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    ABSTRACT: Previous studies show that HCN2 ion channels regulate the firing frequency of nociceptive sensory neurons and thus play a central role in both inflammatory and neuropathic pain conditions. Here we use ivabradine, a clinically approved anti-anginal agent which blocks all HCN channel isoforms approximately equally, to investigate the effect on inflammatory and neuropathic pain of HCN ion channel block. We show that ivabradine does not have major off-target effects on a sample group of Na, Ca and K ion channels and that it is peripherally restricted because it is a substrate for the P-glycoprotein multidrug transporter which is expressed in the blood-brain barrier. Its effects are therefore likely to be due to an action on HCN ion channels in peripheral sensory neurons. Using patch clamp electrophysiology we find that ivabradine is a use-dependent blocker of native HCN channels expressed in small sensory neurons. Ivabradine suppresses the action potential firing which is induced in nociceptive neurons by elevation of intracellular cAMP. In the formalin model of inflammatory pain ivabradine reduces pain behaviour only in the second (inflammatory) phase. In nerve injury and chemotherapy models of neuropathic pain we found rapid and effective analgesia, as effective as gabapentin. We conclude that both inflammatory and neuropathic pain are rapidly inhibited by blocking HCN-dependent repetitive firing in peripheral nociceptive neurons.
    Pain 05/2014; 155(9). DOI:10.1016/j.pain.2014.05.021
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    ABSTRACT: The most prominent example of long-distance migration in the postnatal brain is the rostral migratory stream (RMS) formed by neuroblasts originating in the subventricular zone (SVZ), one of the main neurogenic niches. Stem cell-derived neuroblasts leave the SVZ and migrate rostrally towards the olfactory bulb (OB), where they ultimately differentiate into inhibitory interneurons. This migration is essential for the proper integration of new neurons into the synaptic network and for the regulation of synaptic plasticity and olfactory memory. SVZ-derived postnatal neuroblasts undergo tangential migration independent of radial glia. They slide along each other in chains, which become progressively encased by an astrocytic tunnel throughout adulthood, while keeping in close contact with surrounding blood vessels. Once in the OB, neuroblasts switch to radial migration before differentiating. While the existence of an RMS is still controversial in the adult human brain, prominent migration of SVZ-derived neuroblasts towards the OB is observed in human infants, where it may play an important role in plasticity in a crucial period for the formation of synaptic networks. Moreover, SVZ neuroblasts are able to deviate from their migratory path to reach areas of injury and neurodegeneration. Identifying the extracellular factors and the intracellular mechanisms regulating neuroblast migration can therefore not only clarify a fundamental aspect of postnatal neurogenesis, but can also become relevant for therapeutic strategies exploiting the recruitment of endogenous stem cell-derived neural progenitors. This chapter presents an overview of the wide range of extracellular factors guiding neuroblast migration that have emerged over the last two decades.
    Advances in Experimental Medicine and Biology 01/2014; 800:149-80. DOI:10.1007/978-94-007-7687-6_9
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    ABSTRACT: The endocannabinoid (eCB) system consists of several endogenous lipids, their target CB1 and CB2 receptors and enzymes responsible for their synthesis and degradation. The most abundant eCB in the central nervous system (CNS), 2-arachidonoyl glycerol (2-AG), triggers a broad range of signalling events by acting on CB1, the most abundant G protein-coupled receptor in the CNS. The eCB system regulates many physiological processes including neurogenesis, axon guidance and synaptic plasticity. Recent studies have highlighted an additional important role for eCB signalling in neuronal migration, which is crucial to achieve the complex architecture and efficient wiring of the CNS. Indeed, eCB signalling controls migration both pre- and post-natally, regulating interneuron positioning in the developing cortex and hippocampus and the polarized motility of stem cell-derived neuroblasts. While these effects may contribute to cognitive deficits associated with cannabis consumption, they also provide potential opportunities for endogenous stem cell-based neuroregenerative strategies.
    The international journal of biochemistry & cell biology 12/2013; DOI:10.1016/j.biocel.2013.12.007
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    ABSTRACT: Neuropathic pain represents a major problem in clinical medicine because it causes debilitating suffering and is largely resistant to currently available analgesics. A characteristic of neuropathic pain is abnormal response to somatic sensory stimulation. Thus, patients suffering peripheral neuropathies may experience pain caused by stimuli which are normally nonpainful, such as simple touching of the skin or by changes in temperature, as well as exaggerated responses to noxious stimuli. Convincing evidence suggests that this hypersensitivity is the result of pain remaining centralized. In particular, at the first pain synapse in the dorsal horn of the spinal cord, the gain of neurons is increased and neurons begin to be activated by innocuous inputs. In recent years, it has become appreciated that a remote damage in the peripheral nervous system results in neuronal plasticity and changes in microglial and astrocyte activity, as well as infiltration of macrophages and T cells, which all contribute to central sensitization. Specifically, the release of pronociceptive factors such as cytokines and chemokines from neurons and non-neuronal cells can sensitize neurons of the first pain synapse. In this article we review the current evidence for the role of cytokines in mediating spinal neuron-non-neuronal cell communication in neuropathic pain mechanisms following peripheral nerve injury. Specific and selective control of cytokine-mediated neuronal-glia interactions results in attenuation of the hypersensitivity to both noxious and innocuous stimuli observed in neuropathic pain models, and may represent an avenue for future therapeutic intervention.
    Journal of Pain Research 11/2013; 6:803-814. DOI:10.2147/JPR.S53660
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    ABSTRACT: Peripheral nerve injuries caused by trauma are associated with increased sensory neuron excitability and debilitating chronic pain symptoms. Axotomy-induced alterations in the function of ion channels are thought to largely underlie the pathophysiology of these phenotypes. Here, we characterise the mRNA distribution of Kv2 family members in rat dorsal root ganglia (DRG) and describe a link between Kv2 function and modulation of sensory neuron excitability. Kv2.1 and Kv2.2 were amply expressed in cells of all sizes, being particularly abundant in medium-large neurons also immunoreactive for neurofilament-200. Peripheral axotomy led to a rapid, robust and long-lasting transcriptional Kv2 downregulation in the DRG, correlated with the onset of mechanical and thermal hypersensitivity. The consequences of Kv2 loss-of-function were subsequently investigated in myelinated neurons using intracellular recordings on ex vivo DRG preparations. In naïve neurons, pharmacological Kv2.1/Kv2.2 inhibition by stromatoxin-1 (ScTx) resulted in shortening of action potential (AP) after-hyperpolarization (AHP). In contrast, ScTx application on axotomized neurons did not alter AHP duration, consistent with the injury-induced Kv2 downregulation. In accordance with a shortened AHP, ScTx treatment also reduced the refractory period and improved AP conduction to the cell soma during high frequency stimulation. These results suggest that Kv2 downregulation following traumatic nerve lesion facilitates greater fidelity of repetitive firing during prolonged input and thus normal Kv2 function is postulated to limit neuronal excitability. In summary, we have profiled Kv2 expression in sensory neurons and provide evidence for the contribution of Kv2 dysfunction in the generation of hyperexcitable phenotypes encountered in chronic pain states.
    Experimental Neurology 11/2013; DOI:10.1016/j.expneurol.2013.11.011
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    ABSTRACT: Signalling through EGF, FGF and endocannabinoid (eCB) receptors promotes adult neurogenesis, and this can be modelled in culture using the Cor-1 neural stem cell line. In the present study we show that Cor-1 cells express a TGFβ receptor complex composed of the ActRIIB/ALK5 subunits and that a natural ligand for this receptor complex, GDF11, activates the canonical Smad2/3 signalling cascade and significantly alters the expression of ∼4700 gene transcripts within a few hours of treatment. Many of the transcripts regulated by GDF11 are also regulated by the EGF, FGF and eCB receptors and by the MAPK pathway - however, in general in the opposite direction. This can be explained to some extent by the observation that GDF11 inhibits expression of, and signalling through, the EGF receptor. GDF11 regulates expression of numerous cell-cycle genes and suppresses Cor-1 cell proliferation; interestingly we found down-regulation of Cyclin D2 rather than p27kip1 to be a good molecular correlate of this. GDF11 also inhibited the expression of numerous genes linked to cytoskeletal regulation including Fascin and LIM and SH3 domain protein 1 (LASP1) and this was associated with an inhibition of Cor-1 cell migration in a scratch wound assay. These data demonstrate GDF11 to be a master regulator of neural stem cell transcription that can suppress cell proliferation and migration by regulating the expression of numerous genes involved in both these processes, and by suppressing transcriptional responses to factors that normally promote proliferation and/or migration.
    PLoS ONE 11/2013; 8(11):e78478. DOI:10.1371/journal.pone.0078478
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    ABSTRACT: The single nucleotide polymorphism (SNP) A>G rs2306604 in the gene encoding mitochondrial transcription factor A (TFAM) has been associated with Alzheimer's disease, with the A allele being recognised as a risk factor, but has not been studied in other types of dementia. We hypothesised that TFAM SNP rs2306604 might also be associated with Lewy body dementias. To test this hypothesis rs2306604 genotype was determined in 141 controls and 135 patients with dementia with Lewy bodies (DLB) or Parkinson's disease dementia (PDD). rs2306604 genotype frequencies were significantly different to controls in PDD (p=0.042), but not in DLB (p=0.529). The A allele was also associated with PDD (p=0.024, OR=2.092), but not DLB (p=0.429, OR=1.308). Moreover, the A allele was strongly associated with PDD in males (p=0.001, OR=5.570), but not in females (p=0.832, OR=1.100). Mitochondrial DNA copy number in the prefrontal cortex was also significantly reduced in PDD patients, but this reduction was not associated with rs2306604 genotype. These data show that the TFAM SNP rs2306604 A allele may be a risk factor for PDD, particularly in males, but not for DLB. Therefore, the genetic factors that predispose individuals to develop dementia may differ in PDD and DLB.
    Neuroscience Letters 10/2013; 563. DOI:10.1016/j.neulet.2013.10.045
  • Nature Reviews Neurology 10/2013; DOI:10.1038/nrneurol.2013.215
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    ABSTRACT: Dementia with Lewy bodies (DLB) accounts for 10% to 15%(1) of the 35 million people worldwide with dementia. Making an accurate diagnosis is clinically important as these individuals have the challenging combination of highly frequent and disruptive psychotic symptoms together with a high risk of severe sensitivity reactions, leading to accelerated decline and often death following antipsychotic exposure. There is some evidence to support a preferential response, particularly of neuropsychiatric symptoms, to cholinesterase inhibitors. Further, the increased frequency of fluctuating confusion and of falls, and postural hypotension, may have important implications for clinical management.(2.)
    Neurology 10/2013; DOI:10.1212/01.wnl.0000435567.38352.ca
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    ABSTRACT: RNA silencing is an established method for investigating gene function and has attracted particular interest due to the potential for generating RNA-based therapeutics. Utilising lentiviral vectors as an efficient delivery system that offers stable, long term expression in post-mitotic cells further enhances the therapeutical applicability of an RNA-based gene therapy for the CNS. In this review we provide an overview of both lentiviral vectors and RNA silencing as well as presenting design considerations for generating lentiviral vectors capable of RNA silencing. We go on to describe the current pre-clinical data regarding lentiviral vector mediated RNA silencing for CNS disorders and discuss the concerns of non-specific side-effects associated with lentiviral vectors and siRNAs and how these might be mitigated.
    Human Gene Therapy Methods 10/2013; DOI:10.1089/hgtb.2013.016
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