Telomere length modulates human radiation sensitivity in vitro

The molecular basis of the interindividual differences of normal individuals to ionizing radiation is poorly understood. Several studies in telomerase KO mice with short telomeres have uncovered an inverse relationship between telomere length and radiation sensitivity. The present work aims to determine if chromosome radiosensitivity is correlated with telomere length in healthy individuals. With this purpose, individual radiosensitivity was determined by the micronucleus assay in peripheral blood lymphocytes from two groups of individuals of the same age but with highly heterogeneous telomere length, selected from a population of 181 individuals where we previously measured telomere length. Our study demonstrates that telomere length modulates chromosome in vitro radiosensitivity in healthy individuals as the group with short telomeres presented higher frequencies of ionizing radiation-induced micronuclei when compared to the long telomeres group. This result supports the conclusion that individual telomere length acts as biomarker of individual chromosome instability upon exposure to ionizing radiation.     

Toluene inhibits hippocampal neurogenesis in adult mice

Toluene, a representative industrial solvent and abused inhalant, decreases neuronal activity in vitro and causes mental depression and cognitive impairment in humans. However, the effects of toluene on brain function and the sites of its action are poorly understood. This study investigated the temporal changes of neurogenesis in the hippocampus of adult C57BL/6 mice after acute administration of toluene using two immunohistochemical markers for neurogenesis, Ki-67 and doublecortin (DCX). In addition, after toluene treatment, depression-like behaviors and learning and memory tasks were examined to assess hippocampal neurogenesis-related behavioral dysfunction. The number of Ki-67- and DCX-positive cells in the dentate gyrus of adult hippocampi declined acutely between 0 h and 24 h after toluene treatment (500 mg/kg, i.p.) and increased gradually from 2 to 8 days post-administration. The level of Ki-67 and DCX immunoreactivity decreased in a dose-dependent manner within the range of toluene administered (0-1000 mg/kg). In tail suspension and forced-swim tests performed at 1 and 4 days after toluene treatment (500 mg/kg), mice showed significant depression-like behaviors compared to the vehicle-treated controls. In the contextual fear conditioning and object recognition memory test, the mice trained at 1 and 4 days after toluene treatment showed significant memory defects compared to the vehicle-treated controls. This study suggests that acute exposure to toluene reduces the rate of adult hippocampal neurogenesis and can cause hippocampal dysfunction such as depression and cognitive impairment.     

Agmatine increases proliferation of cultured hippocampal progenitor cells and hippocampal neurogenesis in chronically stressed mice

AIM: To explore the mechanism of agmatine's antidepressant action. METHODS: Male mice were subjected to a variety of unpredictable stressors on a daily basis over a 24-d period. The open-field behaviors of the mice were displayed and recorded using a Videomex-V image analytic system automatically. For bromodeoxyuridine (BrdU; thymidine analog as a marker for dividing cells) labeling, the mice were injected with BrdU (100 mg/kg, ip, twice per d for 2 d), and the hippocampal neurogenesis in stressed mice was measured by immunohistochemistry. The proliferation of cultured hippocampal progenitor cells from neonatal rats was determined by colorimetric assay (cell counting kit-8) and 3H-thymidine incorporation assay. RESULTS: After the onset of chronic stress, the locomotor activity of the mice in the open field significantly decreased, while coadministration of agmatine 10 mg/kg (po) blocked it. Furthermore, the number of BrdU-labeled cells in the hippocampal dentate gyrus significantly decreased in chronically stressed mice, which was also blocked by chronic coadministration with agmatine 10 mg/kg (po). Four weeks after the BrdU injection, some of the new born cells matured and became neurons, as determined by double labeling for BrdU and neuron specific enolase (NSE), a marker for mature neurons. In vitro treatment with agmatine 0.1-10 micromol/L for 3 d significantly increased the proliferation of the cultured hippocampal progenitor cells in a dose-dependent manner. CONCLUSION: We have found that agmatine increases proliferation of hippocampal progenitor cells in vitro and the hippocampal neurogenesis in vivo in chronically stressed mice. This may be one of the important mechanisms involved in agmatine's antidepressant action.     

Increasing hippocampal neurogenesis: a novel mechanism for antidepressant drugs

The birth of new neurons, or neurogenesis, in the hippocampal formation has been demonstrated throughout the lifetime of multiple species including humans. A major finding in the field of depression is that treatment with antidepressant drugs increases hippocampal neurogenesis. This review presents a current summary of this field of study and presents the hypothesis that increasing adult hippocampal neurogenesis may be a new drug target or mechanism for future antidepressant drugs. It has been demonstrated that multiple classes of antidepressant drugs increase hippocampal cell proliferation and neurogenesis in a chronic and not acute time course, which corresponds to the therapeutic time course necessary for effects. Conversely, animal models of depression or stress paradigms decrease cell proliferation. Clinically, there is evidence of reduced hippocampal volume in patients with major depressive disorder or other affective disorders. Taken together, this data indicates that reduced hippocampal cell number may be involved in the pathophysiology of depression and reversal of this may be one way the antidepressant drugs exert their effects. We hypothesize that the next generation of antidepressant drugs will, in addition to their effects on known transmitter or second messenger systems, involve either direct or indirect targeting of neurogenic factors. In addition, the ability of novel compounds to be tested for the neurogenic potential may become an additional way to evaluate a compound for putative antidepressant effects.     

Diallyl disulfide impairs hippocampal neurogenesis in the young adult brain

Garlic and garlic extracts are used as seasonings and are generally considered beneficial to human health, which include antioxidant and neuroprotective properties in neurological disorders. In the present study, we examined the effects of garlic sulfur components on the proliferation of neural progenitor cells (NPCs) and hippocampal neurogenesis. Of the sulfur compounds extracted, diallyl disulfide (DADS) significantly suppressed the proliferation of NPCs, whereas other sulfur containing components had no effect. In order to investigate the effect of DADS on adult hippocampal neurogenesis, DADS was administered orally to young (6 week-old) male C57BL/6 mice for 2 weeks. It was found that 10 mg/kg of DADS significantly decreased the proliferation of NPCs in the dentate gyrus without affecting the survival of newly generated cells. Furthermore, DADS decreased levels of hippocampal BDNF, phosphorylated CREB signaling, and phosphorylated ERKs, which are known to be related to hippocampal neurogenesis and NPCs proliferation. In addition, DADS induced significant memory defects as compared with controls. We report that DADS may have adverse effects on hippocampal neurogenesis and neurocognitive functions by modulating ERK and BDNF-CREB signaling, and suggest that the advisability of consuming large amounts of garlic products should be considered, particularly during the period of neural growth.     

Acrylamide induces cell death in neural progenitor cells and impairs hippocampal neurogenesis

Acrylamide (ACR) is a well-known neurotoxin in mammalian species that causes neuropathy characterized by ataxia and skeletal muscle weakness. Therefore, ACR-mediated axon damage in the central and peripheral nervous systems is considered to be central-peripheral axonopathy. However, the molecular mechanisms underlying ACR's toxicity to neural progenitor cells are unknown. This study investigated the adverse effects of ACR on mouse multipotent neural progenitor cells and adult hippocampal neurogenesis. ACR significantly reduced the proliferation of neural progenitor cells, and high ACR concentrations induced apoptotic and necrotic cell death. We found that elevated intracellular levels of reactive oxygen species were involved in ACR-mediated cytotoxicity. Interestingly, the administration of ACR to young mice resulted in a significant decrease in the number of newly generated cells in the dentate gyrus of the hippocampus, suggesting an impairment of adult neurogenesis. These results suggest that ACR's deleterious effects on the central nervous system are due to the death of neural progenitor cells and impaired adult neurogenesis.     

Effects of brain insults and pharmacological manipulations on the adult hippocampal neurogenesis

During the last two decades, neurogenesis in the adult mammalian brain has been extensively investigated. Studies have indicated that two brain regions, the subgranular zone of the hippocampal dentate gyrus and the subventricular zone of the lateral ventricle, possess the most active progenitor cells that are capable of generating neurons throughout the lifespan of human beings. Adult hippocampal neurogenesis is the focus of this review. We intend to discuss the changes in the hippocampal neurogenesis caused by pathologic brain insults such as brain ischemia, traumatic brain injury, epileptic seizures, neurodegenerative disorder, and psychiatric diseases. Further, we discuss the stimulatory and inhibitory actions on adult hippocampal neurogenesis by biochemicals and pharmacological agents, including antidepressants, antipsychotics, agonists and antagonists of glutamate and GABA, adrenal corticoids, gonadal hormones, growth factors such as insulin-like growth factor I, erythropoietin, and drugs of abuse, including nicotine, alcohol, opiates, cocaine, methamphetamine, and 3,4-methylenedioxymethamphetamine (“ecstasy”).     

Neurotoxic effect of 2,5-hexanedione on neural progenitor cells and hippocampal neurogenesis

2,5-Hexanedione (HD), a metabolite of n-hexane, causes central and peripheral neuropathy leading to motor neuron deficits. Although chronic exposure to n-hexane is known to cause gradual sensorimotor neuropathy, there are no reports on the effects of low doses of HD on neurogenesis in the central nervous system. In the current study, we explored HD toxicity in murine neural progenitor cells (NPC), primary neuronal culture and young adult mice. HD (500 nM50 μM) dose-dependently suppressed NPC proliferation and cell viability, and also increased the production of reactive oxygen species (ROS). HD (10 or 50 mg/kg for 2 weeks) inhibited hippocampal neuronal and NPC proliferation in 6-week-old male ICR mice, as measured by BrdU incorporation in the dentate gyrus, indicating HD impaired hippocampal neurogenesis. In addition, elevated microglial activation was observed in the hippocampal CA3 region and lateral ventricles of HD-treated mice. Lastly, HD dose-dependently decreased the viability of primary cultured neurons. Based on biochemical and histochemical evidence from both cell culture and HD-treated animals, the neurotoxic mechanisms by which HD inhibits NPC proliferation and hippocampal neurogenesis may relate to its ability to elicit an increased generation of deleterious ROS.     

抗抑郁剂对慢性应激小鼠海马神经元再生的影响

目的　探讨抗抑郁剂作用机制。方法　以流式细胞仪法测定细胞DNA合成期 (S期 )百分率 ;用脑冷冻切片的免疫组化实验检测海马齿状回神经元先祖细胞分裂及脑源性神经营养因子 (BDNF)水平。结果　以N 甲基 D 天冬氨酸(NMDA) 6 0 0 μmol·L-1 处理PC1 2细胞 3d后 ,细胞S期百分率明显降低 ,提示高浓度NMDA可抑制细胞分裂。如果同时给予经典抗抑郁剂去甲丙米嗪 (DIM)或氟西丁 (FLU) 1 ,5 μmol·L-1 则明显提高细胞S期百分率。慢性应激 2 4d小鼠海马齿状回颗粒细胞层下区的先祖细胞分裂减2 0 0 3 10 10收稿 ,2 0 0 3 12 17修回 国家自然科学基金资助课题 ,No 3 0 3 0 0 419;北京市自然科学基金资助课题 ,No 70 42 0 5 2作者简介 :李云峰 ,男 ,3 1岁 ,博士 ,副研究员。研究方向 :精神药理学。Tel:0 10 6687460 6 5 ,Fax:0 10 682 1165 6,E mail:lyf619@yahoo .com .cn ;罗质璞 ,男 ,66岁 ,研究员。研究方向 :精神药理学。Tel:0 10 6693 1619 1,Fax :0 10 682 1165 6少 ,同时BDNF水平低下 ,均表现为阳性棕色颗粒缺失 ,若同时给予DIM或FLU 1 0mg·kg-1 (ip)则逆转上述现象 ,明显增加先祖细胞的分裂和BDNF水平 ,二者在时程上一致。结论　促进海马齿状回神经元再生可能是抗抑郁剂共同作用机制之一 ,并且可能与     

Oxotremorine treatment restores hippocampal neurogenesis and ameliorates depression-like behaviour in chronically stressed rats

Rationale  

Chronic stress results in cognitive impairment, affects hippocampal neurogenesis and is known to precipitate affective disorders such as depression. In addition to stress, neurotransmitters such as acetylcholine (ACh) modulate adult neurogenesis. Earlier, we have shown that oxotremorine, a cholinergic muscarinic agonist, ameliorates stress-induced cognitive impairment and restores cholinergic function.     

Capsaicin impairs proliferation of neural progenitor cells and hippocampal neurogenesis in young mice

Capsaicin (N-vanillyl-8-methyl-1-nonenamide) is a major pungent ingredient in hot peppers and induces apoptosis in malignant carcinoma cell lines. However, the adverse effects of capsaicin on neuronal development have not been fully explored. The aim of this study was to determine whether capsaicin affected murine-derived cerebellar multi-potent neural progenitor cells (NPC) or adult hippocampal neurogenesis in vivo. Capsaicin dose-dependently suppressed NPC proliferation, and higher concentrations were cytotoxic. Capsaicin decreased the activation of extracellular signal-regulated kinases (ERK) without markedly affecting p38 kinases. Capsaicin reduced the number of newly generated cells in the dentate gyrus of the hippocampus but did not significantly alter learning and memory performance in young adult mice. Interestingly, capsaicin decreased ERK activation in the hippocampus, suggesting that reduced ERK signaling may be involved in the capsaicin-mediated regulation of hippocampal neurogenesis.     

Moderate ethanol consumption increases hippocampal cell proliferation and neurogenesis in the adult mouse

Alcoholism is a lifelong disease often associated with emotional disturbances and a high risk of relapse even years after detoxification. To explore if cell proliferation in the dentate gyrus of the hippocampus might be important for alcohol-induced brain adaptation, we analysed hippocampal neurogenesis and gliogenesis in adult C57BL/6 mice that consumed moderate levels of ethanol (~6 g/kg.d) in a two-bottle free-choice model during ~10 wk. The mice developed a 53% preference for ethanol vs. water and displayed a blood ethanol concentration of 0.24 per thousand at the time of sacrifice. Bromo-deoxy-uridine (BrdU) was administered in different regimes to analyse proliferation, survival, cell distribution and differentiation of new cells in the dentate gyrus. Moderate ethanol consumption increased the proliferation of cells, which survived and developed a neural phenotype. Ethanol consumption did not induce apoptosis, neither did it change differentiation or the distribution patterns of the newly formed cells. The cell proliferation rate in the dentate gyrus returned to basal levels 3 d after ethanol withdrawal. We conclude that voluntary ethanol intake by mice can change the rate of cell proliferation in the dentate gyrus. These observations add to the emerging picture of dentate gyrus neurogenesis as a highly regulated process. Since there was no increase in apoptosis concomitant with the ethanol-induced increase in neurogenesis, it is possible that the new cells in the dentate gyrus may contribute to the long-lasting changes of brain function after ethanol consumption.     

Exposure to bisphenol A appears to impair hippocampal neurogenesis and spatial learning and memory

Bisphenol A (BPA) is widely used in the manufacture of plastics and epoxy resins, and is known to affect reproductive organ growth and development. However, the effects of BPA on hippocampal neurogenesis are unclear in young adult mice. Therefore, the present study was conducted to examine the effects of BPA on hippocampal neurogenesis and learning as well as memory performance in young adult mice. BPA (1, 5, and 20 mg/kg/day) was administered orally to mice for 2 weeks. It was found that high-dose BPA (20 mg/kg/day) decreased the number of newly generated cells in hippocampus, but that low-dose BPA (1 mg/kg) increased the survival of newly generated cells in hippocampi of young mice. Furthermore, high-dose BPA (20 mg/kg/day) was found to impair learning and memory performance significantly. However, no significant differences were observed between high- and low-dose treated mice in terms of levels of brain-derived neurotrophic factor (BDNF) or reactive oxygen species production in hippocampus. In addition, BPA treatment did not induce neuronal loss or damage or astrocyte activation. These data suggest that exposure to BPA causes fluctuations in hippocampal neurogenesis in young adult mice that result in spatial learning and memory impairment via a BDNF-independent pathway.     

Promoting adult hippocampal neurogenesis: a novel strategy for antidepressant drug screening

Major depression is a common mood disorder that affects overall health; currently, almost all of the available antidepressants have the same core mechanisms of action through promotion of serotonin or noradrenaline function in the brain. The major limitation of today's antidepressants is that chronic treatment (3 - 6 weeks) is required before a therapeutic benefit is achieved. More effective and faster treatments for depression are needed. Adult neurogenesis is the birth of new neurons, which continues postnatally and into adulthood in the brains of multiple species, including humans. Recently, a large body of evidence gives rise to the hypothesis that the antidepressant effect and increases in adult hippocampal neurogenesis may be causally related. Multiple classes of antidepressants increase hippocampal neurogenesis in a chronic, but not acute, time course. This effect corresponds to the therapeutic time lag associated with current antidepressants. In addition, antidepressants are not effective in behavioral models of depression when hippocampal neurogenesis is prevented. This review examines the current understanding of adult neurogenesis and the evidence of the causal relationship between antidepressant effects and adult hippocampal neurogenesis. We also present our recent research findings, which support a promising strategy for enhancing adult hippocampal neurogenesis that might be a new approach for the development of novel antidepressants.     

Neuron stem cell NLRP6 sustains hippocampal neurogenesis to resist stress-induced depression

Neurogenesis decline in hippocampal dentate gyrus (DG) participates in stress-induced depressive-like behaviors, but the underlying mechanism remains poorly understood. Here, we observed low-expression of NOD-like receptor family pyrin domain containing 6 (NLRP6) in hippocampus of stress-stimulated mice, being consistent with high corticosterone level. NLRP6 was found to be abundantly expressed in neural stem cells (NSCs) of DG. Both Nlrp6 knockout (Nlrp6^−/−) and NSC-conditional Nlrp6 knockout (Nlrp6CKO) mice were susceptible to stress, being more likely to develop depressive-like behaviors. Interestingly, NLRP6 was required for NSC proliferation in sustaining hippocampal neurogenesis and reinforcing stress resilience during growing up. Nlrp6 deficiency promoted esophageal cancer-related gene 4 (ECRG4) expression and caused mitochondrial dysfunction. Corticosterone as a stress factor significantly down-regulated NLRP6 expression, damaged mitochondrial function and suppressed cell proliferation in NSCs, which were blocked by Nlrp6 overexpression. ECRG4 knockdown reversed corticosterone-induced NSC mitochondrial function and cell proliferation disorders. Pioglitazone, a well-known clinical drug, up-regulated NLRP6 expression to inhibit ECRG4 expression in its protection against corticosterone-induced NSC mitochondrial dysfunction and proliferation restriction. In conclusion, this study demonstrates that NLRP6 is essential to maintain mitochondrial homeostasis and proliferation in NSCs, and identifies NLRP6 as a promising therapeutic target for hippocampal neurogenesis decline linked to depression.     

High dose bisphenol A impairs hippocampal neurogenesis in female mice across generations

Occupational exposure to welding fumes (WF) is thought to cause Parkinson's disease (PD)-like neurological dysfunction. An apprehension that WF may accelerate the onset of PD also exists. Identifying reliable biomarkers of exposure and neurotoxicity are therefore critical for biomonitoring and neurological risk characterization of WF exposure. Manganese (Mn) in welding consumables is considered the causative factor for the neurological deficits seen in welders. Hence, we sought to determine if Mn accumulation in blood or nail clippings can be a marker for adverse exposure and neurotoxicity. To model this, rats were exposed by intratracheal instillation to dissolved or suspended fume components collected from gas metal arc-mild steel (GMA-MS) or manual metal arc-hard surfacing (MMA-HS) welding. Trace element analysis revealed selective Mn accumulation in dopaminergic brain areas, striatum (STR) and midbrain (MB), following exposure to the two fumes. This caused dopaminergic abnormality as evidenced by loss of striatal tyrosine hydroxylase (Th; 25-32% decrease) and Parkinson disease (autosomal recessive, early onset) 7 (Park7; 25-46% decrease) proteins. While blood Mn was not detectable, Mn levels in nails strongly correlated with the pattern of Mn accumulation in the striatum (R(2)=0.9386) and midbrain (R(2)=0.9332). Exposure to manganese chloride (MnCl(2)) caused similar Mn accumulation in STR, MB and nail. Our findings suggest that nail Mn has the potential to be a sensitive and reliable biomarker for long-term Mn exposure and associated neurotoxicity. The non-invasive means by which nail clippings can be collected, stored, and transported with relative ease, make it an attractive surrogate for biomonitoring WF exposures in occupational settings.