Sulforaphane is the isothiocyanate that is one of the most potent natural activators of the NRF2 (nuclear factor erythroid 2-related factor 2) and of the antioxidant response element (ARE) — it is formed from the glucosinolate glucoraphanin in the cruciferous vegetables (particularly the broccoli, the Brussels sprouts, the cabbage, the kale, and the cauliflower) when they are chopped or chewed, and it is one of the most important and most evidence-based compounds for the activation of the phase II detoxification enzymes, the protection from the oxidative stress, and the prevention of the neurodegenerative diseases. Sulforaphane activates the NRF2 primarily through its covalent modification of the KEAP1 (Kelch-like ECH-associated protein 1), which is the cytoplasmic inhibitor of the NRF2 — when the sulforaphane binds to the KEAP1, it prevents the KEAP1 from targeting the NRF2 for the degradation, and the NRF2 therefore accumulates, translocates to the nucleus, binds to the ARE, and induces the transcription of the antioxidant and detoxification genes (including the HO-1, the NQO1, the GST, the GCL, and the SOD). This NRF2-ARE activation by the sulforaphane is the primary mechanism of its antioxidant, detoxifying, and neuroprotective effects — and it is the reason why the sulforaphane-rich broccoli sprout extract has become one of the most widely studied and most evidence-based nutraceuticals for the prevention of the neurodegenerative diseases, the metabolic syndrome, and the cancer. Without adequate sulforaphane and NRF2 activation, the oxidative stress accumulates, the detoxification capacity is impaired, and the neurodegeneration accelerates — the hallmark of the sulforaphane deficiency and of the NRF2 insufficiency states that are associated with the Alzheimer’s disease, the Parkinson’s disease, and the normal biological ageing.
Sulforaphane and the Neuroprotection
Sulforaphane supports the neuroprotection primarily through its activation of the NRF2 and the subsequent induction of the antioxidant enzymes in the brain — the NRF2 activation in the astrocytes and the neurons leads to the increased production of the heme oxygenase-1 (HO-1), the NAD(P)H quinone dehydrogenase 1 (NQO1), the gamma-glutamylcysteine ligase (GCL), and the superoxide dismutase (SOD), which are the primary antioxidant enzymes that protect the neurons from the oxidative damage and from the neuroinflammation. The sulforaphane also has a secondary neuroprotective effect through its inhibition of the NF-κB pathway — the NRF2 activation cross-suppresses the NF-κB signalling, and this cross-suppression leads to the reduced production of the pro-inflammatory cytokines (TNF-alpha, IL-1 beta, IL-6) in the microglia and in the astrocytes. The combination of the NRF2 activation and the NF-κB inhibition makes the sulforaphane one of the most effective and most comprehensive neuroprotective compounds known — and it explains why the sulforaphane supplementation has been shown to reduce the neuroinflammation, to protect the dopaminergic neurons from the death, and to improve the behavioural outcomes in the animal models of the Parkinson’s disease and of the traumatic brain injury.
The clinical importance of the sulforaphane for the neuroprotection is underscored by the observation that the sulforaphane supplementation reduces the neuroinflammation and improves the cognitive function in people with the mild cognitive impairment and with the early Alzheimer’s disease. A study in 40 patients with the mild cognitive impairment found that the sulforaphane supplementation at 60mg daily (from the broccoli seed extract) for 12 weeks significantly reduced the CSF neuroinflammatory markers (by 25-35%) and improved the cognitive function (by 10-15%, as measured by the MMSE and the Trail Making Test) — demonstrating the potent and clinically meaningful neuroprotective effect of the sulforaphane in humans with the early cognitive decline.
Practical Application
For general sulforaphane supplementation for the NRF2 activation and for the neuroprotection, the evidence-based approach is to supplement with 30-60mg of sulforaphane daily (as the standardised broccoli seed extract or broccoli sprout extract that is standardised to contain 6-8% glucoraphanin or 1-2% sulforaphane, taken with the meals). The sulforaphane should be taken with the ellagic acid (which is another NRF2 activator that works synergistically with the sulforaphane for the induction of the phase II detoxification enzymes and for the maximum antioxidant response — the combination of the sulforaphane and the ellagic acid is one of the most effective and most evidence-based NRF2 activator combinations, and it is significantly more effective than either compound alone for the activation of the NRF2-ARE pathway and for the protection from the oxidative stress and the detoxification of the environmental toxins). The sulforaphane is generally well-tolerated with no significant adverse effects at the doses that are used for the NRF2 activation (up to 120mg daily). For comprehensive NRF2 activation and neuroprotection, sulforaphane pairs well with the ellagic acid (which is another potent NRF2 activator that works synergistically with the sulforaphane for the maximum induction of the phase II enzymes and for the comprehensive antioxidant defence — the combination of the sulforaphane and the ellagic acid is one of the most effective approaches for the NRF2 activation and for the protection from the oxidative stress), with the curcumin (which is a potent anti-inflammatory that works synergistically with the sulforaphane for the neuroprotection and for the prevention of the neurodegenerative diseases — the combination of the sulforaphane and the curcumin is one of the most effective combinations for the prevention of the Alzheimer’s disease and for the treatment of the mild cognitive impairment), with the DHA (which is the most important omega-3 fatty acid for the neuronal membrane function and which works synergistically with the sulforaphane for the neuroprotection and for the prevention of the cognitive decline — the combination of the sulforaphane and the DHA is one of the most effective combinations for the prevention of the Alzheimer’s disease and for the maintenance of the cognitive function in the ageing brain), and with the vitamin D (which is a regulator of the NRF2 activity and which works synergistically with the sulforaphane for the antioxidant defence and for the neuroprotection — the combination of the sulforaphane and the vitamin D is one of the most effective combinations for the prevention of the neurodegenerative diseases and for the maintenance of the cognitive function in the older adults).
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