Clinical translational neuroimaging of the antioxidant effect of N‐acetylcysteine on neural microstructure

Abstract

Purpose: Oxidative stress and downstream effectors have emerged as important pathological processes that drive psychiatric illness, suggesting that antioxidants may have a therapeutic role in psychiatric disease. However, no imaging biomarkers are currently available to track therapeutic response. The purpose of this study was to examine whether advanced DWI techniques are able to sensitively detect the potential therapeutic effects of the antioxidant N-acetylcysteine (NAC) in a Disc1 svΔ2 preclinical rat model of psychiatric illness.Methods: Male and female Disc1 svΔ2 rats and age-matched, sex-matched Sprague-Dawley wild-type controls were treated with a saline vehicle or NAC before ex vivo MRI acquisition at P50. Imaging data were fit to DTI and neurite orientation dispersion and density imaging models and analyzed for region-specific changes in quantitative diffusion metrics. Brains were further processed for cellular quantification of microglial density and morphology. All experiments were repeated for Disc1 svΔ2 rats exposed to chronic early-life stress to test how geneenvironment interactions might alter effectiveness of NAC therapy. Results:The DTI and neurite orientation dispersion and density imaging analyses demonstrated amelioration of early-life, sex-specific neural microstructural deficits with concomitant differences in microglial morphology across multiple brain regions relevant to neuropsychiatric illness with NAC treatment, but only in male Disc1 svΔ2 rats. Addition of chronic early-life stress reduced the ability of NAC to restore microstructural deficits. Conclusion:These findings provide evidence for a treatment pathway targeting endogenous antioxidant capacity, and the clinical translational utility of neurite orientation dispersion and density imaging microstructural imaging to sensitively detect microstructural alterations resulting from antioxidant treatment.

Chronic N-Acetylcysteine Treatment Prevents Amphetamine-Induced Hyperactivity in Heterozygous Disc1 Mutant Mice, a Putative Prodromal Schizophrenia Animal Model

“…Aside from the effects of NAC on the neurotransmitter systems, a recent elegant imaging study showed the involvement of microglia in a Disc1 mutant rat model. Microglial morphology and neural microstructural features in male Disc1 mutant rats were restored by NAC treatment, whereas chronic early-life stress reduced the therapeutic effects of NAC [ 75 ]. Since microglial activity is important for brain development, the pruning of dendritic spines as well as neuroinflammation and neuronal functions, the role of NAC in neuron–microglia interaction is warranted for further exploration [ 76 ].…”

Quantitative diffusion imaging and genotype‐by‐sex interactions in a rat model of Alexander disease

“…Ex vivo imaging and analysis, including standard data preprocessing, study template generation, and ROI analyses, was performed as previously described. 11 Briefly, all animals (n = for all genotypes) at 56 days of age were transcardially perfused with phosphate-buffered saline (PBS) followed by 4% paraformaldehyde (PFA) in PBS. The brains were then extracted from the cranial vault and postfixed in 4% PFA.…”