Brain‐derived neurotrophic factor (BDNF) is implicated in the pathophysiology of major depression; mice lacking BDNF expression through promoter IV (BDNF‐KIV) exhibit a depression‐like phenotype. We tested our hypothesis that deficits caused by promoter IV deficiency (depression‐like behavior, decreased levels of BDNF, and neurogenesis in the hippocampus) could be rescued by a 3‐week treatment with different types of antidepressants: fluoxetine, phenelzine, duloxetine, or imipramine. Each antidepressant reduced immobility time in the tail suspension test without affecting locomotor activity in the open field test in both BDNF‐KIV and control wild type mice, except that phenelzine increased locomotor activity in wild type mice and anxiety‐like behavior in BDNF‐KIV mice. The antidepressant treatments were insufficient to reverse decreased BDNF levels caused by promoter IV deficiency. No antidepressant treatment increased the hippocampal progenitors of either genotype, whereas phenelzine decreased the surviving progenitors in both genotypes. The antidepressant treatments differently affected the dendritic extension of hippocampal immature neurons: fluoxetine and imipramine increased extension in both genotypes, duloxetine increased it only in BDNF‐KIV mice, and phenelzine decreased it only in wild type mice. Interestingly, a saline‐only injection increased neurogenesis and dendrite extensions in both genotypes. Our results indicate that the behavioral effects in the tail suspension test by antidepressants do not require promoter IV‐driven BDNF expression and occur without a detectable increase in hippocampal BDNF levels and neurogenesis but may involve increased dendritic reorganisation of immature neurons. In conclusion, the antidepressant treatment demonstrated limited efficacy; it partially reversed the defective phenotypes caused by promoter IV deficiency but not hippocampal BDNF levels. 相似文献
The polysialylated form of the neuronal cell adhesion molecule (PSA‐NCAM) is expressed by immature neurons in the amygdala of adult mammals, including non‐human primates. In a recent report we have also described the presence of PSA‐NCAM‐expressing cells in the amygdala of adult humans. Although many of these cells have been classified as mature interneurons, some of them lacked mature neuronal markers, suggesting the presence of immature neurons. We have studied, using immunohistochemistry, the existence and distribution of these immature neurons using post mortem material. We have also analysed the presence of proliferating cells and the association between immature neurons and specialised astrocytes. These parameters have also been studied for comparative purposes in the amygdalae of cats and squirrel monkeys. Our results demonstrate that cells coexpressing doublecortin and PSA‐NCAM, but lacking neuronal nuclear antigen expression, were present in the amygdala of adult humans. These cells were organised in elongated clusters, which were located between the white matter of the dorsal hippocampus and the basolateral amygdaloid nucleus. These clusters were not associated with astroglial specialised structures. No cells expressing the proliferative marker Ki67 were observed in the amygdaloid parenchyma, although some of them were found in the vicinity of the lateral ventricle. Immature neurons were also present in the amygdala of squirrel monkeys and cats. These cells also appeared clustered in monkeys, although not as organised as in humans. In cats these cells are scarce, appear isolated and most of the PSA‐NCAM‐expressing structures corresponded to processes apparently originating from the paleocortical layer II. 相似文献
Di-2-ethylhexyl phthalate (DEHP) is the most commonly used phthalate for the production of flexible polyvinyl chloride. Recent studies in humans reported a widespread DEHP exposure, raising concerns in infants whose metabolic and excretory systems are immature. DEHP is a potential endocrine-disrupting chemical, but the effects of postnatal DEHP exposure on neuronal development are unclear. The dentate gyrus (DG) is critical in the consolidation of information from short- to long-term memory, as well as spatial learning. We evaluated neurodevelopmental toxicity due to neonatal DEHP exposure by assessing neurogenesis in the DG. Newborn mice were orally administered DEHP from postnatal day (PND) 12 to 25. We performed immunostaining using neuronal markers at different stages to assess whether DEHP exposure affects neurons at specific differentiation stages at PND 26 and PND 110. We found that in mice, postnatal DEHP exposure led to a decrease in the number of Type-1, -2a, -2b, and -3 neural progenitor cells, as well as granule cells in the hippocampal DG at PND 26. Further, the results showed that neural progenitor cell proliferation and differentiation were also reduced in the hippocampal DG of the DEHP-exposed mice. However, no effect on memory and learning was observed. Overall, our results suggest that neurodevelopmental toxicity due to postnatal DEHP exposure might affect postnatal DG morphogenesis. 相似文献
In the months following transection of adult rat peripheral nerve some sensory neurons undergo apoptosis. Two weeks after sciatic nerve transection some neurons in the L4 and L5 dorsal root ganglia begin to show immunoreactivity for nestin, a filament protein expressed by neuronal precursors and immature neurons, which is stimulated by neurotrophin-3 (NT-3) administration. The aim of this study was to examine whether NT-3 administration could be compensating for decreased production of neurotrophins or their receptors after axotomy, and to determine the effect on nestin synthesis. The levels of mRNA in the ipsilateral and contralateral L4 and L5 dorsal root ganglia were analyzed using real-time polymerase chain reaction, 1 day, 1, 2 and 4 weeks after unilateral sciatic nerve transection and NT-3 or vehicle administration via s.c. micro-osmotic pumps. In situ hybridization was used to identify which cells and neurons expressed mRNAs of interest, and the expression of full-length trkC and p75NTR protein was investigated using immunohistochemistry. Systemic NT-3 treatment increased the expression of brain-derived neurotrophic factor, nestin, trkA, trkB and trkC mRNA in ipsilateral ganglia compared with vehicle-treated animals. Some satellite cells surrounding neurons expressed trkA and trkC mRNA and trkC immunoreactivity. NT-3 administration did not affect neurotrophin mRNA levels in the contralateral ganglia, but decreased the expression of trkA mRNA and increased the expression of trkB mRNA and p75NTR mRNA and protein. These data suggest that systemically administered NT-3 may counteract the decrease, or even increase, neurotrophin responsiveness in both ipsi- and contralateral ganglia after nerve injury. 相似文献
Postmitotic neurons must survive for the entire life of the organism and be able to respond adaptively to adverse conditions of oxidative and genotoxic stress. Unrepaired DNA damage can trigger apoptosis of neurons which is typically mediated by the ataxia telangiectasia mutated (ATM)-p53 pathway. As in all mammalian cells, telomeres in neurons consist of TTAGGG DNA repeats and several associated proteins that form a nucleoprotein complex that prevents chromosome ends from being recognized as double strand breaks. Proteins that stabilize telomeres include TRF1 and TRF2, and proteins known to play important roles in DNA damage responses and DNA repair including ATM, Werner and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). We have been performing studies of developing and adult neurons aimed at understanding the effects of global and telomere-directed DNA damage responses in neuronal plasticity and survival in the contexts of aging and neurodegenerative disorders. Deficits in specific DNA repair proteins, including DNA-PKcs and uracil DNA glycosylase (UDG), render neurons vulnerable to adverse conditions of relevance to the pathogenesis of neurodegenerative disorders such as Alzheimer's disease and stroke. Similarly, early postmitotic neurons with reduced telomerase activity exhibit accentuated responses to DNA damage and are prone to apoptosis demonstrating a pivotal role for telomere maintenance in both mitotic cells and postmitotic neurons. Our recent findings suggest key roles for TRF2 in regulating the differentiation and survival of neurons. TRF2 affects cell survival and differentiation by modulating DNA damage pathways, and gene expression. A better understanding of the molecular mechanisms by which neurons respond to global and telomere-specific DNA damage may reveal novel strategies for prevention and treatment of neurodegenerative disorders. Indeed, work in this and other laboratories has shown that dietary folic acid can protect neurons against Alzheimer's disease by keeping homocysteine levels low and thereby minimizing the misincorporation of uracil into DNA in neurons. 相似文献
Ischemic preconditioning (IPC) before subsequent prolonged ischemia is considered an emerging endogenous means of ischemic brain protection. We tested whether IPC induces endogenous neurogenesis in the subventricular zone (SVZ) and angiogenesis in the peri-ischemic area. Middle cerebral artery occlusion was administered to rats by filament insertion for 10 min (IPC) and/or 2 h (prolonged focal ischemia [PFI]). IPC alone increased 5'-bromo-2'-deoxyuridine (BrdU) (+) cells 2.5-fold in the SVZ compared with controls at 7 days. The numbers of BrdU/doublecortin (Dcx) or BrdU/neuronal nuclei (NeuN) double-labeled cells also increased, but extents of BrdU/glial fibrillary acidic protein (GFAP) double-labeling in the SVZ were not different. The IPC+PFI group showed about a 40% reduction in infarct volume. PFI increased BrdU (+) cells in the SVZ, and this was greatly enhanced by IPC treatment. The number of BrdU/Dcx double-labeled cells was strongly increased in ischemic brains administered IPC. Differentiation into mature neurons was also enhanced at 14 and 28 days. In addition, IPC significantly promoted angiogenesis in the ischemic penumbra as indicated by von Willebrand factor (vWF) staining. Our results indicate that IPC enhances neurogenesis in the SVZ even without subsequent PFI, and also enhances neurogenesis and angiogenesis after subsequent PFI. We conclude that IPC confers neuroprotection, and also promotes endogenous neurogenesis and angiogenesis. 相似文献
Introduction: Alzheimer’s disease (AD), which accounts for three fourth of all cases of dementia, is a major public health problem in modern society and, yet, there is no effective treatment available that can prevent or inhibit this chronic progressive neurodegenerative disease. A major current drug target is intraneuronal abnormally hyperphosphorylated microtubule-associated protein tau which is a histopathological hallmark of this disease and of a family of neurodegenerative diseases called tauopathies.
Areas covered: In this review, the authors discuss a growing number of studies that describe the nature and mechanism of tau pathology and various drug discovery options and most recent developments in tau-based therapeutics. PubMed was used to obtain relevant literature while clinicaltrials.gov site and Google search were employed to obtain the latest information on tau based AD clinical trials.
Expert opinion: In authors’ opinion, loss of neuronal connectivity leads to the hyperphosphorylation of tau and is thus a key therapeutic target. Rescue of neuronal connectivity loss and hyperphosphorylation of tau are most promising approaches. Consequently, tau immunotherapy has a high therapeutic potential. 相似文献