Precise spatiotemporal control of voltage-gated sodium channels by photocaged saxitoxin

Here we report the pharmacologic blockade of voltage-gated sodium ion channels (NaVs) by a synthetic saxitoxin derivative affixed to a photocleavable protecting group. We demonstrate that a functionalized saxitoxin (STX-eac) enables exquisite spatiotemporal control of NaVs to interrupt action potentials in dissociated neurons and nerve fiber bundles. The photo-uncaged inhibitor (STX-ea) is a nanomolar potent, reversible binder of NaVs. We use STX-eac to reveal differential susceptibility of myelinated and unmyelinated axons in the corpus callosum to NaV-dependent alterations in action potential propagation, with unmyelinated axons preferentially showing reduced action potential fidelity under conditions of partial NaV block. These results validate STX-eac as a high precision tool for robust photocontrol of neuronal excitability and action potential generation.

Wild Honey Poisoning: A Case Report from Remote Mountains

Wild honey is consumed as a tonic in different parts of the world with a belief of increasing libido and treating various musculoskeletal, gastrointestinal and cardiovascular symptoms. However, honey produced from the nectar of several species of the Ericaceae (Rhododendron) family may contain grayanotoxins which act on sodium ion channels and place them in partially open state which causes symptoms like sweating, dizziness and altered sensorium owing to their effect on cardiac muscles and nervous system. We report a case of 60 years male who consumed wild honey as a pain reliever and later presented to the emergency room of Manang District Hospital with bradycardia, hypotension and altered mental status.

Mechanism of Curcuma longa and Its Neuroactive Components for the Management of Epileptic Seizures: A Systematic Review

: Curcuma longa (Turmeric) is a tropical herbaceous perennial plant of the family Zingiberaceae and contains curcuminoids, sesquiterpenoids and monoterpenoids as its major components. Given the broad range of activities that Curcuma Longa possesses and also its use as a traditional epilepsy remedy, this review attempts to systematically review the experimentally proven activities of Curcuma longa and its bioactive components, which are related to the management of epileptic seizures. Using the PRISMA model, five databases (Google Scholar, PubMed, ScienceDirect, SCOPUS and SpringerLink) were searched using the keywords [“Curcuma longa” AND “Epilepsy”] and [“Curcuma longa” AND “Seizures”], leaving with 34 articles that met the inclusion criteria. The present systematic review elaborated on the experimentally proven potential of Curcuma longa components, such as an aqueous extract of Curcuma longa itself, Curcuma longa oil and active constituents like curcuminoids and bisabolene sesquiterpenoids found in Curcuma longa with anti-seizure potential. Using human equivalent dose calculations, human treatment parameters were suggested for each component by analysing various studies in this review. This review also determined that the principal components possibly exert their anti-seizure effect via the reduction of corticosterone, modulation of neurotransmitters signalling, modulation of sodium ion channels, reduction of oxidative DNA damage, reduction of lipid peroxidation, upgregulation of brain-derived neurotrophic factor (BDNF) and γ-aminobutyric acid (GABA) mediated inhibition. It is anticipated that this review will help pave the way for future research into the development of Curcuma longa and its neuroactive constituents as potential drug candidates for the management of epilepsy.

On Local Activity and Edge of Chaos in a NaMLab Memristor

Local activity is the capability of a system to amplify infinitesimal fluctuations in energy. Complex phenomena, including the generation of action potentials in neuronal axon membranes, may never emerge in an open system unless some of its constitutive elements operate in a locally active regime. As a result, the recent discovery of solid-state volatile memory devices, which, biased through appropriate DC sources, may enter a local activity domain, and, most importantly, the associated stable yet excitable sub-domain, referred to as edge of chaos, which is where the seed of complexity is actually planted, is of great appeal to the neuromorphic engineering community. This paper applies fundamentals from the theory of local activity to an accurate model of a niobium oxide volatile resistance switching memory to derive the conditions necessary to bias the device in the local activity regime. This allows to partition the entire design parameter space into three domains, where the threshold switch is locally passive (LP), locally active but unstable, and both locally active and stable, respectively. The final part of the article is devoted to point out the extent by which the response of the volatile memristor to quasi-static excitations may differ from its dynamics under DC stress. Reporting experimental measurements, which validate the theoretical predictions, this work clearly demonstrates how invaluable is non-linear system theory for the acquirement of a comprehensive picture of the dynamics of highly non-linear devices, which is an essential prerequisite for a conscious and systematic approach to the design of robust neuromorphic electronics. Given that, as recently proved, the potassium and sodium ion channels in biological axon membranes are locally active memristors, the physical realization of novel artificial neural networks, capable to reproduce the functionalities of the human brain more closely than state-of-the-art purely CMOS hardware architectures, should not leave aside the adoption of resistance switching memories, which, under the appropriate provision of energy, are capable to amplify the small signal, such as the niobium dioxide micro-scale device from NaMLab, chosen as object of theoretical and experimental study in this work.

Synthesis and Evaluation of Novel α-Aminoamides Containing Benzoheterocyclic Moiety for the Treatment of Pain

Novel α-aminoamide derivatives containing different benzoheterocyclics moiety were synthesized and evaluated as voltage-gated sodium ion channels blocks the treatment of pain. Compounds 6a, 6e, and 6f containing the benzofuran group displayed more potent in vivo analgesic activity than ralfinamide in both the formalin test and the writhing assay. Interestingly, they also exhibited potent in vitro anti-Nav1.7 and anti-Nav1.8 activity in the patch-clamp electrophysiology assay. Therefore, compounds 6a, 6e, and 6f, which have inhibitory potency for two pain-related Nav targets, could serve as new leads for the development of analgesic medicines.

Precise spatiotemporal control of voltage-gated sodium channels by photocaged saxitoxin

SummaryHere we report the pharmacologic blockade of voltage-gated sodium ion channels (NaV) by a synthetic saxitoxin derivative affixed to a photocleavable protecting group. We demonstrate that a functionalized saxitoxin (STX-eac) enables exquisite spatiotemporal control of NaV blockade to interrupt action potentials (APs) in dissociated neurons and nerve fiber bundles. The photo-uncaged inhibitor (STX-ea) is a nanomolar potent, reversible binder of NaVs. We use STX-eac to reveal differential susceptibility of myelinated and unmyelinated axons in the corpus callosum to NaV-dependent alterations in AP propagation, with unmyelinated axons preferentially showing reduced AP fidelity under conditions of partial NaV blockade. These results validate STX-eac as a high precision tool for robust photocontrol of neuronal excitability and AP generation.