Antioxidant strategy to rescue synaptosomes from oxidative damage and energy failure in neurotoxic models in rats: protective role of S-allylcysteine

Abstract

The functional preservation of nerve endings since the early stages of toxicity in a given damaging insult-either acute or chronic-by means of antioxidant and neuroprotective agents is a primary need to design therapeutic strategies for neurodegenerative disorders, with particular emphasis on those diseases with excitotoxic and depleted energy metabolism components. S-allylcysteine (SAC), a well-known antioxidant agent, was tested as a post-treatment in different in vitro and in vivo neurotoxic models. Quinolinic acid (QUIN) was used as a typical excitotoxic/pro-oxidant inducer, 3-nitropropionic acid (3-NP) was employed as a mitochondrial function inhibitor, and their combination (QUIN + 3-NP) was also evaluated in in vitro studies. For in vitro purposes, increasing concentrations of SAC (10-100 microM) were added to isolated brain synaptosomes at different times (1, 3 and 6 h) after the incubation with toxins (100 microM QUIN, 1 mM 3-NP or the combination of QUIN (21 microM) + 3-NP (166 microM). Thirty minutes later, lipid peroxidation (LP) and mitochondrial dysfunction (MD) were evaluated. For in vivo studies, SAC (100 mg/kg, i.p.) was given to QUIN- or 3-NP-striatally lesioned rats for 7 consecutive days (starting 120 min post-lesion). LP and MD were evaluated 7 days post-lesion in isolated striatal synaptosomes. Circling behavior was also assessed. Our results describe a differential pattern of protection achieved by SAC, mostly expressed in the 3-NP toxic model, in which nerve ending protection was found within the first hours (1 and 3) after the toxic insult started, supporting the concept that the ongoing oxidative damage and energy depletion can be treated during the first stages of neurotoxic events.

Quinolinic Acid, an Endogenous Molecule Combining Excitotoxicity, Oxidative Stress and Other Toxic Mechanisms

“…This was assumed to modulate the polyamine binding site at the NMDAr function and also exert antioxidant effects—, the energy precursor and antioxidant L-carnitine,17 the selective neuronal nitric oxide synthase inhibitor Nomega-Nitro-l-arginine-methyl esther34—acting by recovering the protein tyrosine phosphorylation pattern affected by QUIN—, the antioxidant element selenium35—acting by reducing the proapoptotic signaling derived from NF-κB pathway and stimulating glutathione peroxidase activity—, the free radical scavenger and signaling molecule melatonin,36 and the singlet oxygen and superoxide scavenger 6-hydroxymelatonin,37 among several others. Recently, our group has carried out studies in vitro and in vivo to investigate whether the antioxidant S-allylcysteine can recover the synaptosomes from the toxic insult caused by QUIN, even when this agent is administered in post-lesion schemes 38. The findings of this study suggest that the optimum time window for pharmacological intervention to achieve functional preservation of nerve endings is short, 1 to 3 h post-lesion.…”

The Antioxidant Mechanisms Underlying the Aged Garlic Extract- and S-Allylcysteine-Induced Protection

“…Alternatively, the effect of SAC was evaluated in a combined model of excitotoxicity/energy deficit produced by the coadministration of quinolinate and 3-nitropropionate acid in brain synaptosomal membranes. SAC abolished the quinolinic acid plus 3-nitropropionate acid-induced lipid peroxidation [113, 114]. The protective effect of SAC in these models has been attributed to its ability to preserve the cell redox status through its antioxidant properties and probably to its iron-binding properties.…”

Mitochondrial pharmacology: Electron transport chain bypass as strategies to treat mitochondrial dysfunction

“…SAC protected nerve ending within the first hours (1 and 3) after the toxic insult with 3-NP. SAC protected nerve endings from oxidative damage and energy depletion caused by mitochondrial dysfunction by 3-NP [36]. Tetramethylpyrazine (TMP) is a principal ingredient of the plant Ligusticum wallichi Franchat , used for treatment of cardiovascular and cerebrovascular ischemic disorders (used in Chinese medicine).…”