S-allyl cysteine protects against MPTP-induced striatal and nigral oxidative neurotoxicity in mice: Participation of Nrf2

Abstract

The neuroprotective properties of S-allyl cysteine (SAC) have been demonstrated in different neurotoxic paradigms, and it may be partially attributable to its antioxidant and anti-inflammatory profile. Recently, SAC has also been shown to induce neuroprotection in the rat striatum in a toxic model induced by 6-hydroxydopamine in rats through a concerted antioxidant response involving Nrf2 transcription factor nuclear transactivation and Phase 2 enzymes' upregulation. In this work, we investigated whether the SAC-induced in vivo striatal and nigral neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridinium (MPTP) toxicity recruits Nrf2 transactivation in C57BL/6J mice. SAC (120 mg/kg, i.p. × 5 days) partially ameliorated the MPTP (30 mg/kg, i.p. × 5 days)-induced striatal and nigral dopamine and tyrosine hydroxylase depletion, attenuated the loss of Mn-SOD and HO-1 activities, and preserved the protein content of these enzymes. While no significant changes were detected for the striatal Nrf2 nuclear protein levels, the nigral Nrf2 nuclear content was decreased by MPTP and stimulated by SAC. Our findings suggest that SAC can exert neuroprotection since the origin of the dopaminergic lesion-at the substantia nigra (SN)-not only by means of direct antioxidant actions, but also through Nrf2 nuclear transactivation and Phase 2 enzymes upregulation.

Diphenyl Diselenide Modulates Gene Expression of Antioxidant Enzymes in the Cerebral Cortex, Hippocampus and Striatum of Female Hypothyroid Rats

“…Here, the striatal Nrf-2 expression was not modified by MTZ exposure. We did not expect this result since several studies, mainly related to Parkinson disease models, have demonstrated that this transcription factor in the striatum and/or dopaminergic neurons can be modulated by different drugs, including methamphetamine, 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinium (MPTP) [81,82]. The results obtained here indicate that the pattern of gene expression in response to hypothyroidism is complex and depends on the brain region considered.…”

Acute restraint stress reduces hippocampal oxidative damage and behavior in rats: Effect of S-allyl cysteine

“…We also found that, contrary to what would be expected in a stress protocol, the elevated-plus maze and forced-swimming tests revealed that animals subjected to acute restraint are less depressed, exhibit less anxiety, and are more prompt to show their survival instinct by struggling and socializing [45,47], therefore supporting our suggestion that under the experimental conditions employed in this study, acute stress represents a phase in which individuals are still capable to display "fighting-back" adaptive responses to counteract adverse situations. Noteworthy, the use of SAC as pretreatment in stressed rats ameliorated and/or prevented all the behavioral alterations explored herein, thereby supporting the involvement of oxidative stress in acute restraint stress and emphasizing the many beneficial properties exerted by this antioxidant in in vivo toxic models [13,14,38,39]. Nonetheless, although brief and transitory, the behavioral changes Stress is known to stimulate the activation of numerous pathways leading to altered levels of hormones, neurotransmitters, oxidants, and several other substances.…”

“…In light of the preventive effects exerted by SAC in this study, we suggest that most of its actions could correspond to its properties as free radical scavenger [7,21,30], although in addition to its direct scavenging activity, SAC has been shown to exert protection in the model of hemi-parkinsonism induced by MPTP through the stimulation of the Nrf2 pathway [14]. This transcription factor is currently in charge of signaling for the synthesis of antioxidant defenses (phase 2 enzymes) to counteract toxic insults and to preserve the redox homeostasis [9].…”

“…New clues on the protective actions of SAC have been recently revealed through the neurotoxic model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the rat nervous system. Accordingly, SAC was not only able to reduce oxidative stress [13], but it also exerted modulatory actions on the antioxidant transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), thus providing an integral antioxidant response through phase 2 enzymes [14].…”

“…SAC was synthesized according to previous reports [13,14]. In brief, L-cysteine reacts with allyl bromide and the product was purified by recrystallization from ethanol-water.…”