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The endogenous gasotransmitter hydrogen sulphide (H2S) is an important regulator of the cardiovascular system, particularly of myocardial function. Moreover, H2S exhibits cardioprotective activity against ischemia/reperfusion (I/R) or hypoxic injury, and is considered an important mediator of "ischemic preconditioning", through activation of mitochondrial potassium channels, reduction of oxidative stress, activation of the endogenous "anti-oxidant machinery" and limitation of inflammatory responses. Accordingly, H2S-donors, i.e. pro-drugs able to generate exogenous H2S, are viewed as promising therapeutic agents for a number of cardiovascular diseases. The novel H2S-donor 4-carboxy phenyl-isothiocyanate (4CPI), whose vasorelaxing effects were recently reported, was tested here in different experimental models of myocardial I/R. In Langendorff-perfused rat hearts subjected to I/R, 4CPI significantly improved the post-ischemic recovery of myocardial functional parameters and limited tissue injury. These effects were antagonized by 5-hydroxydecanoic acid (a blocker of mitoKATP channels). Moreover, 4CPI inhibited the formation of reactive oxygen species. We found the whole battery of H2S-producing enzymes to be present in myocardial tissue: cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (MPST). Notably, 4CPI down-regulated the post-ischemic expression of CSE. In Langendorff-perfused mouse hearts, 4CPI reduced the post-ischemic release of norepinephrine and the incidence of ventricular arrhythmias. In both rat and mouse hearts, 4CPI did not affect the degranulation of resident mast cells. In isolated rat cardiac mitochondria, 4CPI partially depolarized the mitochondrial membrane potential; this effect was antagonized by ATP (i.e., the physiological inhibitor of KATP channels). Moreover, 4CPI abrogated calcium uptake in the mitochondrial matrix. Finally, in an in vivo model of acute myocardial infarction in rats, 4CPI significantly decreased I/R-induced tissue injury. In conclusion, H2S-donors, and in particular isothiocyanate-based H2S-releasing drugs like 4CPI, can actually be considered a suitable pharmacological option in anti-ischemic therapy.

Neurotoxicity is the limiting side effect of the anticancer agent oxaliplatin. A tangled panel of symptoms, sensory loss, paresthesia, dysesthesia, pain may be disabling for patients adversely affecting quality of life. Pharmacological treatments demonstrating a therapeutic effect on oxaliplatin’s cumulative neurotoxicity are unsatisfactory and limited to symptomatic effects. Astragalus membranaceus is an adaptogenic herb from the traditional Chinese medicine. Aimed to study the antineuropathic profile of this plant, a hydroalcoholic extract from selected roots of A. membranaceus was obtained and characterized. A. membranaceus extract was tested in a rat model of painful oxaliplatin-induced neuropathy (2.4 mgkg-1 intraperitoneally, daily for 21 days). The extract was administered per os (300 mgkg-1) once a day, starting from the first day of oxaliplatin injection until the 20th. On day 21 A. membranaceus extract treatment was able to significantly reduce oxaliplatin-dependent pain, when evaluated as an increase on suprathreshold stimulation (hyperalgesia-related measure) or as a decrease in pain threshold (allodyniarelated measure). The extract strongly prevented the serious nephro- and hepato-toxicity induced by repeated treatment with the anticancer drug. In the nervous system the hydroalcoholic extract reduced the morphometric alterations induced by oxaliplatin in the dorsal root ganglia, and significantly prevented the changes in the activating transcription factor 3 and in the phosphorylated heavy chain of neurofilament expression levels both in nerves and ganglia. In the dorsal horn of the spinal cord and in pain related cerebral areas A. membranaceus extract prevented the oxaliplatininduced increase of glial density. The hydroalcoholic extract of Astragalus membranaceus relieves pain and promotes the rescue mechanisms that protect nervous tissue from the damages triggering chronic pain. A safe profile strongly suggests the usefulness of this natural product in oxaliplatin-induced neuropathy., Italian Journal of Anatomy and Embryology, Vol 119, No 1 (Supplement) 2014

The design of compounds that are able to inhibit cyclooxygenase (COX) and to release nitric oxide (NO) should give rise to drugs endowed with an overall safer profile for the gastrointestinal and cardiovascular systems. Herein we report a new class of pyrrole-derived nitrooxy esters (11a-j), cyclooxygenase-2 (COX-2) selective inhibitors endowed with NO releasing properties, with the goal of generating new molecules able to both strongly inhibit this isoform and reduce the related adverse side effects. Taking into account the metabolic conversion of nitrooxy esters into corresponding alcohols, we also studied derivatives 12a-j. All compounds proved to be very potent and selective COX-2 inhibitors; nitrooxy derivatives displayed interesting ex vivo NO-dependent vasorelaxing properties. Compounds 11c, 11d, 12c, and 12d were selected for further in vivo studies that highlited good anti-inflammatory and antinociceptive activities. Finally, two selected compounds (11c and 12c) tested in human whole blood (HWB) assay proved to be preferential inhibitors of COX-2.

An opioid is a chemical that binds to opioid receptors, which are widely distributed in the central and peripheral nervous system and gastrointestinal tract. The different effects elicited by activation of these receptors are due to their specific neuronal and extraneuronal distribution. The painkiller effect of opioids is induced by the synergy of the two events, namely reduction of pain threshold and emotional detachment from pain. The opioid effects transcending analgesia include sedation, respiratory depression, constipation and a strong sense of euphoria. There are opioid-like substances endogenously produced by the body. Naturally occurring peptides, called enkephalins, have opioid-like activities but are not derived from opium and exert opioid-like effects by interacting with opioid receptors on cell membranes. Yet, animals do contain the same morphine precursors and metabolites as opium poppy and are able to synthesize endogenous morphine alkaloid. Experimental and clinical studies show that opioids, at doses comparable to those of endogenous opioids, can activate pronociceptive systems, leading to pain hypersensitivity and short-term tolerance, a phenomenon encountered in postoperative pain management by acute opioid administration. Whether endogenous opioids play a role in the acute pain necessary to the survival of the individual, remains an open question.

Microglial cells are the brain resident macrophages that, in response to brain injury, changes its phenotype from ramified to ‘‘activated’’ ameboid, increase motility to the site of damage and secrete soluble factors that modulate surrounding environment [1]. Astrocytes are the predominant glial cell type in the CNS that play a central role in forming the inhibitory glial scar contributing to neuroprotection and repair. As well as microglia they change morphology after injury, undergoing to hypertrophy and forming a dense network bording the lesion site [2]. Both, in healthy and damaged CNS, these processes are controlled by intracellular interactions of glial cells with several components of the brain microenvironment [3]. Between them sialic acids are one of the most important glycans expressed at the cell surface and recently it has been demonstrated that polysialic acid (PSA), a linear homopolymer attached to the neural cell adhesion molecule (NCAM), has a central role in restoring adult injured tissue by creating conditions permissive for architectural remodeling. The aim of this study was to evaluate the glial cells sialic acids expression pattern in a rat model of traumatic brain injury complicated by sepsis. PSA content was evaluated by immunohistochemistry, whereas expression of sialic acid and the different types of sialic acid residues was evidenced by fluorescent lectin histochemistry. Experiments were performed on adult male rats assigned to four groups: 1) sham-operated; 2) Caecal Ligation and Puncture (CLP) (clinically model of polymicrobial infection that mimics human sepsis); 3) Controlled Cortical Impact (CCI) (clinically model of brain cortical injury); 4) sepsis superimposed to traumatic brain injury (CLP + CCI). The evaluations were carried out 14 days from CLP, CCI or CCI+CLP. Our results showed that in the lesional region sepsis associated with CCI causes a significant increase in sialic acid linked α2,3 (MALI) and α2,6 to galactose/galactosamine (SNA) in respect to sham, CLP, and CCI rats (P, Italian Journal of Anatomy and Embryology, Vol 117, No 2 (Supplement) 2012

Arterial hypertension is accompanied by significant cardiovascular and renal changes as well as by increased production of reactive oxygen species (ROS) Spontaneously hypertensive rats (SHR) are a widely used animal model in hypertension research. They are normotensive at birth and develop hypertension gradually. From the 6th month hypertension becomes stable and is accompanied by the development of cardiovascular, renal and brain injury as well as ROS production increase. This study has evaluated in 20-week-old SHR and normotensive Wistar Kyoto (WKY) rats the effect of treatment for 2 weeks with a daily dose of 12.5 nM/Kg racemic (+/-)-, (+)- or (-)-thioctic acid on heart and kidney oxidative stress and microanatomy. Loose ligation of the right sciatic nerve (Chronic constriction injury, CCI) was made to increase oxidative stress condition. Systolic blood pressure was unaffected by treatment with thioctic acid. In the heart hypertension and CCI were accompanied by left ventricular hypertrophy, increased size of cardiocytes and signs of fibrosis. In the kidney hypertension and CCI increased oxidative damage with obvious signs of glomerular and tubular changes. (+)-Thioctic acid and to a lesser extent (+/-)-thioctic acid countered in part these changes which were unaffected or worsened by (-)-thioctic acid. These data indicate that the naturally occurring enantiomer (+) - thioctic acid has a protective effect on hypertension/oxidative stress-related cardiac or renal microanatomical changes. (-)-Thioctic acid which is not present in nature and derives from chemical processes of synthesis of the compound has probably a negative activity on parameters investigated. Its presence in the racemic thioctic acid is probably the reason of the lower pharmacological activity noticeable with this form of the compound. Appropriate antioxidant strategy could be helpful in combination with antihypertensive drugs in the treatment of hypertensive organ damage. The more pronounced effect of (+)-thioctic acid may have consequences worthwhile of being investigated in clinical studies., Italian Journal of Anatomy and Embryology, Vol 117, No 2 (Supplement) 2012

Oxaliplatin, a platinum-based chemotherapeutic agent, has become a standard treatment for advanced colorectal cancer. The dose-limiting toxicity of this compound is the development of a peripheral neuropathy. Recently, we described a characteristic glia activation profile in the presence of oxaliplatin-dependent neuropathic pain in the rat. In the present study, aimed to evaluate the glia role in neuropathy induced by oxaliplatin, we continuosly infused in the rat, by intrathecal route, minocycline, a tetracycline derivative that specifically inhibits microglia, or fluorocitrate, an astrocyte metabolic inhibitor of the citric acid cycle. Both compounds were able to significantly reduce oxaliplatin-dependent pain, when evaluated as an increase on suprathreshold stimulation (hyperalgesia-related measure) or as a decrease in pain threshold (allodynia-related measure) [1]. In the dorsal horn of the lumbar spinal cord minocycline was able to reduce in a time-dependent manner the Iba1 positive cell increase evoked by the anticancer treatment. Similarly fluorocitrate-treated animals showed a decreased in GFAP-positive cell with respect to the oxaliplatin-treated group. Minocycline and fluorocitrate did not show cross-action on astrocyte and microglia, respectively. The morphometric determinations performed on the DRG neurons evidenced that oxaliplatin decreased the soma area of the medium (600-1200 μm2) and large neurons (>1200 μm2) as well as the incidence of eccentric nucleoli and of multinucleolated neurons were significatively increased in oxaliplatin treated rats. Neither minocycline nor fluorocitrate were able to prevent nervous tissue alteration. In summary, these data highlight the central role of glia cell in oxaliplatin-dependent neuropathic pain. On the contrary, glia inhibition does not induce neurorestorative processes suggesting the need of glia signalling modulation to obtain at the same time pain relief and neuroprotection., Italian Journal of Anatomy and Embryology, Vol 118, No 2 (Supplement) 2013

BACKGROUND AND PURPOSE: Hydrogen sulfide (H(2)S)‐releasing agents are viewed as potential antihypertensive drugs. Recently, natural isothiocyanates emerged as original H(2)S‐donor agents. Among them, erucin, present in some edible cruciferous plants, shows suitable H(2)S‐releasing properties and features of “druggability.” The aim of this work was to investigate the erucin‐mediated release of H(2)S inside vascular cells, its vasorelaxing effects, and activity on BP of normo and hypertensive animals. EXPERIMENTAL APPROACH: Intracellular H(2)S‐release and the hyperpolarizing effect of erucin were tested using fluorescent dye, in human aortic smooth muscle cells (HASMCs). Its direct vasorelaxing effect and ability to inhibit noradrenaline‐induced vasoconstriction were evaluated on endothelium‐intact or ‐denuded rat aortic rings. Its vasodilator properties were tested in coronary arteries using Langendorff‐perfused rat hearts. Finally, erucin's antihypertensive activity was evaluated in vivo in normotensive and spontaneously hypertensive rats (SHRs) by recording systolic BP using the tail‐cuff method. KEY RESULTS: Erucin induced the release of H(2)S inside HASMCs. Moreover, erucin hyperpolarized the membrane of HASMCs membrane in a concentration‐dependent manner. It induced vasodilatation of rat aortic rings, in endothelium‐denuded vessels. This effect was further improved by the presence of endothelial NO. When pre‐incubated with rat aortic rings, erucin induced concentration‐dependent inhibition of noradrenaline‐induced vasoconstriction. Erucin did not affect basal coronary flow but restored the flow to normal in pre‐contracted coronary vessels. Finally, in vivo, erucin decreased systolic BP in SHRs by about 25%, and restored the BP to values observed in normotensive rats. CONCLUSIONS AND IMPLICATIONS: Erucin is an H(2)S donor endowed with vasorelaxing and antihypertensive effects. LINKED ARTICLES: This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc