Sulforaphane Augments Glutathione and Influences Brain Metabolites in Human Subjects: A Clinical Pilot Study

Abstract

Schizophrenia and other neuropsychiatric disorders await mechanism-associated interventions. Excess oxidative stress is increasingly appreciated to participate in the pathophysiology of brain disorders, and decreases in the major antioxidant, glutathione (GSH), have been reported in multiple studies. Technical cautions regarding the estimation of oxidative stress-related changes in the brain via imaging techniques have led investigators to explore peripheral GSH as a possible pathological signature of oxidative stress-associated brain changes. In a preclinical model of GSH deficiency, we found a correlation between whole brain and peripheral GSH levels. We found that the naturally occurring isothiocyanate sulforaphane increased blood GSH levels in healthy human subjects following 7 days of daily oral administration. In parallel, we explored the potential influence of sulforaphane on brain GSH levels in the anterior cingulate cortex, hippocampus, and thalamus via 7-T magnetic resonance spectroscopy. A significant positive correlation between blood and thalamic GSH post- and pre-sulforaphane treatment ratios was observed, in addition to a consistent increase in brain GSH levels in response to treatment. This clinical pilot study suggests the value of exploring relationships between peripheral GSH and clinical/neuropsychological measures, as well as the influences sulforaphane has on functional measures that are altered in neuropsychiatric disorders.

Antioxidants as a Potential Target against Inflammation and Oxidative Stress in Attention-Deficit/Hyperactivity Disorder

“…The combination of NAC and SFN significantly reduced oxidative stress, delayed the onset of epilepsy, blocked disease progression, and reduced the frequency of spontaneous seizures in animals [83]. Also, in a clinical pilot study, treatment with SFN increased the antioxidant GSH, suggesting a need to explore possible correlations between GSH and clinical/neuropsychological measures and any positive influence that the treatment of SFN could have on neuropsychiatric disorders [26]. Even though the antioxidative effect of SFN supplementation in ADHD has not been studied, this could constitute a promising approach for oxidative imbalances linked with ADHD.…”

“…Neuroinflammation and oxidative stress play a role in the pathophysiology of ADHD due to genetic and environmental factors, catecholaminergic dysregulation, and medications used for treatment, all factors which could produce inflammation and oxidative stress, which increases the symptoms and, as a consequence, leads to establishing a vicious circle (Figure 1). Hence, antioxidants against inflammation and oxidative stress have been used to manage other disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, autism, schizophrenia, and depression [23][24][25][26][27][28]. Accordingly, antioxidant modulators could be helpful as a multi-target adjuvant therapy in ADHD.…”

The glutathione cycle shapes synaptic glutamate activity

“…Sulforaphane (54) is a potent inducer of the Nrf2 transcription factor, has excellent blood brain barrier penetration (55), and might expand the size of the glutathione reservoir by increasing expression of GCL, the rate liming step in glutathione biogenesis. Recent studies in human subjects show that sulforaphane elevates glutathione levels and those of other brain metabolites (56). Sulforaphane has also been reported to improve symptoms of autistic spectrum disorder (57).…”

Astrocyte redox dysregulation causes prefrontal hypoactivity: sulforaphane treats non-ictal pathophysiology in ALDH7A1-mediated epilepsy

“…SFN remains stable and bioactive in rodent chow (Fig. S6A), and oral administration is sufficient to increase levels of glutathione 45 , allowing for long-term dietary supplementation. Dietary SFN supplementation has therapeutic relevance as it is safely tolerated in humans and under investigation for the treatment of a variety of disorders in humans [46][47][48][49] .…”

“…These genetic ALDH deficiencies could be treated by using SFN to compensate for the affected ALDH isoenzyme, particularly the cognitive and mood dysfunctions in these diseases that may involve cortical E-I imbalance. Due to its function as an indirect antioxidant, SFN is already under clinical investigation for autism spectrum disorder46 and has been suggested as a possible therapy for cognitive deficits in schizophrenia45 . Due to its effect on ALDHs, SFN could be particularly effective in subsets of patients with ALDH deficiency/aldehyde toxicity.…”