Inhibition of N-type calcium ion channels by tricyclic antidepressants – experimental and theoretical justification for their use for neuropathic pain

A number of tricyclic antidepressants (TCAs) are commonly prescribed off-label for the treatment of neuropathic pain. The blockade of neuronal calcium ion channels is often invoked to partially explain the...

Transmitter and ion channel profiles of neurons in the primate abducens and trochlear nuclei

Extraocular motoneurons initiate dynamically different eye movements, including saccades, smooth pursuit and vestibulo-ocular reflexes. These motoneurons subdivide into two main types based on the structure of the neuro-muscular interface: motoneurons of singly-innervated (SIF), and motoneurons of multiply-innervated muscle fibers (MIF). SIF motoneurons are thought to provoke strong and brief/fast muscle contractions, whereas MIF motoneurons initiate prolonged, slow contractions. While relevant for adequate functionality, transmitter and ion channel profiles associated with the morpho-physiological differences between these motoneuron types, have not been elucidated so far. This prompted us to investigate the expression of voltage-gated potassium, sodium and calcium ion channels (Kv1.1, Kv3.1b, Nav1.6, Cav3.1–3.3, KCC2), the transmitter profiles of their presynaptic terminals (vGlut1 and 2, GlyT2 and GAD) and transmitter receptors (GluR2/3, NMDAR1, GlyR1α) using immunohistochemical analyses of abducens and trochlear motoneurons and of abducens internuclear neurons (INTs) in macaque monkeys. The main findings were: (1) MIF and SIF motoneurons express unique voltage-gated ion channel profiles, respectively, likely accounting for differences in intrinsic membrane properties. (2) Presynaptic glutamatergic synapses utilize vGlut2, but not vGlut1. (3) Trochlear motoneurons receive GABAergic inputs, abducens neurons receive both GABAergic and glycinergic inputs. (4) Synaptic densities differ between MIF and SIF motoneurons, with MIF motoneurons receiving fewer terminals. (5) Glutamatergic receptor subtypes differ between MIF and SIF motoneurons. While NMDAR1 is intensely expressed in INTs, MIF motoneurons lack this receptor subtype entirely. The obtained cell-type-specific transmitter and conductance profiles illuminate the structural substrates responsible for differential contributions of neurons in the abducens and trochlear nuclei to eye movements.

The Role of K+, Ca2+ channels and Endothelial Hyperpolarizing Factors in Vasorelaxation Induced by Tribulus terrestris

The present study focused on the relaxant effect of themethanolic extract (ME) of Tribulus terristris on rats’ thoracic aortae and included the study of underlying vasorelaxation mechanisms. The methanolic extract produced concentration-dependent relaxation in rats’ aorta. The methanolic extract produced concentration-dependent relaxation in the aortic rings. The use of different K+ channel blockers (BaCl2, 4-AP, GLIB, and TEA) indicated that Kv, KATP, KIR, and KCa and L-type Ca channels played no role in the methanolic extractinduced relaxation. However, with respect to endothelium-derived hyperpolarizing factors, PGI2 and sGC produced a mild inhibition in the relaxation response to ME while NO produced no effect at all. Based on the novel results of the current study, it can be concluded that T. terrestris methanolic extract (ME) mediated relaxation in isolated rat aortic tissues in a concentration-dependent manner. Moreover, we discovered that ME-mediated relaxation is endothelium-dependent and that potassium and calcium ion channels play no role in this relaxation with a limited role of PGI2 and sGC.

Protein interaction studies for understanding the tremor pathway in Parkinson’s disease.

Background: Tremor is one of the most noticeable features, which occurs during the early stages of Parkinson’s disease (PD). It is one of the major pathological hallmarks and does not have any interpreted mechanism. In this study we have framed a hypothesis and deciphered protein-protein interactions between the proteins involved in impairment in sodium and calcium ion channels and thus cause synaptic plasticity leading to a tremor. Methods: Literature mining for retrieval of proteins was done using Science Direct, PubMed Central, SciELO and JSTOR databases. A well thought approach was used and a list of differentially expressed proteins in PD was collected from different sources. A total of 71 proteins were retrieved and a protein interaction network was constructed between them by using Cytoscape.v.3.7. The network was further analysed using BiNGO plugin for retrieval of overrepresented biological processes in Tremor-PD datasets. Hub nodes were also generated in the network. Results: The Tremor-PD pathway was deciphered which demonstrates the cascade of protein interactions that might lead to tremors in PD. Major proteins involved were LRRK2, TUBA1A, TRAF6, HSPA5, ADORA2A, DRD1, DRD2, SNCA, ADCY5, TH etc. Conclusion: In the current study it is predicted that ADORA2A and DRD1/DRD2 are equally contributing to the progression of disease by inhibiting the activity of adenylyl cyclase and thereby increases the permeability of the blood brain barrier causing an influx of neurotransmitters and together they alter the level of dopamine in the brain which eventually leads to tremor.

Pharmacological mechanism of topiramate in the prophylaxis and treatment of migraine: a review

Objective: This review sought to bring evidence of studies addressing the mechanisms of action of topiramate in the prevention and treatment of migraine. Background: Migraine is a neurovascular disorder that affects a large part of the world population. The use of prophylactics contributes to the decrease in the frequency and severity of this disease. Among the antiepileptic drugs, the topiramate, has proven to be the most effective for the treatment of migraine. Although the mechanism of action of this drug is still not well elucidated in the literature, there are several molecular mechanisms proposed. Methodology: A survey was carried out in the literature, from February to March 2018, in different databases, using the descriptors: topiramate, migraine and mechanisms of action. After a careful selection, 25 manuscripts were chosen for this review. Results: Evidence from a number of studies has indicated that the main mechanisms of action of topiramate are related to the modulation of voltage-dependent sodium and calcium ion channels, blockade of excitatory glutamate transmission and inhibition by gamma-aminobutyric acid receptors (GABA), AMPA/kainate and some isoenzymes of carbonic anhydrase. In addition, topiramate is involved in the suppression of cortical spreading depression, besides influencing trigeminovascular activity, and neuronal excitability. Conclusion: Thus, topiramate could be involved in the prevention of major events of the pathophysiology of migraine. Acting directly on cortical spreading depression (DAC), trigeminovascular signals and decreased central sensitization of migraine pain.