Microglial responses around intrinsic CNS neurons are correlated with axonal regeneration

Background  

Microglia/macrophages and lymphocytes (T-cells) accumulate around motor and primary sensory neurons that are regenerating axons but there is little or no microglial activation or T-cell accumulation around axotomised intrinsic CNS neurons, which do not normally regenerate axons. We aimed to establish whether there was an inflammatory response around the perikarya of CNS neurons that were induced to regenerate axons through a peripheral nerve graft.     

Analysis of axonal regeneration in the central and peripheral nervous systems of the NG2-deficient mouse

Background  

The chondroitin sulphate proteoglycan NG2 blocks neurite outgrowth in vitro and has been proposed as a major inhibitor of axonal regeneration in the CNS. Although a substantial body of evidence underpins this hypothesis, it is challenged by recent findings including strong expression of NG2 in regenerating peripheral nerve.     

Wallerian-like axonal degeneration in the optic nerve after excitotoxic retinal insult: an ultrastructural study

Background  

Excitotoxicity is involved in the pathogenesis of a number neurodegenerative diseases, and axonopathy is an early feature in several of these disorders. In models of excitotoxicity-associated neurological disease, an excitotoxin delivered to the central nervous system (CNS), could trigger neuronal death not only in the somatodendritic region, but also in the axonal region, via oligodendrocyte N-methyl-D-aspartate (NMDA) receptors. The retina and optic nerve, as approachable regions of the brain, provide a unique anatomical substrate to investigate the "downstream" effect of isolated excitotoxic perikaryal injury on central nervous system (CNS) axons, potentially providing information about the pathogenesis of the axonopathy in clinical neurological disorders.     

Myelin contributes to the parallel orientation of axonal growth on white matter in vitro

Background  

The fly visual system is a highly ordered brain structure with well-established physiological and behavioral functions. A large number of interneurons in the posterior part of the third visual neuropil, the lobula plate tangential cells (LPTCs), respond to visual motion stimuli. In these cells the mechanism of motion detection has been studied in great detail. Nevertheless, the cellular computations leading to their directionally selective responses are not yet fully understood. Earlier studies addressed the neuropharmacological basis of the motion response in lobula plate interneurons. In the present study we investigated the distribution of the respective neurotransmitter receptors in the fly visual system, namely nicotinic acetylcholine receptors (nAChRs) and GABA receptors (GABARs) demonstrated by antibody labeling.     

The pathophysiology of prospective memory failure after diffuse axonal injury - Lesion-symptom analysis using diffusion tensor imaging

Background  

Prospective memory (PM) is one of the most important cognitive domains in everyday life. The neuronal basis of PM has been examined by a large number of neuroimaging and neuropsychological studies, and it has been suggested that several cerebral domains contribute to PM. For these activation studies, a constellation of experimental PM trials was developed and adopted to healthy subjects. In the present study, we used a widely used clinical PM assessment battery to determine the lesions attributable to PM failure, with the hypothesis that lesion-symptom analysis using diffusion tensor imaging (DTI) in subjects with diffuse axonal injury (DAI) can reveal the neuronal basis of PM in everyday life.     

Disruption of spinal cord white matter and sciatic nerve geometry inhibits axonal growth in vitro in the absence of glial scarring

Background  

Axons within the mature mammalian central nervous system fail to regenerate following injury, usually resulting in long-lasting motor and sensory deficits. Studies involving transplantation of adult neurons into white matter implicate glial scar-associated factors in regeneration failure. However, these studies cannot distinguish between the effects of these factors and disruption of the spatial organization of cells and molecular factors (disrupted geometry). Since white matter can support or inhibit neurite growth depending on the geometry of the fiber tract, the present study sought to determine whether disrupted geometry is sufficient to inhibit neurite growth.     

Hsp27 and axonal growth in adult sensory neurons <Emphasis Type="Italic">in vitro</Emphasis>

Background  

Neurite growth can be elicited by growth factors and interactions with extracellular matrix molecules like laminin. Among the targets of the signalling pathways activated by these stimuli are cytoskeletal elements, such as actin, tubulin and neurofilaments. The cytoskeleton can also be modulated by other proteins, such as the small heat shock protein Hsp27. Hsp27 interacts with actin and tubulin in non-neuronal cells and while it has been suggested to play a role in the response of some neurons to injury, there have been no direct studies of its contribution to axonal regeneration.     

Voxel- and atlas-based analysis of diffusion tensor imaging may reveal focal axonal injuries in mild traumatic brain injury -- comparison with diffuse axonal injury

Background

The diagnosis and management of mild traumatic brain injury (MTBI) continue to be subjects of debate, with varying opinions regarding the extent to which tissue-based impairments versus the impacts of other stressors cause ongoing disability. Detecting areas of the brain with abnormalities that can explain symptoms and behavior in patients with MTBI is important in order to confirm the diagnosis of MTBI.

Methods

In this study, we calculated diffusion maps from results of diffusion tensor imaging (DTI) performed in an apparently healthy control group. We then compared these maps with those of patients with MTBI (MTBI group) or diffuse axonal injury (DAI group). All diffusion maps were normalized to the International Consortium for Brain Mapping atlas for atlas-based analysis and were segmented and normalized by the Diffeomorphic Anatomical Registration Through Exponentiated Lie tool in SPM8 to reduce misregistration.

Results

All diffusion measures in the DAI group were lower than in the control group. There were significant differences in the body and splenium of the corpus callosum, fornix and right cerebral peduncle in the DAI group compared with the control group (P<.001). The MTBI group had higher axial diffusivity than the control group in the right corticospinal tract, left medial lemniscus, left inferior cerebellar peduncle, bilateral anterior limb of the internal capsule, right anterior corona radiata, bilateral cingulum (cingulate gyrus) and left superior frontooccipital fasciculus (P<.05).

Conclusions

Voxel- and atlas-based analysis of DTI might suggest that patients with MTBI have focal axonal injury and that the pathophysiology is significantly different from that of DAI. These findings will help in the diagnosis of patients with MTBI.     

Tri-partite complex for axonal transport drug delivery achieves pharmacological effect

Background

Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System) neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior.

Results

We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle.

Conclusion

Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal transport holds great promise. The data shown here provide a basic framework for the intraneural pharmacology of this tripartite complex. The pharmacologically efficacious drug delivery demonstrated here verify the fundamental feasibility of using axonal transport for targeted drug delivery.     

A novel and facile synthesis of N-cyclohexyl-benzofurans by one-pot three-component reaction

Abstract  

A simple and efficient synthesis of N-cyclohexyl-benzofuran derivatives was achieved via a one-pot three-component reaction of cyclohexylisocyanide, an aromatic aldehydes, and phenols in DMF for 10 h with good yields.     

Growth Cone Pathfinding: a competition between deterministic and stochastic events

Background  

Growth cone migratory patterns show evidence of both deterministic and stochastic search modes.     

Levamizole enhances immune responsiveness to intra-dermal and intra-muscular hepatitis B vaccination in chronic hemodialysis patients

Background  

Hemodialysis patient are at high risk for hepatitis B virus (HBV) infection.     

Breakup modes of a laminar hollow water jet

Graphical Abstract  

     

Flow visualization of supersonic transverse jet over Mach 2 freestream of a sharp cone

Graphical abstract  

     

Probing local innate immune responses after mucosal immunisation

Background  

Intranasal immunisation is potentially a very effective route for inducing both mucosal and systemic immunity to an infectious agent.     

Visualizations of the flow around a swimmer in turbulent regime

Graphical abstract  

     

A Canadian national survey of attitudes and knowledge regarding preventive vaccines

Background  

Vaccines have virtually eliminated many diseases, but public concerns about their safety could undermine future public health initiatives.     

Coherent structures of the turbulent round jet in different focal lengths

Graphical abstract  

     

Evidence for non-independent gating of P2X<Subscript>2</Subscript> receptors expressed in <Emphasis Type="Italic">Xenopus</Emphasis>oocytes

Background  

P2X₂ receptor is an ATP-activated ion channel which is widely expressed in the nervous system, and mediates synaptic transmission.