Multifunctional tellurium molecule protects and restores dopaminergic neurons in Parkinson's disease models

Abstract

In Parkinson's disease (PD) dopaminergic neurons in the substantia nigra (SN) become dysfunctional and many ultimately die. We report that the tellurium immunomodulating compound ammonium trichloro(dioxoethylene-O,O'-)tellurate (AS101) protects dopaminergic neurons and improves motor function in animal models of PD. It is effective when administered systemically or by direct infusion into the brain. Multifunctional activities of AS101 were identified in this study. These were mainly due to the peculiar Tellur(IV)-thiol chemistry of the compound, which enabled the compound to interact with cysteine residues on both inflammatory and apoptotic caspases, resulting in their inactivation. Conversely, its interaction with a key cysteine residue on p21(ras), led to its activation, an obligatory activity for AS101-induced neuronal differentiation. Furthermore, AS101 inhibited IL-10, resulting in up-regulation of GDNF in the SN. This was associated with activation of the neuroprotective kinases Akt and mitogen-activated protein kinases, and up-regulation of the antiapoptotic protein Bcl-2. Inhibition of caspase-1 and caspase-3 activities were associated with decreased neuronal death and inhibition of IL-1beta. We suggest that, because multiple mechanisms are involved in the dysfunction and death of neurons in PD, use of a multifunctional compound, exerting antiapoptotic, anti-inflammatory, and neurotrophic-inducing capabilities may be potentially efficacious for the treatment of PD.

Crystallographic and docking (Cathepsins B, K, L and S) studies on bioactive halotelluroxetanes

“…These observations have encouraged further studies of tellurium- 3 (22) based compounds as inhibitors of this class of enzyme. In this context, Cunha and co-workers have presented series of organotellurium compounds that show irreversible inhibitory activity greater than AS-101 against Cathepsin B as well as being irreversible inhibitors against Cathepsins K, L and S [31,32].…”

“…Hence, the tellurium atom is five-coordinate within a C2ClO2 donor set. 6 (22) edge lengths of approximately 2.1 and 2.9 Å. Within the ring, short O1⋯O1 i contacts of 2.662(2) Å are noted; symmetry operation i: 1-x, -y, 1-z.…”

“…The layers stack along the b-axis without directional interactions between them, Figure 3b. 8 (22) view of the unit cell contents down the a-axis highlighting the stacking of layers along the b-axis. The C-H … Cl interactions are represented as purple dashed lines.…”

“…Due to the chemical similarities to tellurium, selenium's heavier congener, tellurium compounds have also attracted interest in the pharmaceutical context [11,12]. Thus, tellurium compounds have shown promise since they are an immunomodulator in organisms [13] and display anti-oxidant [14][15][16], anti-parasitic [17,18] and anti-inflammatory [19] activities, are known to be neuroprotective [20,21] and have potential to be developed as anti-cancer agents [22][23][24]. The most notable tellurium compound that exerts biological activity is found in the salt ammonium trichlorido (dioxyethylene-O,Oꞌ)tellurate, known as AS-101 ( Figure 1a) [25].…”

Evaluation of the effect of natural peptide 'Urocortin' on corticotrophin releasing factor (CRF) receptor expression in ND7/23 cells

“…Therefore, protection of neuronal cells using Ucn can be extremely useful for untreatable neuronal disorders (Martin et al, 2007). The latest efforts to treat such disorders have been focused on the neuronal level by protecting the neurons from apoptosis (Sredni et al, 2007). The main aim of the study was to explore more about the neuro-protective role of Ucn in cells subjected to oxidative stress by hydrogen peroxide.…”