resolved using an Equity-5 fused silica capillary column with a poly (5% diphenyl-95% dimethylsiloxane) stationary phase. Base peaks or prominent peaks of MA, AM, MDMA, MDEA, MBDB, MDA, and BDB appeared at m/z 154, 140, 154, 168, 168, 135, and 135, respectively. These occurred due to α-cleavage from the amide nitrogen, splitting into the TFA imine species and benzyl or methylenedioxybenzyl cations. Further prominent fragment ions at m/z 118 for MA and AM, m/z 162 for MDMA, MDEA, and MDA, and m/z 176 for MBDB and BDB were produced by cleavage of the phenylpropane or methylenedioxypropane hydrocarbon radical cation via a hydrogen rearrangement. These fragmentation pathways for the TFA derivatives of all the compounds are summarized and illustrated in this paper. 1. Introduction In recent years, extensive attention in clinical and forensic toxicology has focused on the increasing abuse of methamphetamine (MA), amphetamine (AM), and methylenedioxyphenylalkylamine derivatives, such as 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyethylamphetamine (MDEA), N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB), 3,4-methylenedioxyamphetamine (MDA), and 3,4-(methylenedioxyphenyl)-2-butanamine (BDB). A number of severe and even fatal intoxications attributable to these drugs have been reported [1–4]. Consequently, detection and identification analyses for these compounds are routinely performed in clinical and forensic laboratories. Several gas chromatographic methods to analyze MA, AM, MDMA, MDEA, MBDB, MDA, and BDB in doping control and toxicological analysis have been reported [5–8]. Because of their relatively low molecular weights, high polarity, and volatility, derivatization is necessary when using gas chromatography (GC) [9]. Acylation is one of the most popular derivatization reactions for primary and secondary amines and converts compounds into derivatives that are more easily separated or give an enhanced
Phosphorylated low-density lipoprotein receptor-related protein 6 is prevalent in hippocampal progenitor cells and circuits of aged human hippocampus  [PDF]
Christopher P. Sullivan, Rosemary Elliott-Bryant, Anish Kanesa-Thasan, Ann C. McKee, Richard E. Fine, John M. Wells, Peter J. Morin
Advances in Alzheimer's Disease (AAD) , 2013, DOI: 10.4236/aad.2013.24017
Abstract: Wnt signaling has been implicated in Alzheimer’s disease (AD) pathogenesis, but no studies have described Wnt signaling in aging brain. Phosphorylation of the Wnt coreceptor, low-density lipoprotein receptor-related protein 6 (Lrp6), is a sensitive indicator of Wnt ligand-receptor interaction and canonical Wnt signaling. We report that in aged human temporal lobe, the phospho-Lrp6 (pLrp6) epitope localizes to neurons in the entorhinal cortex (EC), the dentate gyrus (DG), and the hippocampal formation, especially in the CA3 field. Activated Lrp6 is detected in neuronal soma and in neuronal processes, particularly in the mossy fiber terminals in the stratum lucidum of CA3. These three regions and their connectivity represent the afferent arm of the major hippocampal circuit. In the DG, cells positive for pLrp6 include Type 1 and Type 2 hippocampal progenitor cells. Overall, these data indicate regional Wnt receptor activation in the human hippocampus that is most prominent in the cells comprising the afferent arm of the major hippocampal circuit that is associated with learning and memory functions. These findings are consistent with data from rodent studies which suggest an important role for Wnts in adult neurogenesis in the human DG. We speculate that Wnt signaling may be an activity-dependent trophic influence in the hippocampus.
Identification of proteins involved in neural progenitor cell targeting of gliomas
Karin Staflin, Thole Zuchner, Gabriella Honeth, Anna Darabi, Cecilia Lundberg
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-206
Abstract: Using microarrays we screened for candidate genes involved in the functional mechanism of tumor inhibition by comparing glioma cell lines to neural progenitor cells with or without anti-tumor activity. The expression of candidate genes was confirmed at RNA level by quantitative RT-PCR and at the protein level by Western blots and immunocytochemistry. Moreover, we have developed in vitro assays to mimic the antitumor effect seen in vivo.We identified several targets involved in glioma growth and migration, specifically CXCL1, CD81, TPT1, Gas6 and AXL proteins. We further showed that follistatin secretion from the NPC has the potential to decrease tumor proliferation. In vitro co-cultures of NPC and tumor cells resulted in the inhibition of tumor growth. The addition of antibodies against proteins selected by gene and protein expression analysis either increased or decreased the proliferation rate of the glioma cell lines in vitro.These results suggest that these identified factors might be useful starting points for performing future experiments directed towards a potential therapy against malignant gliomas.Current treatment for GBM has proven ineffective mainly due to the disseminating nature of the tumor in addition to the resistance to irradiation and chemotherapy. Novel approaches have tried to utilize the migratory potential of neural progenitor cells (NPC) and their ability to functionally integrate into host tissues to target this invasive tumor [1-6]. In previous studies we have shown that specific embryonic rat neural progenitor cells have the ability to target malignant gliomas in the rat striatum [7]. These cells can inhibit the growth of a solid tumor in the animals, preventing proliferation as well as invasion. The embryonic neural progenitor cells are able to cure up to 40% of the animals in co-inoculation experiments, with no trace of a tumor burden 6 months after finishing the experiment. This significant antitumor effect is quite remarkable in light
Frizzled-5 Receptor Is Involved in Neuronal Polarity and Morphogenesis of Hippocampal Neurons  [PDF]
Paula G. Slater, Valerie T. Ramirez, Christian Gonzalez-Billault, Lorena Varela-Nallar, Nibaldo C. Inestrosa
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0078892
Abstract: The Wnt signaling pathway plays important roles during different stages of neuronal development, including neuronal polarization and dendritic and axonal outgrowth. However, little is known about the identity of the Frizzled receptors mediating these processes. In the present study, we investigated the role of Frizzled-5 (Fzd5) on neuronal development in cultured Sprague-Dawley rat hippocampal neurons. We found that Fzd5 is expressed early in cultured neurons on actin-rich structures localized at minor neurites and axonal growth cones. At 4 DIV, Fzd5 polarizes towards the axon, where its expression is detected mainly at the peripheral zone of axonal growth cones, with no obvious staining at dendrites; suggesting a role of Fzd5 in neuronal polarization. Overexpression of Fzd5 during the acquisition of neuronal polarity induces mislocalization of the receptor and a loss of polarized axonal markers. Fzd5 knock-down leads to loss of axonal proteins, suggesting an impaired neuronal polarity. In contrast, overexpression of Fzd5 in neurons that are already polarized did not alter polarity, but decreased the total length of axons and increased total dendrite length and arborization. Fzd5 activated JNK in HEK293 cells and the effects triggered by Fzd5 overexpression in neurons were partially prevented by inhibition of JNK, suggesting that a non-canonical Wnt signaling mechanism might be involved. Our results suggest that, Fzd5 has a role in the establishment of neuronal polarity, and in the morphogenesis of neuronal processes, in part through the activation of the non-canonical Wnt mechanism involving JNK.
Ryanodine receptor-mediated Ca2+ release underlies iron-induced mitochondrial fission and stimulates mitochondrial Ca2+ uptake in primary hippocampal neurons  [PDF]
Carol D. SanMartín,Andrea C. Paula-Lima,Steffen Hartel,Marco T. Nú?ez,Cecilia Hidalgo
Frontiers in Molecular Neuroscience , 2014, DOI: 10.3389/fnmol.2014.00013
Abstract: Mounting evidence indicates that iron accumulation impairs brain function. We have reported previously that addition of sub-lethal concentrations of iron to primary hippocampal neurons produces Ca2+ signals and promotes cytoplasmic generation of reactive oxygen species. These Ca2+ signals, which emerge within seconds after iron addition, arise mostly from Ca2+ release through the redox-sensitive ryanodine receptor (RyR) channels present in the endoplasmic reticulum. We have reported also that addition of synaptotoxic amyloid-β oligomers to primary hippocampal neurons stimulates RyR-mediated Ca2+ release, generating long-lasting Ca2+ signals that activate Ca2+-sensitive cellular effectors and promote the disruption of the mitochondrial network. Here, we describe that 24 h incubation of primary hippocampal neurons with iron enhanced agonist-induced RyR-mediated Ca2+ release and promoted mitochondrial network fragmentation in 43% of neurons, a response significantly prevented by RyR inhibition and by the antioxidant agent N-acetyl-L-cysteine. Stimulation of RyR-mediated Ca2+ release by a RyR agonist promoted mitochondrial Ca2+ uptake in control neurons and in iron-treated neurons that displayed non-fragmented mitochondria, but not in neurons with fragmented mitochondria. Yet, the global cytoplasmic Ca2+ increase induced by the Ca2+ ionophore ionomycin prompted significant mitochondrial Ca2+ uptake in neurons with fragmented mitochondria, indicating that fragmentation did not prevent mitochondrial Ca2+ uptake but presumably decreased the functional coupling between RyR-mediated Ca2+ release and the mitochondrial Ca2+ uniporter. Taken together, our results indicate that stimulation of redox-sensitive RyR-mediated Ca2+ release by iron causes significant neuronal mitochondrial fragmentation, which presumably contributes to the impairment of neuronal function produced by iron accumulation.
Methamphetamine use and rates of incarceration among street-involved youth in a Canadian setting: a cross-sectional analysis
M-J Milloy, Thomas Kerr, Jane Buxton, Julio Montaner, Evan Wood
Substance Abuse Treatment, Prevention, and Policy , 2009, DOI: 10.1186/1747-597x-4-17
Abstract: The relationship between ever being imprisoned and ever using methamphetamine was estimated using a multivariate logistic regression analysis while also considering potentially confounding secondary demographic, social and behavioural variables.Of the 478 youth recruited into ARYS between September 2005 and October 2006, 385 (80.5%) reported ever being incarcerated overnight or longer. In the multivariate model, methamphetamine use was independently associated with ever being incarcerated (Adjusted Odds Ratio: 1.79, 95% Confidence Interval [CI]: 1.03 – 3.13).Incarceration was very common in this cohort and strongly linked with ever using methamphetamine. This finding is of concern and, along with the previously identified risks of drug-related harm associated with incarceration, supports the development of novel public policy, such as community-based drug treatment, to address the use of methamphetamine among street youth.The use of methamphetamine in Western settings is of increasing concern [1,2], especially among street-involved youth [3,4], a vulnerable population already burdened by high levels of morbidity and mortality [5,6]. According to the United Nations Office on Drugs and Crime, methamphetamine now constitutes the second most commonly used illicit drug internationally, second only to marijuana [7].For older drug users, especially those who use injection drugs (IDU), the dynamics linking drug use, marginalisation and imprisonment are well described [8-10]. Arrest and imprisonment is a common experience, with a history of incarceration reported by at least 75% of participants in community-recruited samples of IDU in Europe [11], Thailand [12] and the United States [13]. Incarceration may be a risk factor for drug related harm among IDU, since exposure to correctional environments has consistently been associated with an increased likelihood of HIV risk behavior and HIV infection [14,15] as well as increased risk of fatal overdose upon release [16].Sparked
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