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.     

Acute stress alters transcript expression pattern and reduces processing of proBDNF to mature BDNF in <Emphasis Type="Italic">Dicentrarchus labrax</Emphasis>

Background  

Stress involves alterations of brain functioning that may precipitate to mood disorders. The neurotrophin Brain Derived Neurotrophic Factor (BDNF) has recently been involved in stress-induced adaptation. BDNF is a key regulator of neuronal plasticity and adaptive processes. Regulation of BDNF is complex and may reflect not only stress-specific mechanisms but also hormonal and emotional responses. For this reason we used, as an animal model of stress, a fish whose brain organization is very similar to that of higher vertebrates, but is generally considered free of emotional reactions.     

Stability and modal analysis of shock/boundary layer interactions

The dynamics of oblique shock wave/turbulent boundary layer interactions is analyzed by mining a large-eddy simulation (LES) database for various strengths of the incoming shock. The flow dynamics is first analyzed by means of dynamic mode decomposition (DMD), which highlights the simultaneous occurrence of two types of flow modes, namely a low-frequency type associated with breathing motion of the separation bubble, accompanied by flapping motion of the reflected shock, and a high-frequency type associated with the propagation of instability waves past the interaction zone. Global linear stability analysis performed on the mean LES flow fields yields a single unstable zero-frequency mode, plus a variety of marginally stable low-frequency modes whose stability margin decreases with the strength of the interaction. The least stable linear modes are grouped into two classes, one of which bears striking resemblance to the breathing mode recovered from DMD and another class associated with revolving motion within the separation bubble. The results of the modal and linear stability analysis support the notion that low-frequency dynamics is intrinsic to the interaction zone, but some continuous forcing from the upstream boundary layer may be required to keep the system near a limit cycle. This can be modeled as a weakly damped oscillator with forcing, as in the early empirical model by Plotkin (AIAA J 13:1036–1040, 1975).     

Principle of stationary phase for propagating wave packets in the unidimensional scattering problem

We point out some incompatibilities which appear when one applies the stationary phase method for deriving phase times to obtain the spatial localization of wave packets scattered by a unidimensional potential barrier. We concentrate on the above barrier diffusion problem where the wave packet collision implies the possibility of multiple reflected and transmitted wave packets, which, depending on the boundary conditions, can overlap or stand in relative separation in space. We demonstrate that the indiscriminate use of the method for such a particular configuration leads to paradoxical results for which the correct interpretation, confirmed by analytical/numerical calculations, imposes the necessity of the appearance of multiple peaks as a consequence of multiple reflections by the barrier steps. Also at Instituto de Física Gleb Wataghin, UNICAMP, PO Box 6165, 13083-970 Campinas, SP, Brazil.     

Designing local orthogonal bases on finite groups II: Nonabelian case

We extend to general finite groups a well-known relation used for checking the orthogonality of a system of vectors as well as for orthogonalizing a nonorthogonal one. This in turn, is used for designing local orthogonal bases obtained by unitary transformations of a single prototype filter. The first part of this work considered the abelian groups of unitary transformations, while here we deal with nonabelian groups. As an example, we show how to build such bases where the group of unitary transformations consists of modulation and rotations. Such bases are useful for building systems for evaluation image quality.     

Etude expérimentale et théorique de la substitution de N-méthyl-halogéno-triazoles-1,2,4 par les réactifs nucléophiles

Kinetic studies of the substitution of isomeric N-methyl-halogeno-1,2,4-triazoles with piperidine or the methoxide ion have been carried out. The experimental results show that the 1-mcthyl-5-halogcno isomer is more reactive than the 4-methvl-3-halogeno isomer. Various theoretical treatments of the reaction have been applied. The calculations show that the “frontier charge” and “delocalised bond” models give (he best results.     

A high power CH3OH FIR laser system with long-term stability

A CH₃OH FIR system has been developed for plasma diagnostics. A CO₂ laser devoted to pump the CH₃OH molecule has been studied. Different internal diameters of FIR cavity, input coupling holes and focusing lenses have been experimented.It has been found that the system formed by three subsystems-pump laser, guiding channel and FIR cavity-behaves like an unique system. A long term stability has been reached with a proper system design.Work supported by ENEA contract No. C/451 (Dipart. Fusione, Associazione Euratom-Enea, CRE Frascati, C.P. 65, 00044 Frascati, Italy).Student     

Single line high efficiency tunable fir generation by resonant four-wave mixing in CH3 pumped by a multiatmosphere tunable CO2 laser

By pumping CH₃F with a high pressure tunable TE-CO₂ laser, the resonant four-wave mixing process (RFWM) generates a very efficient tunable single line FIR emission at the Raman frequency. This result is strictly related to the spectroscopic structure of the CH₃F molecule. By means of this process, a tunable FIR emission on a 0.1 cm^–1 bandwidth 150 kW (8 mJ) single line, is obtained which can be used for many FIR multiphoton applications.     

A positron lifetime study in quenched Pb(Ag) alloys

Positron lifetime measurements have been made in quenched or irradiated pure Pb and in quenched Pb(Ag) alloys. From positron investigation of annealing behaviour, the precipitation of silver atoms in dilute alloys should be understood in terms of (Ag-Pb) interstitially migrating pairs. The presence of di-interstitials (Ag-Ag) or complexes [Ag(S)-V] as mobile defects responsible for the Ag transport process in concentrated alloys is discussed.