Reversal of age‐related oxidative stress prevents hippocampal synaptic plasticity deficits by protecting d‐serine‐dependent NMDA receptor activation

Abstract

SummaryOxidative stress (OS) resulting from an imbalance between antioxidant defenses and the intracellular accumulation of reactive oxygen species (ROS) contributes to age-related memory deficits. While impaired synaptic plasticity in neuronal networks is thought to underlie cognitive deficits during aging, whether this process is targeted by OS and what the mechanisms involved are still remain open questions. In this study, we investigated the age-related effects of the reducing agent N-acetyl-L-cysteine (L-NAC) on the activation of the N-methyl-D-aspartate receptor (NMDA-R) by its co-agonist D-serine, because alterations in this mechanism contribute greatly to synaptic plasticity deficits in aged animals. Long-term dietary supplementation with L-NAC prevented oxidative damage in the hippocampus of aged rats. Electrophysiological recordings in the CA1 of hippocampal slices indicated that NMDA-R-mediated synaptic potentials and thetaburst-induced long-term potentiation (LTP) were depressed in aged animals, deficits that could be reversed by exogenous D-serine. Chronic treatment with L-NAC, but not acute application of the reducing agent, restored potent D-serine-dependent NMDA-R activation and LTP induction in aged rats. In addition, it is also revealed that the age-related decrease in D-serine levels and in the expression of the synthesizing enzyme serine racemase, which underlies the decrease in NMDA-R activation by the amino acid, was rescued by long-term dietary treatment with L-NAC. Our results indicate that protecting redox status in aged animals could prevent injury to the cellular mechanisms underlying cognitive aging, in part by maintaining potent NMDA-R activation through the D-serine-dependent pathway.

Characterization of RA839, a Noncovalent Small Molecule Binder to Keap1 and Selective Activator of Nrf2 Signaling

“…Further studies will have to show whether Nrf2 has a direct effect on Srr gene expression. The first evidence for this might come from the observation that serine racemase expression is regulated by oxidative stress (29). Although Nrf2 activation has not been directly associated with eNOS signaling, two genes (Fifg and Prkaa2) of this canonical pathway that were regulated by RA839 are regulated by Nrf2 and protect against oxidative stress, respectively (30 -32).…”

The endocannabinoid system in normal and pathological brain ageing

“…Not surprising therefore that anti-oxidants were intensively tested as potential therapeutic agents against the negative consequences of brain ageing and neurodegenerative disorders [84][85][86]. Generally, it was found that anti-oxidant treatment or activation of anti-oxidative pathways improve brain functions and partially restores age-dependent changes in gene expression both in normal ageing [87,88] and in models of accelerated ageing [89,90]. Clinical data suggest that dietary anti-oxidants have some protective effects against AD, Parkinson's disease and amyotrophic lateral sclerosis [91] and also in pharmacological and genetic models of neurodegenerative disorders [92][93][94].…”

Oxidative Stress and the Central Nervous System

“…And, oxidative stress-initiated neuroendocrine alterations within the amygdala, including amygdalar hyperactivity and dendritic shrinking (Wellman, 2001;Vyas et al, 2002;Kreibich and Blendy 2004;Brown et al, 2005;Radley et al, 2006;Wood et al, 2010), can further potentiate synaptic disturbances by disrupting the hippocampus-amygdala projections. Furthermore, free radicals are known to oxidize the extracellular sites of glutamatergic N-methyl-D-aspartate receptors, leading to attenuation of LTP and synaptic neurotransmission (Haxaire et al, 2012;Lee et al, 2012;Rai et al, 2013). Collectively, these events offer an attractive explanation for oxidative stress-induced behavioral and cognitive impairment.…”