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There are several endogenous molecules that can trigger migraine attacks when administered to humans. Notably, calcitonin gene-related peptide (CGRP) has been identified as a key player in a signalling cascade involved in migraine attacks, acting through the second messenger cyclic adenosine monophosphate (cAMP) in various cells, including intracranial vascular smooth muscle cells. However, it remains unclear whether intracellular cAMP signalling requires CGRP receptor activation during a migraine attack in humans. To address this question, we conducted a randomized, double-blind, placebo-controlled, parallel trial using a human provocation model involving the administration of CGRP and cilostazol in individuals with migraine pretreated with erenumab or placebo. Our study revealed that migraine attacks can be provoked in patients by cAMP-mediated mechanisms using cilostazol, even when the CGRP receptor is blocked by erenumab. Furthermore, the dilation of cranial arteries induced by cilostazol was not influenced by the CGRP receptor blockade. These findings provide clinical evidence that cAMP-evoked migraine attacks do not require CGRP receptor activation. This discovery opens up new possibilities for the development of mechanism-based drugs for the treatment of migraine. [ABSTRACT FROM AUTHOR]

Because MCUB deletion increases cooperative activation and uptake rate when mitochondria are exposed to high Ca SP 2+ sp conditions, MCUB SP -/- sp cells are poised to mCa SP 2+ sp overload and permeability transition pore opening. Consequently, mitochondria from these hearts show reduced mCa SP 2+ sp amount and uptake rate following a Ca SP 2+ sp bolus. Lambert and colleagues correlated the cardioprotection afforded by enforced MCUB expression to reduced opening of the permeability transition pore upon a high Ca SP 2+ sp bolus challenge. In pathologic conditions, such as I/R injury, MCUB overexpression prevents mCa2+ overload and permeability transition pore opening, thus affording cardioprotection. [Extracted from the article]

Aims: Attenuation of the effects of natriuretic peptides has been demonstrated in animal models but studies in humans are scarce, particularly concerning renal attenuation. We investigated the attenuation of B-type natriuretic peptide (BNP) in chronic advanced heart failure (HF). [ABSTRACT FROM PUBLISHER]

Chronic dichlorvos exposure (6 mg/kg b.wt/day) for a period of 8 weeks resulted in significant reduction in body weight gain of the male Wistar rats. However, the dietary intake remained unchanged in experimental animals following dichlorvos treatment. Activity of the synthesizing enzyme of acetylcholine (ACh) ie, choline acetyltransferase, was found to be significantly increased and the activity of hydrolyzing enzyme, acetyl cholinesterase (AChE), was inhibited in all the three brain regions studied. Chronic dichlorvos treatment also caused significant reduction in both high affinity (HA) and low affinity (LA) choline uptake (CU), with maximal effect being observed in the brain stem followed by cerebellum and cerebrum. Muscarinic receptor binding was significantly decreased in brain stem and cerebellum as reflected in the decreased receptor number (Bmax), without any change in the binding affinity (Kd) of the receptors. Dichlorvos treatment caused marked inhibition in cAMP synthesis as indicated by decreased adenylate cyclase activity as well as cAMP levels in cerebrum, cerebellum and brain stem. Our study shows that organophosphates may interact with muscarinic receptor-linked second messenger system and this could be a potential mechanism for the neurotoxic effects observed after repeated exposure to low levels of organophosphates, which are unexplainable on the basis of cholinergic hyperactivity. [ABSTRACT FROM AUTHOR]

Stromal–epithelial interactions, which regulate the migration of prostate epithelial cells, play an important role in prostate development, prostatic hyperplasia, and prostate cancer. The objective of this study was to determine how the prostate stroma stimulates the migration of primary prostate epithelial cells (PECs). In the Boyden chamber assay, PEC migration was strongly induced by the conditioned medium of primary prostate stromal cells (PSC-CM). Stimulation of PEC migration depended on the concerted action of adhesion and motility factors in the PSC-CM. Immobilized proteins from PSC-CM mediated adhesion, spreading, and head-to-tail polarization of PECs. Migration induced by immobilized PSC-CM proteins was significantly increased by hepatocyte growth factor/scatter factor (HGF/SF). Inhibition of P13-kinase or Src-family kinases, but not MEK or PLCχ, abolished migration in the Boyden chamber assay. Consistent with their concerted activity in migration assays, the combination of adhesion and motility factors was required for efficient activation of the P13-kinase/Akt pathway. HGF/SF in the PSC-CM was the principal stimulator of the P13-kinase/Akt pathway and an important mediator of PSC-CM-induced PEC migration. In conclusion, our data show that the migration of primary PECs is regulated by the P13-kinase and Src-family kinase signaling pathways and that the activation of the P13-kinase pathway requires adhesion and motility factors from the prostate stroma. [Copyright &y& Elsevier]

Over the past decade, the focus of research into the pathophysiology of mood disorders (bipolar disorder and unipolar depression in particular) has shifted from an interest in the biogenic amines to an emphasis on second messenger systems within cells. Second messenger systems rely on cell membrane receptors to relay information from the extracellular environment to the interior of the cell. Within the cell, this information is processed and altered, eventually to the point where gene and protein expression patterns are changed. There is a preponderance of evidence implicating second messenger systems and their primary contact with the extracellular environment, G proteins, in the pathophysiology of mood disorders. After an introduction to G proteins and second messenger pathways, this review focuses on the evidence implicating G proteins and two second messenger systems—the adenylate cyclase (cyclic adenosine monophosphate, cAMP) and phosphoinositide (protein kinase C, PKC) intracellular signaling cascades—in the pathophysiology and treatment of bipolar disorder and unipolar depression. Emerging evidence implicates changes in cellular resiliency, neuroplasticity and additional cellular pathways in the pathophysiology of mood disorders. The systems discussed within this review have been implicated in neuroplastic processes and in modulation of many other cellular pathways, making them likely candidates for mediators of these findings. [Copyright &y& Elsevier]

Objective: Inositol is a constituent of the intracellular phosphatidyl inositol (PI) second messenger system, which is linked to various neurotransmitter receptors. Inositol crosses the blood–brain barrier in pharmacological doses, and has shown efficacy in a small double-blind study of unipolar depression. This pilot study evaluated its potential efficacy and safety in bipolar depression. Methods: Twenty-four consenting adult men and women with DSM-IV bipolar depression (bipolar I=21; bipolar II=3) were randomly assigned to receive either 12 g of inositol or d-glucose as placebo for 6 weeks. Efficacy and safety ratings were done weekly. Thymoleptic medications (lithium, valproate, carbamazepine) in stable doses and at therapeutic levels at study entry were continued unchanged. Results: Two subjects receiving placebo dropped out early due to worsening or non-adherence to the protocol. Among the 22 subjects who completed the trial, six (50%) of the inositol-treated subjects responded with a 50% or greater decrease in the baseline Hamilton Depression Rating Scale (HAM-D) score and a Clinical Global Improvement (CGI) scale score change of ‘much’ or ‘very much’ improved, as compared to three (30%) subjects assigned to placebo, a statistically non-significant difference. On the Montgomery–Asberg Depression Rating Scale (MADRS), eight (67%) of twelve inositol-treated subjects had a 50% or greater decrease in the baseline MADRS scores compared to four (33%) of twelve subjects assigned to placebo (p=0.10). Inositol was well tolerated with minimal side effects, and thymoleptic blood levels were unaltered. Conclusions: These pilot data suggest a controlled study with an adequate sample size, and the appropriate rating scale may demonstrate efficacy for inositol in bipolar depression. The tolerability and the ‘natural substance’ aspect of inositol may be particularly appealing to subjects with bipolar depression. [ABSTRACT FROM AUTHOR]