Hydrogel-based electrodes for selective cervical vagus nerve stimulation.

Electrical vagus nerve stimulation (VNS) has the potential to treat a wide variety of diseases by modulating afferent and efferent communication to the heart, lungs, esophagus, stomach, and intestines. Although distal vagal nerve branches, close to end organs, could provide a selective therapeutic approach, these locations are often surgically inaccessible. In contrast, the cervical vagus nerve has been targeted for decades using surgically implantable helix electrodes to treat epileptic seizures and depression; however, to date, clinical implementation of VNS has relied on an electrode with contacts that fully wrap around the nerve, producing non-selective activation of the entire nerve.

Effect of knockout of the ASIC3 on cardiovascular reflexes arising from hindlimb muscle in decerebrated rats.

The exercise pressor reflex is initiated by the contraction-induced activation of group III and IV muscle afferents. The reflex is manifested by increases in arterial blood pressure and cardiac output, which, in turn, are generated by increases in the sympathetic outflow to the heart and vasculature and decreases in the vagal outflow to the heart. In previous experiments, we used a pharmacological approach to assess the role played by the acid-sensing ion channel 3 (ASIC3) on group III and IV afferents in evoking the exercise pressor reflex.

The role played by oxidative stress in evoking the exercise pressor reflex in health and simulated peripheral artery disease.

Key Points: Ligating the femoral artery of a rat for 72 h, a model for peripheral artery disease, causes an exaggerated exercise pressor reflex in response to muscle contraction. Likewise, the hindlimb muscles of rats with ligated femoral arteries show increased levels of reactive oxygen species. Infusion of tiron, a superoxide scavenger, attenuated the exaggerated pressor reflex and reduced reactive oxygen species production in rats with ligated femoral arteries.

Low-frequency stimulation of group III and IV hind limb afferents evokes reflex pressor responses in decerebrate rats.

Contraction of freely perfused hind limb muscles in decerebrate rats evokes the exercise pressor reflex, resulting in sympathetic activation and increased blood pressure. This reflex is propagated along mechanically sensitive group III and metabolically sensitive group IV afferent nerve fibers. Recent research by our laboratory has focused on the exaggeration of the exercise pressor reflex in decerebrate rats with simulated peripheral artery disease, which was induced by ligating the femoral artery for 72 h before the start of the experiment.

Functional insight into development of positive allosteric modulators of AMPA receptors.

Positive allosteric modulators of α-amino-3-hydroxy-5-methyl-isoxazole-propionic acid (AMPA) ionotropic glutamate receptors facilitate synaptic plasticity and contribute essentially to learning and memory, properties which make AMPA receptors targets for drug discovery and development. One region at which several different classes of positive allosteric modulators bind lies at the dimer interface between the ligand-binding core of the second, membrane-proximal, extracellular domain of AMPA receptors. This solvent-accessible binding pocket has been the target of drug discovery efforts, leading to the recent delineation of five "subsites" which differentially allow access to modulator moieties, and for which distinct modulator affinities and apparent efficacies are attributed.

A charge-inverting mutation in the "linker" region of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors alters agonist binding and gating kinetics independently of allosteric modulators.

AMPA receptors are gated through binding of glutamate to a solvent-accessible ligand-binding domain. Upon glutamate binding, these receptors undergo a series of conformational rearrangements regulating channel function. Allosteric modulators can bind within a pocket adjacent to the ligand-binding domain to stabilize specific conformations and prevent desensitization.

Functional analysis of a novel positive allosteric modulator of AMPA receptors derived from a structure-based drug design strategy.

Positive allosteric modulators of α-amino-3-hydroxy-5-methyl-isoxazole-propionic acid (AMPA) receptors facilitate synaptic plasticity and can improve various forms of learning and memory. These modulators show promise as therapeutic agents for the treatment of neurological disorders such as schizophrenia, ADHD, and mental depression. Three classes of positive modulator, the benzamides, the thiadiazides, and the biarylsulfonamides differentially occupy a solvent accessible binding pocket at the interface between the two subunits that form the AMPA receptor ligand-binding pocket.