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

Abstract

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 β (Aβ) 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 Aβ-degrading enzyme neprilysin in the wild type APC, while in the 3×Tg-AD APC exposed to glutamate, it decreased the intracellular content of Aβ 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 Aβ 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 Novel Alpha-2 Adrenoceptor Inhibitor Beditin Reduces Cytotoxicity and Huntingtin Aggregates in Cell Models of Huntington’s Disease

“…Furthermore, beditin exhibits pronounced calcium-antagonistic properties, significantly reducing the entry of labeled calcium into the cytosol, as well as into the mitochondria and endoplasmic reticulum during ischemia [ 11 ]. A study of a methyl derivative of beditin, mesedin, on the differentiation and functional markers of neuronal precursors and astroglia led to the conclusion that mesedin can be considered as a valuable drug candidate for neurodegenerative disorders, like Alzheimer’s disease (AD), which are associated with hypoxia, beta amyloid (Aβ) accumulations, and glutamate toxicity [ 12 ]. One of the most effective and widely used α2-AR blockers among the 1,4-benzodioxane derivatives, idazoxan, contains a five-membered heterocycle with two nitrogen atoms.…”

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

“…In mice, the hypoxia-inducible factor 1α (HIF-1α) generated upon oxygen deprivation has been demonstrated to be a crucial factor in collagen cross-linking, contributing to liver fibrosis in NAFLD [40]. In neural cells, an α2-AR blockade due to mesedin has led to the improved survival of astroglia, neurons, and neuronal progenitors, mediated partially by the upregulation of interleukin-10 (IL-10) [11]. Extrapolating this result to the progression of liver injury, it can be assumed that mesedin may exert its antifibrotic properties through IL-10, which is known to possess strong protective features in hepatocytes and to induce the senescence of activated HSCs [41,42].…”

“…Extrapolating this result to the progression of liver injury, it can be assumed that mesedin may exert its antifibrotic properties through IL-10, which is known to possess strong protective features in hepatocytes and to induce the senescence of activated HSCs [41,42]. By acknowledging the antihypoxic properties of mesedin in the central nervous system in vitro and in vivo [9][10][11], future investigations of mesedin's effects on parenchymal and nonparenchymal liver cells exposed to hypoxia can provide additional mechanistic insight into the function of hepatic α2-AR and the feasibility of its blockade in the treatment of chronic liver injury.…”

“…In a model of focal ischemia, mesedin improved memory and anxiety symptoms and decreased oxidative stress markers in brain tissue [9,10]. In astroglial primary culture of normal and Alzheimer's mouse model (3xTg-AD) brains, the increased survival of neurons, upregulated neurogenesis markers, and anti-inflammatory cytokines have been observed upon treatment with mesedin [11].…”

“…In light of the aforementioned controversial discussion around the role of α2-ARs in liver fibrosis/cirrhosis, we sought to investigate the influence of the novel α2-AR blocker mesedin (2-(2-methyl-amino-thiozolyl)-1,4-benzodioxane hydrochloride) [15] on the two main nonparenchymal liver cell types, hepatic stellate cells and liver sinusoidal endothelial cells, which are key players in the fibrotic reorganization of liver tissue and the permeability of the blood-tissue barrier during cirrhosis. Mesedin was used as a novel α2-adrenoblocker because of its selectivity to α2-adrenoreceptors and its lower toxicity compared to known structural analogs, such as idazoxan (as previously discussed in Reference [11]). Notably, the levels of α1-, β1-, and β2-AR have been previously assessed in HSCs in vitro [16], while the influence of liver injury and HSC activation on α2-AR expression remains largely unexplored.…”