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ABSTRACT: Aim: To explore the hypothesis that grafts of exogenous stem cells in the spinal cord of athymic rats or rats with transgenic motor neuron disease can induce endogenous stem cells and initiate intrinsic repair mechanisms that can be exploited in amyotrophic lateral sclerosis therapeutics. Materials & methods: Human neural stem cells (NSCs) were transplanted into the lower lumbar spinal cord of healthy rats or rats with transgenic motor neuron disease to explore whether signals related to stem cells can initiate intrinsic repair mechanisms in normal and amyotrophic lateral sclerosis subjects. Patterns of migration and differentiation of NSCs in the gray and white matter, with emphasis on the central canal region and ependymal cell-driven neurogenesis, were analyzed. Results: Findings suggest that there is extensive cross-signaling between transplanted NSCs and a putative neurogenic niche in the ependyma of the lower lumbar cord. The formation of a neuronal cord from NSC-derived cells next to ependyma suggests that this structure may serve a mediating or auxiliary role for ependymal induction. Conclusion: These findings raise the possibility that NSCs may stimulate endogenous neurogenesis and initiate intrinsic repair mechanisms in the lower spinal cord.
Regenerative Medicine 11/2012; 7(6):785-97. · 3.72 Impact Factor
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Vassilis E. Koliatsos,
Ibolja Cernak,
Leyan Xu,
Yeajin Song,
Alena Savonenko,
Barbara J. Crain,
Charles G. Eberhart,
Constantine E. Frangakis,
Tatiana Melnikova,
Hyunsu Kim,
Deidre Lee
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ABSTRACT: The increased use of explosives in recent wars has increased the number of veterans with blast injuries. Of particular interest is blast injury to the brain, and a key question is whether the primary overpressure wave of the blast is injurious or whether brain injury from blast is mostly due to secondary and tertiary effects. Using a shock tube generating shock waves comparable to open-field blast waves, we explored the effects of blast on parenchymatous organs of mice with emphasis on the brain. The main injuries in nonbrain organs were hemorrhages in the lung interstitium and alveolar spaces and hemorrhagic infarcts in liver, spleen, and kidney. Neuropathological and behavioral outcomes of blast were studied at mild blast intensity, that is, 68 ± 8 kPag (9.9 ±1.2 psig) static pressure, 103 kPag (14.9 psig) total pressure and 183 ± 14 kPag (26.5 ± 2.1 psig) membrane rupturepressure. Under these conditions, weobserved multifocal axonal injury, primarily in the cerebellum/brainstem, the corticospinal system, and the optic tract. We also found prolonged behavioral and motor abnormalities, including deficits in social recognition and spatial memory and in motor coordination. Shielding of the torso ameliorated axonal injury and behavioral deficits. These findings indicate that long CNS axon tracts are particularly vulnerable to the effects of blast, even at mild intensities that match the exposure of most veterans in recent wars. Prevention of some of these neurological effects by torso shielding may generate new ideas as to how to protect military and civilian populations in blast scenarios.
Journal of Neuropathology and Experimental Neurology 04/2011; 70(5):399-416. · 4.26 Impact Factor
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ABSTRACT: Stem cells provide novel sources of cell therapies for motor neuron disease that have recently entered clinical trials. In the present study, we transplanted human neural stem cells (NSCs) into the ventral horn of both the lumbar (L4-L5) and cervical (C4-C5) protuberance of SOD1 G93A rats, in an effort to test the feasibility and general efficacy of a dual grafting paradigm addressing several muscle groups in the front limbs, hind limbs and the respiratory apparatus. Transplantation was done prior to the onset of motor neuron disease. Compared with animals that had received dead NSC grafts (serving as controls), rats with live NSCs grafted at the two spinal levels lived 17 days longer. Disease onset in dually grafted animals was delayed by 10 days compared to control animals. Disease duration in NSC-grafted animals was longer by 7 days compared to controls. Our results support the potential of NSC grafts at multiple levels of spinal cord as future cellular therapy for motor neuron disease.
Neuroscience Letters 03/2011; 494(3):222-6. · 2.11 Impact Factor
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ABSTRACT: The production of cardiomyocytes from human induced pluripotent stem cells (hiPSC) holds great promise for patient-specific cardiotoxicity drug testing, disease modeling, and cardiac regeneration. However, existing protocols for the differentiation of hiPSC to the cardiac lineage are inefficient and highly variable. We describe a highly efficient system for differentiation of human embryonic stem cells (hESC) and hiPSC to the cardiac lineage. This system eliminated the variability in cardiac differentiation capacity of a variety of human pluripotent stem cells (hPSC), including hiPSC generated from CD34(+) cord blood using non-viral, non-integrating methods.
We systematically and rigorously optimized >45 experimental variables to develop a universal cardiac differentiation system that produced contracting human embryoid bodies (hEB) with an improved efficiency of 94.7±2.4% in an accelerated nine days from four hESC and seven hiPSC lines tested, including hiPSC derived from neonatal CD34(+) cord blood and adult fibroblasts using non-integrating episomal plasmids. This cost-effective differentiation method employed forced aggregation hEB formation in a chemically defined medium, along with staged exposure to physiological (5%) oxygen, and optimized concentrations of mesodermal morphogens BMP4 and FGF2, polyvinyl alcohol, serum, and insulin. The contracting hEB derived using these methods were composed of high percentages (64-89%) of cardiac troponin I(+) cells that displayed ultrastructural properties of functional cardiomyocytes and uniform electrophysiological profiles responsive to cardioactive drugs.
This efficient and cost-effective universal system for cardiac differentiation of hiPSC allows a potentially unlimited production of functional cardiomyocytes suitable for application to hPSC-based drug development, cardiac disease modeling, and the future generation of clinically-safe nonviral human cardiac cells for regenerative medicine.
PLoS ONE 01/2011; 6(4):e18293. · 4.09 Impact Factor
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ABSTRACT: Current experimental models of blast injuries used to study blast-induced neurotrauma (BINT) vary widely, which makes the comparison of the experimental results extremely challenging. Most of the blast injury models replicate the ideal Friedländer type of blast wave, without the capability to generate blast signatures with multiple shock fronts and refraction waves as seen in real-life conditions; this significantly reduces their clinical and military relevance. Here, we describe the pathophysiological consequences of graded blast injuries and BINT generated by a newly developed, highly controlled, and reproducible model using a modular, multi-chamber shock tube capable of tailoring pressure wave signatures and reproducing complex shock wave signatures seen in theater. While functional deficits due to blast exposure represent the principal health problem for today's warfighters, the majority of available blast models induces tissue destruction rather than mimic functional deficits. Thus, the main goal of our model is to reliably reproduce long-term neurological impairments caused by blast. Physiological parameters, functional (motor, cognitive, and behavioral) outcomes, and underlying molecular mechanisms involved in inflammation measured in the brain over the 30 day post-blast period showed this model is capable of reproducing major neurological changes of clinical BINT.
Neurobiology of Disease 11/2010; 41(2):538-51. · 5.40 Impact Factor
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Cerebrum: the Dana forum on brain science 11/2010; 2010:25.
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ABSTRACT: Nitric oxide (NO) is a gas messenger with diverse physiological roles in the nervous system, from modulation of synaptic plasticity and neurogenesis to the mediation of neuronal death. NO production in the brain is catalyzed by three isoforms of NO synthase (NOS) including neuronal NOS (nNOS), inducible NOS and endothelial NOS. In this report, we demonstrate a method for in vitro and in vivo silencing of nNOS using RNAi strategies. Because of their efficiency in infecting postmitotic cells like neurons, lentiviral vectors were used as nNOS shRNA carriers. Of the siRNA sequences screened, one corresponding to exon 10 of the rat nNOS specifically and efficiently inhibited nNOS expression at the mRNA and protein level. In vitro experiments using rat cortical neurons showed the general efficacy of shRNA vectors in silencing constitutively expressed nNOS. To demonstrate the anatomical specificity of nNOS silencing in vivo, vectors were used to selectively knock-down the endogenous nNOS expression in cortical GABAergic interneurons of rat piriform cortex. Our findings show that the method reported here can achieve stable and highly effective nNOS suppression in an anatomically defined brain region. The ability of our nNOS silencing vectors to effectively and precisely silence nNOS expression shows their value as research tools for further studies of the role of nNOS in specific brain circuits. Furthermore, our findings raise the possibility for future considerations of lentiviral strategies as therapies for diseases of the nervous system involving NO neurotoxic cascades.
Journal of neuroscience methods 06/2009; 179(2):292-9. · 2.30 Impact Factor
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ABSTRACT: Cell replacement strategies for degenerative and traumatic diseases of the nervous system depend on the functional integration of grafted cells into host neural circuitry, a condition necessary for the propagation of physiological signals and, perhaps, targeting of trophic support to injured neurons. We have recently shown that human neural stem cell (NSC) grafts ameliorate motor neuron disease in SOD1 transgenic rodents. Here we study structural aspects of integration of neuronally differentiated human NSCs in the motor circuitry of SOD1 G93A rats. Human NSCs were grafted into the lumbar protuberance of 8-week-old SOD1 G93A rats; the results were compared to those on control Sprague-Dawley rats. Using pre-embedding immuno-electron microscopy, we found human synaptophysin (+) terminals contacting the perikarya and proximal dendrites of host alpha motor neurons. Synaptophysin (+) terminals had well-formed synaptic vesicles and were associated with membrane specializations primarily in the form of symmetrical synapses. To analyze the anatomy of motor circuits engaging differentiated NSCs, we injected the retrograde transneuronal tracer Bartha-pseudorabies virus (PRV) or the retrograde marker cholera toxin B (CTB) into the gastrocnemius muscle/sciatic nerve of SOD1 rats before disease onset and also into control rats. With this tracing, NSC-derived neurons were labeled with PRV but not CTB, a pattern suggesting that PRV entered NSC-derived neurons via transneuronal transfer from host motor neurons but not via direct transport from the host musculature. Our results indicate an advanced degree of structural integration, via functional synapses, of differentiated human NSCs into the segmental motor circuitry of SOD1-G93A rats.
The Journal of Comparative Neurology 03/2009; 514(4):297-309. · 3.81 Impact Factor
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ABSTRACT: Stem cell transplantation, a widely accepted therapeutic approach to diseases of modular organs such as the heart and the endocrine pancreas, remains a controversial option for the nervous system. However, historical advances in the 1990s on key aspects of neural plasticity and the appreciation of the selective vulnerability of nerve cells and systems in degenerative and traumatic diseases require a re-examination of this scepticism. The successes and failures with prior trophic factor therapies are particularly enlightening; many lessons from this era can be creatively absorbed as the early outcomes with stem cell grafts in animal models of disease are evaluated. Stem cell grafting into spinal cord, traditionally a doomed enterprise because of lack of neurogenicity in this region and multiple early failures, is becoming promising again with recent findings from the authors' laboratory and elsewhere that specific types of cells and methods of culture are associated with much improved biological and functional outcomes.
Expert opinion on biological therapy 03/2008; 8(2):137-41. · 3.22 Impact Factor
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ABSTRACT: The extremely elongated processes of neurons—especially axons—present an unusual challenge to the metabolic machinery of the
cell. A consequence of this geometry is that the metabolic and specialized (e.g., transmission) needs of axon terminals are
dependent on the perikaryon (the primary biosynthetic site of the neuron) via shipment of the necessary material along the
axon. This fundamental neuronal process is called “anterograde transport” and proceeds along at least five different rate
classes, the highest of which (20–400 mm/d) constitute the fast anterograde transport and the lowest of which (0.1–20 mm/d)
represent slow anterograde transport (Vallee and Bloom, 1991). An estimated fraction equivalent to 10–70% of fast anterograde
transport is returned to the cell body via retrograde transport (Vallee and Bloom, 1991), with velocities ranging from 120
to 240 mm/ d (Schwab and Thoenen, 1980). Retrograde transport, much like fast anterograde transport, is blocked by microtubule
assembly inhibitors such as colchicine and vinblastine (Grafstein and Forman, 1980), an effect that underlies an important
role for microtubules in this biological process. The role of microtubules in retrograde transport has been clarified recently,
with the discovery of the microtubule-associated motor proteins kinesin (responsible for anterograde transport) and MAP 1C
(responsible for retrograde transport) (Vallee and Bloom, 1991).
02/2008: pages 247-290;
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Donald L. Price, Vassilis E. Koliatsos,
Philip C.-Y. Wong,
Carlos A. Pardo,
David R. Borchelt,
Michael K. Lee,
Don W. Cleveland,
John W. Griffin,
Paul N. Hoffman,
Linda C. Cork,
Sangram S. Sisodia
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ABSTRACT: The phenotypes of many neurological diseases, including motor neuron disease (amyotrophic lateral sclerosis; ALS) and Alzheimer's disease (AD), are determined by the vulnerabilities of populations of nerve cells and the character/evolution of cellular abnormalities. Because different cell types respond selectively to individual trophic factors, these factors may be useful in ameliorating pathology in cells that express their cognate receptors. To test therapies for ALS and AD, investigators require model systems. Although there are a variety of models of ALS, two models are particularly attractive: transgenic mice that express human superoxide dismutase 1 (SOD-1) mutations linked to familial ALS develop paralysis associated with a gain of adverse property of the mutant SOD; and axotomy of facial axons in neonatal rats, a manipulation that causes retrograde cell degeneration, which can be ameliorated by several trophic factors.
09/2007: pages 3 - 17; , ISBN: 9780470514863
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ABSTRACT: Pyramidal relay neurons in limbic cortex are vulnerable to denervation lesions, i.e. pyramidal neurons in layer IIalpha of piriform cortex undergo transsynaptic apoptosis after lesions that interrupt their inputs from the olfactory bulb. We have previously established the role of inhibitory interneurons in elaborating signals that lead to the apoptosis of projection neurons in these lesion models, i.e. the upregulation of neuronal NOS and release of nitric oxide. Thus, we have proposed that cortical interneurons play an essential role in transducing injury to degenerative effects for nearby pyramidal neurons. In the present study, we extend the previous findings to a toxic model of degeneration of pyramidal neurons in the adult paralimbic cortex, i.e. after exposure to the NMDA channel blocker MK801. Our findings indicate that treatment of adult rats with MK801 in doses previously found to cause alterations in pyramidal neurons of the retrosplenial cortex (5mg/kg) results in an active caspase 3 (+), ultrastructurally apoptotic type of cell death involving the same projection neurons of layer IIalpha that are also vulnerable to bulbotomy lesions. Interneurons of layer I are induced by MK801 treatment to higher levels of nNOS expression and the selective nNOS inhibitor BRNI ameliorates pyramidal cell apoptosis caused by MK801. Our results indicate that certain pyramidal neurons in piriform cortex are very sensitive to NMDA blockade as they are to disconnection from modality-specific afferents and that inhibitory interneurons play significant roles in mediating various types of pro-apoptotic insults to cortical projection neurons via nNOS/NO signaling.
Neuropharmacology 07/2007; 52(7):1528-37. · 4.81 Impact Factor
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ABSTRACT: Effective treatments for degenerative and traumatic diseases of the nervous system are not currently available. The support or replacement of injured neurons with neural grafts, already an established approach in experimental therapeutics, has been recently invigorated with the addition of neural and embryonic stem-derived precursors as inexhaustible, self-propagating alternatives to fetal tissues. The adult spinal cord, i.e., the site of common devastating injuries and motor neuron disease, has been an especially challenging target for stem cell therapies. In most cases, neural stem cell (NSC) transplants have shown either poor differentiation or a preferential choice of glial lineages.
In the present investigation, we grafted NSCs from human fetal spinal cord grown in monolayer into the lumbar cord of normal or injured adult nude rats and observed large-scale differentiation of these cells into neurons that formed axons and synapses and established extensive contacts with host motor neurons. Spinal cord microenvironment appeared to influence fate choice, with centrally located cells taking on a predominant neuronal path, and cells located under the pia membrane persisting as NSCs or presenting with astrocytic phenotypes. Slightly fewer than one-tenth of grafted neurons differentiated into oligodendrocytes. The presence of lesions increased the frequency of astrocytic phenotypes in the white matter.
NSC grafts can show substantial neuronal differentiation in the normal and injured adult spinal cord with good potential of integration into host neural circuits. In view of recent similar findings from other laboratories, the extent of neuronal differentiation observed here disputes the notion of a spinal cord that is constitutively unfavorable to neuronal repair. Restoration of spinal cord circuitry in traumatic and degenerative diseases may be more realistic than previously thought, although major challenges remain, especially with respect to the establishment of neuromuscular connections.
PLoS Medicine 03/2007; 4(2):e39. · 16.27 Impact Factor
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ABSTRACT: Because neurotrophic factors can prevent natural and experimental cases of neural cell death and induce and maintain differentiation, they are especially attractive agents for the treatment of neurodegenerative diseases, such as Alzheimer's disease (AD). The present report argues for the specific role of particular families of trophic factors, such as neurotrophins (e.g., nerve growth factor [NGF]) and neurokines (e.g, ciliary neurotrophic factor [CNTF]), for the promotion of the survival and phenotype of subsets of central nervous system (CNS) neurons vulnerable in AD, such as basal forebrain cholinergic neurons and cortical projection neurons. Although there is ample evidence for the therapeutic role of NGF in experimental or natural injury of cholinergic neurons, not enough progress has been made on trophic models involving cortical neurons. Further understanding of the mechanisms of cell death in AD and elucidation of the transduction cascades of trophic factors will undoubtedly refine our current concepts of a neurotrophic treatment for AD.
Annals of the New York Academy of Sciences 12/2006; 695(1):292 - 299. · 3.15 Impact Factor
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ABSTRACT: Experimental therapeutics for degenerative and traumatic diseases of the nervous system have been recently enriched with the addition of neural stem cells (NSCs) as alternatives to fetal tissues for cell replacement. Neurodegenerative diseases present the additional problem that cell death signals may interfere with the viability of grafted cells. The adult spinal cord raises further challenges for NSC differentiation because of lack of intrinsic developmental potential and the negative outcomes of several prior attempts.
NSCs from human fetal spinal cord were grafted into the lumbar cord of SOD1 G93A rats. The differentiation fate of grafted NSCs and their effects on motor neuron number, locomotor performance, disease onset, and survival trends/longevity were assessed. Trophic mechanisms of observed clinical effects were explored with molecular and cellular methodologies.
Human NSCs showed extensive differentiation into neurons that formed synaptic contacts with host nerve cells and expressed and released glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor. NSC grafts delayed the onset and progression of the fulminant motor neuron disease typical of the rat SOD1 G93A model and extended the lifespan of these animals by more than 10 days, despite the restricted grafting schedule that was limited to the lumbar protuberance.
NSC grafts can survive well in a neurodegenerative environment and exert powerful clinical effects; at least a portion of these effects may be related to the ability of these grafts to express and release motor neuron growth factors delivered to host motor neurons via graft-host connections.
Transplantation 11/2006; 82(7):865-75. · 4.00 Impact Factor
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ABSTRACT: A concern recently has been raised that human embryonic stem cell (HESC) lines cultured with currently available methods may have limited clinical usefulness due to the immunogenicity of the nonhuman sialic acid Neu5Gc incorporated into their membranes during culturing. We find this concern has little relevance to neural differentiation protocols with B27/N2/noggin because of the gradual decline of Neu5Gc to less than 1% in differentiating cells upon switching to B27/N2 medium.
Experimental Neurology 11/2006; 201(2):525-9. · 4.70 Impact Factor
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ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a target for cell-replacement therapies, including therapies based on human neural stem cells (NSCs). These therapies must be first tested in the appropriate animal models, including transgenic rodents harboring superoxide dismutase (SOD1) mutations linked to familial ALS. However, these rodent subjects reject discordant xenografts. In the present investigation, we grafted NSCs from human embryonic spinal cord into the ventral lumbar cord of 2-month-old SOD1-G93A transgenic mice. Animals were immunosuppressed with FK506, FK506 plus rapamycin, FK506 plus rapamycin plus mycophenolate mofetil, or CD4 antibodies. With FK506 monotherapy, human NSC grafts were rejected within 1 week, whereas combinations of FK506 with one or two of the other agents or CD4 antibodies protected grafts into end-stage illness (i.e., more than 2 months after grafting). The combination of FK506 with rapamycin appeared to be optimal with respect to efficacy and simplicity of administration. Graft protection was achieved via the blockade of CD4- and CD8-cell infiltration and attenuation of the microglial phagocytic response from the host. Surviving NSCs differentiated extensively into neurons that began to establish networks with host nerve cells, including alpha-motor neurons. Immunosuppressed animals with live cells showed later onset and a slower progression of motor neuron disease and lived longer compared with immunosuppressed control animals with dead NSC grafts. Our findings indicate that combined immunosuppression promotes the survival of human NSCs grafted in the spinal cord of SOD1-G93A mice and, in doing so, allows the differentiation of NSCs into neurons and leads to the improvement of key parameters of motor neuron disease.
Stem Cells 09/2006; 24(8):1976-85. · 7.78 Impact Factor
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ABSTRACT: Work on acute models of cortical injury has revealed a population of small GABAergic interneurons that are induced to increase their low constitutive expression of neuronal nitric oxide (NO) synthase (nNOS). In some cases, this activation may play a role in NO-mediated degeneration of pyramidal neurons. In this report, we explore the anatomy of various classes of cortical nNOS (+) (nitrergic) neurons, with emphasis on small interneurons, in the medial temporal lobe of subjects with Alzheimer's disease (AD) from two well-characterized cohorts, the Baltimore Longitudinal Study on Aging (BLSA) and the Religious Order Study (ROS). We find that small calbindin (+) cortical interneurons are induced to high levels of NADPHd/nNOS reactivity early in AD and abound in areas with emerging neurofibrillary pathology, that is, in entorhinal cortex in the beginning of the limbic stage of Braak, in hippocampal CA1 in the mature limbic stage and in temporal neocortex in the late limbic stage. This pattern was robust and significant in the younger of the two AD cohorts studied (BLSA), but persisted as a trend in the older cohort (ROS). In optimally prepared material, we find a significant correlation between numbers of these interneurons and markers of neuronal cell death, for example, caspase-3 activation. Our results show that small cortical inhibitory interneurons represent an extensive signaling system that is induced to higher levels of NADPHd/nNOS expression early in the paralimbic-limbic-neocortical sequence of AD progression. We propose that nNOS/NO signaling initiated in these interneurons can serve as a marker of early cortical injury in AD. The specific role played by inhibitory interneurons and NO in the elaboration of specific neuropathologies associated with AD, that is, Abeta and neurofibrillary deposits and cell death deserves further exploration in experimental animal models.
Acta Neuropathologica 09/2006; 112(2):147-62. · 9.32 Impact Factor
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ABSTRACT: We have previously shown that pyramidal neurons engaged in cortico-cortical connectivity in limbic cortex are vulnerable to denervation lesions, i.e. relay pyramidal neurons in layer II of piriform cortex undergo transsynaptic apoptosis after lesions interrupting their inputs from the olfactory bulb (bulbotomies). At least one trigger of this transsynaptic degenerative phenomenon is the activation of inhibitory interneurons in layer I, which are induced to upregulate neuronal nitric oxide synthase (nNOS) and release NO. Thus, we have demonstrated that cortical interneurons play an essential role in transducing injury to apoptotic signaling that selectively targets pyramidal neurons. In the present study, we confirm the role of nNOS with pharmacological inhibition of a significant approximately 30% of transsynaptic apoptosis with the selective nNOS inhibitor BRNI at optimal doses. Outcomes were studied both at the histological and molecular level using DNA blots. We also show that the first-generation competitive non-NMDA (AMPA) antagonist NBQX ameliorates transsynaptic apoptosis by the same margin of difference as BRNI and it also reduces nNOS activation as indicated by a significant decrease in NADPH diaphorase histochemical activity in layer I of piriform cortex. Our findings confirm the role of nNOS activation/NO release in transsynaptic apoptosis and show that glutamatergic agonism at AMPA sites also plays a significant role. In addition, our data suggest that AMPA agonism may occur upstream to nNOS upregulation in inhibitory interneurons of layer I. In concert, our findings indicate that transsynaptic neuronal degeneration in limbic cortex involves complex AMPA-glutamatergic and nitrinergic signaling events. An AMPA-mediated upregulation of nNOS and release of NO by inhibitory interneurons may play a prominent role in this type of injury.
Neuropharmacology 08/2006; 51(1):67-76. · 4.81 Impact Factor
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ABSTRACT: The mechanism of action of commonly used antidepressants remains an issue of debate. In the experiments reported here we studied the effects of three representative compounds, the selective serotonin reuptake inhibitor fluoxetine, the selective serotonin reuptake enhancer tianeptine and the selective norepinephrine reuptake inhibitor desipramine on the structure of central serotonin pathways after a 4-week administration. We found that the serotonin modulators fluoxetine and tianeptine, but not desipramine, increase the density of 5-HT and serotonin transporter (SERT)-immunoreactive axons in the neocortical layer IV and certain forebrain limbic areas, such as piriform cortex and the shell region of nucleus accumbens. These changes were noted in the absence of a significant effect of serotonin antidepressants on the expression of tryptophan hydroxylase (TPH-2), i.e. the rate-limiting enzyme for 5-HT biosynthesis and of SERT at the mRNA level. In addition, we found that anterogradely filled terminal axons from injections of biotinylated dextran amine into the dorsal raphe showed significantly more branching in animals treated with fluoxetine compared with animals treated with liposyn vehicle. Our findings suggest that antidepressants may exert very selective structural effects on their cognate monoamine systems in normal animals and raise the possibility that neurotrophic mechanisms may play a role in their clinical efficacy.
Journal of Neurochemistry 02/2006; 96(2):396-406. · 4.06 Impact Factor
