Front Cell Neurosci
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Front Cell Neurosci · Jan 2014
ReviewPeroxisome proliferator-activated receptor agonists modulate neuropathic pain: a link to chemokines?
Chronic pain presents a widespread and intractable medical problem. While numerous pharmaceuticals are used to treat chronic pain, drugs that are safe for extended use and highly effective at treating the most severe pain do not yet exist. Chronic pain resulting from nervous system injury (neuropathic pain) is common in conditions ranging from multiple sclerosis to HIV-1 infection to type II diabetes. ⋯ Experimental evidence suggests a connection between the pain ameliorating effects of PPAR agonists and suppression of inflammatory gene expression, including chemokines. In early clinical research, one PPARα agonist, palmitoylethanolamide (PEA), shows promise in relieving chronic pain. If this link can be better established, PPAR agonists may represent a new drug therapy for neuropathic pain.
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Chronic pain represents a major problem in clinical medicine. Whilst the acute pain that is associated with tissue injury is a protective signal that serves to maintain homeostasis, chronic pain is a debilitating condition that persists long after the inciting stimulus subsides. Chronic neuropathic pain that develops following damage or disease of the nervous system is partially treated by current therapies, leaving scope for new therapies to improve treatment outcome. ⋯ Thus, identification of mechanisms regulating neuro-immune interactions that occur during neuropathic pain may provide future therapeutic targets. Specifically, chemokines and their receptors play a pivotal role in mediating neuro-immune communication which leads to increased nociception. In particular, the chemokine Fractalkine (FKN) and the CX3CR1 receptor have come to light as a key signaling pair during neuropathic pain states.
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Front Cell Neurosci · Jan 2014
Differential neuroprotective potential of CRMP2 peptide aptamers conjugated to cationic, hydrophobic, and amphipathic cell penetrating peptides.
The microtubule-associated axonal specification collapsin response mediator protein 2 (CRMP2) is a novel target for neuroprotection. A CRMP2 peptide (TAT-CBD3) conjugated to the HIV transactivator of transcription (TAT) protein's cationic cell penetrating peptide (CPP) motif protected neurons in the face of toxic levels of Ca(2+) influx leaked in via N-methyl-D-aspartate receptor (NMDAR) hyperactivation. Here we tested whether replacing the hydrophilic TAT motif with alternative cationic (nona-arginine (R9)), hydrophobic (membrane transport sequence (MTS) of k-fibroblast growth factor) or amphipathic (model amphipathic peptide (MAP)) CPPs could be superior to the neuroprotection bestowed by TAT-CBD3. ⋯ Neither peptide altered surface trafficking of NMDARs. Neuroprotection conferred by MTS-CBD3 peptide is likely due to its increased uptake coupled with decreased efflux when compared to TAT-CBD3. Overall, our results demonstrate that altering CPPs can bestow differential neuroprotective potential onto the CBD3 cargo.
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Front Cell Neurosci · Jan 2014
Gene regulatory network analysis reveals differences in site-specific cell fate determination in mammalian brain.
Neurogenesis-the generation of new neurons-is an ongoing process that persists in the adult mammalian brain of several species, including humans. In this work we analyze two discrete brain regions: the subventricular zone (SVZ) lining the walls of the lateral ventricles; and the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus in mice and shed light on the SVZ and SGZ specific neurogenesis. We propose a computational model that relies on the construction and analysis of region specific gene regulatory networks (GRNs) from the publicly available data on these two regions. ⋯ Finally, we conclude that there are fundamental differences between SGZ and SVZ neurogenesis. We argue that these regulatory mechanisms are linked to the observed differential neurogenic potential of these regions. The presence of nuclear and cell surface receptors in the region specific regulatory circuits indicate the significance of niche derived extracellular factors, hormones and region specific factors such as the oxygen sensitivity, dictating SGZ and SVZ specific neurogenesis.
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Front Cell Neurosci · Jan 2014
The role of α-E-catenin in cerebral cortex development: radial glia specific effect on neuronal migration.
During brain development, radial glial cells possess an apico-basal polarity and are coupled by adherens junctions (AJs) to an F-actin belt. To elucidate the role of the actin, we conditionally deleted the key component α-E-catenin in the developing cerebral cortex. ⋯ Interestingly, this phenotype closely resembled the phenotype obtained by conditional RhoA deletion, both in regard to the macroscopic subcortical band heterotopia and the subcellular increase in G-actin/F-actin ratio. These data therefore together corroborate the role of the actin cytoskeleton and its anchoring to the AJs for neuronal migration disorders.