Neuroprotective, Neurogenic, and Amyloid Beta Reducing Effect of a Novel Alpha 2-Adrenoblocker, Mesedin, on Astroglia and Neuronal Progenitors upon Hypoxia and Glutamate Exposure.

Locus coeruleus-noradrenergic system dysfunction is known to contribute to the progression of Alzheimer's disease (AD). Besides a variety of reports showing the involvement of norepinephrine and its receptor systems in cognition, amyloid ß (Aß) metabolism, neuroinflammation, and neurogenesis, little is known about the contribution of the specific receptors to these actions. Here, we investigated the neurogenic and neuroprotective properties of a new α2 adrenoblocker, mesedin, in astroglial primary cultures (APC) from C57BL/6 and 3×Tg-AD mice. Our results demonstrate that mesedin rescues neuronal precursors and young neurons, and reduces the lactate dehydrogenase (LDH) release from astroglia under hypoxic and normoxic conditions. Mesedin also increased choline acetyltransferase, postsynaptic density marker 95 (PSD95), and Aß-degrading enzyme neprilysin in the wild type APC, while in the 3×Tg-AD APC exposed to glutamate, it decreased the intracellular content of Aß and enhanced the survival of synaptophysin-positive astroglia and neurons. These effects in APC can at least partially be attributed to the mesedin's ability of increasing the expression of Interleukine(IL)-10, which is a potent anti-inflammatory, neuroprotective neurogenic, and Aß metabolism enhancing factor. In summary, our data identify the neurogenic, neuroprotective, and anti-amyloidogenic action of mesedin in APC. Further in vivo studies are needed to estimate the therapeutic value of mesedin for AD.

The regulatory effects of mesedin and beditin alpha2-adrenoblockers on the functional activity of the nervous, cardiovascular, and endocrine systems in rats under the hypoxic conditions.

One of the reasons of the development of pathologies causing death is hypoxia. The purposes of this study were (1) to study some physiological and biochemical mechanisms of α2-adrenoblockers, which ensure the tissue resistance increase to hypoxia; (2) to offer new drugs contributing to the increase of tissues' stability towards the hypoxic affection; and (3) to submit new medications to surpass by their anti-hypoxic activity of those already used in modern medicine and have some advantages. The reactivity of postsynaptic vascular α2-adrenoceptors was determined on the damaged spinal cord expressed by the blood pressure increase in response to intravenous administration of azepexole that selectively binds to α2-adrenoceptors. Determination of the systemic hemodynamic values and the vascular resistance to the blood flow was performed by the method with plastic microspheres of marked isotopes. pO2 in the blood and the oxygen-transporting function were determined in a sample of 0.1 ml of blood in 30, 90, and 180 min after the α2-adrenoblockers' injections. It has been found that one of the major hemodynamic effects of mesedin and beditin was an improvement in cardiac output, as well as a prolonged increase in coronary blood flow and vasodilation of the heart vessels. Some anti-hypoxic mechanisms of the studied α2-adrenoblockers are an improvement of blood oxygen-transporting function followed by tissue oxygenation and the increased level of corticosterone and resistance to hypoxia. Revealing the mechanisms of action of the postsynaptic α2-adrenoceptors suggests that mesedin and beditin are potentially effective therapeutic means for many hypoxic conditions.

The Novel Alpha-2 Adrenoceptor Inhibitor Beditin Reduces Cytotoxicity and Huntingtin Aggregates in Cell Models of Huntington's Disease.

Huntington's disease (HD) is a monogenetic neurodegenerative disorder characterized by the accumulation of polyglutamine-expanded huntingtin (mHTT). There is currently no cure, and therefore disease-slowing remedies are sought to alleviate symptoms of the multifaceted disorder. Encouraging findings in Alzheimer's and Parkinson's disease on alpha-2 adrenoceptor (α2-AR) inhibition have shown neuroprotective and aggregation-reducing effects in cell and animal models. Here, we analyzed the effect of beditin, a novel α2- adrenoceptor (AR) antagonist, on cell viability and mHTT protein levels in cell models of HD using Western blot, time-resolved Foerster resonance energy transfer (TR-FRET), lactate dehydrogenase (LDH) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) cytotoxicity assays. Beditin decreases cytotoxicity, as measured by TUNEL staining and LDH release, in a neuronal progenitor cell model (STHdh cells) of HD and decreases the aggregation propensity of HTT exon 1 fragments in an overexpression model using human embryonic kidney (HEK) 293T cells. α2-AR is a promising therapeutic target for further characterization in HD models. Our data allow us to suggest beditin as a valuable candidate for the pharmaceutical manipulation of α2-AR, as it is capable of modulating neuronal cell survival and the level of mHTT.

Alpha2-Adrenoblockers Regulate Development of Oxidative Stress and Cognitive Behaviour of Rats under Chronic Acoustic Stress Conditions.

Noise is a wide-spread stress factor in modern life produced by urbanization, traffic, and an industrialized environment. Noise stress causes dysfunction and neurotransmission impairment in the central nervous system, as well as changes in hormone levels. In this study, we have examined the level of α-Tocopherol (α-T) and malondialdehyde (MDA) in plasma and the erythrocytes' membrane (EM), as well as the behavioral characteristics of a noise-induced stress model in rats. In addition, the modulating effect of α2-adrenoblockers, beditin, and mesedin on the aforementioned parameters has been investigated. For these purposes, albino male rats were divided into four groups: (1) untreated; (2) noise-exposed, (3) noise-exposed and beditin-treated (2 mg/kg, i.p.), and (4) noise-exposed and mesedin-treated (10 mg/kg, i.p.) animals. Noise-exposed groups were treated with 91dBA noise on 60 days with a daily duration of 8 h. Increased MDA and decreased α-T levels in plasma and EM were observed upon chronic high-level noise exposure. Locomotor and behavioral activity assessed with a Y-maze revealed disorientation and increased anxiety under chronic noise exposure. Prominently, α2-adrenoblockers alleviated both behavioral deficits and oxidative stress, providing evidence for the involvement of α2-adrenoceptor in the pathophysiology of noise-induced stress.

Adrenergic alpha-2 receptor antagonists cease augmented oxidation of plasma proteins and anxiety of rats caused by chronic noise exposure.

BACKGROUND: Noise is one of the environmental factors, which is considered as a powerful stressor for the organism. Generally, the acoustic stress affects the behavior and physiological state of humans and animals. AIMS: The goal of this study is to investigate the relationship between chronic noise exposure and the effects of adrenergic alpha-2 receptor antagonists, beditin and mesedin, on the anxiety and oxidation of plasma proteins and fibrinogen in rats. METHODS: The experiments were carried out on non-linear albino male rats, divided into four groups (six animals in each): 1. Healthy controls 2. Exposed to noise of a level 91 dB(A), eight hours daily, during 7, 30 and 60 days; 3. Injected with 2 mg/kg of beditin (2-(2-amino-4-thiazolyl)-1,4-benzodioxane hydrochloride)); 4. Injected with 10 mg/kg mesedin (2-(2-methyl-amino-thiozolyl)-1,4-benzodioxane hydrochloride). For evaluating the cognitive impairment, the Any-maze test was applied. The level of carbonylation of proteins was assessed by reaction with 2,4-dinitrophenylhydrazine, spectrophotometrically. RESULTS: Chronic noise decreased locomotor activity and increased anxiety and oxidation of plasma protein and fibrinogen. Intensity of these changes were dependent on the duration of noise exposure. CONCLUSION: The Alpha 2 adrenoblockers alleviate oxidative modification of plasma proteins and reduce the cognitive impairment caused by chronic exposure to noise.

α2-Adrenergic Receptor in Liver Fibrosis: Implications for the Adrenoblocker Mesedin.

The noradrenergic system is proposed to play a prominent role in the pathogenesis of liver fibrosis. While α1- and ß-adrenergic receptors (ARs) are suggested to be involved in a multitude of profibrogenic actions, little is known about α2-AR-mediated effects and their expression pattern during liver fibrosis and cirrhosis. We explored the expression of α2-AR in two models of experimental liver fibrosis. We further evaluated the capacity of the α2-AR blocker mesedin to deactivate hepatic stellate cells (HSCs) and to increase the permeability of human liver sinusoidal endothelial cells (hLSECs). The mRNA of α2a-, α2b-, and α2c-AR subtypes was uniformly upregulated in carbon tetrachloride-treated mice vs the controls, while in bile duct-ligated mice, only α2b-AR increased in response to liver injury. In murine HSCs, mesedin led to a decrease in α-smooth muscle actin, transforming growth factor-ß and α2a-AR expression, which was indicated by RT-qPCR, immunocytochemistry, and Western blot analyses. In a hLSEC line, an increased expression of endothelial nitric oxide synthase was detected along with downregulated transforming growth factor-ß. In conclusion, we suggest that the α2-AR blockade alleviates the activation of HSCs and may increase the permeability of liver sinusoids during liver injury.