Effect of treatment with the antioxidant alpha-lipoic (thioctic) acid on heart and kidney microvasculature in spontaneously hypertensive rats

Endothelial cells represent an important vascular site of signaling and development of damage during ischemia, inflammation and other pathological conditions. Excessive reactive oxygen species production causes pathological activation of endothelium including exposure of cell to adhesion molecules. Intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and platelet-endothelial cell adhesion molecule-1 (PECAM-1) are members of the immunoglobulin super-family which are present on the surface of endothelial cells. These molecules represent important markers of endothelial inflammation. The present study was designed to investigate, with immunochemical and immunohistochemical techniques, the effect of treatment with (+/-)-alpha lipoic (thioctic) acid and its enantiomers on heart and kidney endothelium in spontaneously hypertensive rats (SHR). Arterial hypertension is accompanied by an increased oxidative stress status in the heart characterized by thiobarbituric acid reactive substances (TBARS) and nucleic acid oxidation increase. The higher oxidative stress also modifies adhesion molecules expression. In the heart VCAM-1, which was higher than ICAM-1 and PECAM-1, was increased in SHR. ICAM-1, VCAM-1 and PECAM-1 expression was significantly greater in the renal endothelium of SHR. (+/-)-Alpha lipoic acid and (+)-alpha lipoic acid treatment significantly decreased TBARS levels, the nucleic acid oxidation and prevented adhesion molecules expression in cardiac and renal vascular endothelium. These data suggest that endothelial molecules may be used for studying the mechanisms of vascular injury on target organs of hypertension. The effects observed after treatment with (+)-alpha lipoic acid could open new perspectives for countering heart and kidney microvascular injury which represent a common feature in hypertensive end-organs damage

Toxicological Profile of the Pain-Relieving Antioxidant Compound Thioctic Acid in Its Racemic and Enantiomeric Forms

Thioctic acid is a multipotent antioxidant compound existing as dextrorotatory (+), eutomer and naturally occurring and levorotatory (-). It has been proven to help fight many pathologies and is sold as racemate. In agreement with studies claiming a greater biopotency of the eutomer compared to the levorotatory compound, we recently preclinically and clinically showed that (+) thioctic acid is a pain-reliever as effective as double-dosed racemate. We investigated acute and subchronical toxicity of (+/-) thioctic acid, (-) thioctic acid, (+) thioctic acid and (+) salt thioctic acid on Sprague-Dawley rats. For acute toxicity, compounds were administered intraperitoneally (i.p.) with a single-injection at 125, 240, 360, 480 µmol/kg, then rodents were tested for motorial coordination and minimum lethal dose (LDmin). A subtoxic dose (360 µmol/kg) was administered i.p. for 15 days and we finally evaluated motorial impairment, glycemia, organ toxicity, and apoptosis state. Acutely administered, the highest doses of all thioctic acid compounds negatively affected motorial ability and (-) thioctic acid LDmin resulted higher than the others. Subchronic administrations caused overall body weight loss, motorial impairment, mass loss in some organs. (+/-) and (-) thioctic acid injections enhanced caspase-3 activity in some organs, (-) enantiomer-treated animals displayed more marked organ toxicity signs. Together with our previous study on the biologic role of enantiomers, these data suggest a therapeutic use of (+) enantiomer-based formulations, thus lowering dose and toxicity without affecting the positive effects brought by the drug

Effect of thioctic acid enantiometers on cardiac and renal hypertensive damage

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

Thioctic acid enantiomers prevent central nervous system changes occurring in a model of compressive neuropathy

Thioctic or alpha-lipoic acid (ALA) is a naturally occurring antioxidant. It has two optical isomers designated as (R+) and (S-). Naturally occurring ALA is the (R+)-isoform, but synthetic ALA available as a registered drug or as a nutraceutical is a mixture of (R+) and (S-)-isoforms. ALA has been proposed as a potential therapeutic agent in the treatment or prevention of several pathologies related to an imbalance of the oxidoreductive status. Oxidative stress may have a relevant role in the development of neurological disorders. Peripheral neuropathy is one of these disorders characterized by myelin damage and axonal degeneration causing chronic pain syndromes with allodynia, hyperalgesia, altered sensitive information processing and impaired nerve function. The present study was designed to assess if compression of sciatic nerve, induced by loose ligation of it, is accompanied by an increased oxidative stress and by central nervous system damage. This study has also investigated the role of ALA enantiometers treatment in preventing damage related to oxidative stress. Loose ligation of the right sciatic nerve was performed in spontaneously hypertensive rats (SHR), used as a model of enhanced oxidative stress, and normotensive Wistar-Kyoto rats (WKY) used as a reference group. Animals with sciatic nerve ligation were left untreated or were treated intraperitoneally for 14 days with racemic-ALA (25 and 50 mg/Kg/day), (R+)-ALA(25 mg/Kg/day), (S-)-ALA (25 mg/Kg/day) and with the anticonvulsant agent used in treating neuropathic pain pregabalin (50 mg/Kg/day). Loose ligation increased astrogliosis in lumbar spinal cord and in brain at the levels of primary and secondary motor and general sensory cortices. Astrogliosis is probably related to the increase of oxidative stress in the model of compressive neuropathy used. Treatment for 14 days with (R+)-thioctic acid decreased the number and size of astrocytes, racemic-ALA was less effective, whereas the (S-) enantiomer and pregabalin were without effect. Moreover, in the brain of SHR neuronal damage and decreased expression of neurofilament phosphorilated (NFP) protein was noticeable. The number of neurons and the expression of NFP were not affected by antioxidant treatment. The present study has documented the occurrence of microanatomical changes in the central nervous system consequent to peripheral nerve damage. These changes are countered by antioxidant treatment being (R+)-thioctic acid the most effective agent. This may have consequences in terms of clinical applications

Substrate-integrated waveguide filters based on mushroom-shaped resonators

This paper presents a new class of quasi-elliptic pass-band filters in substrate-integrated waveguide technology, which exhibits compact size and modular geometry. These filters are based on mushroom-shaped metallic resonators, and they can be easily implemented using a standard dual-layer printed circuit board manufacturing process. The presented filters exploit non-resonating modes to obtain coupling between non-adjacent nodes in the case of in-line geometry. The resulting structure is very compact and capable of transmission zeros. In this work, the singlet configuration is preliminarily investigated, and a parametric study is performed. The design of three-pole, four-pole, and higher-order filters is illustrated with examples and thoroughly discussed. A four-pole filter operating at the frequency of 4 GHz has been manufactured and experimentally verified, to validate the proposed technique.</jats:p

Substrate Integrated Waveguide Filters with Stacked Cavities

In this paper the strategy for obtaining substrate integrated waveguide filters for easy manufacturing is illustrated and discussed. The basic idea is to obtain a multilayer filter where just thru-hole vias are used, thus making easier the manufacturing process. This is obtained by designing the filter with identical cavities where evanescent SIW sections are exploited. Furthermore, it is also shown that evanescent cavities can be exploited for the tuning of cavity resonance frequencies

Innovative Filters in Partially Air-Filled in Substrate Integrated Waveguide Technology

International audienceThis paper presents a novel class of substrate integrated waveguide filters, based on partially air-filled rectangular cavities. These partially-air filled cavity implements a doublet, that exhibits a frequency response with two poles and two transmission zeros. Two different topologies are proposed: in the first one, the partially air-filled region is located in the center of the rectangular cavity and this allows to locate two zeros below the pass band; in the second topology, two partially air-filled regions are located at the sides of the rectangular cavity and this allows to locate arbitrarily the two zeros, either both below, or both above, or one below and one above the pass band. Prototypes of the two topologies have been designed and experimentally verified

A dual-mode quasi-elliptic filter in air-filled substrate integrated waveguide technology

This paper presents a novel quasi-elliptic band-pass filter in air-filled substrate integrated waveguide (SIW) technology. It is based on a dual-mode cavity resonator and features a frequency response with two poles and two transmission zeros. This structure exploits the properties of the air-filled SIW, which has been recently proposed to realize integrated interconnects and allows for reduced losses. The geometry of the air-filled area in the SIW resonator allows controlling the pass band of the filter, by setting the frequency of the first and second cavity modes. The position of the input/output microstrip lines, conversely, permits to modify the location of the transmission zeros. As an example, a band-pass filter operating at the frequency of 3.6 GHz, with a relative bandwidth of 1.4% and two transmission zeros, has been designed, fabricated, and experimentally verified