Luteolin is the flavone that is one of the most potent natural inhibitors of the neuroinflammation — it is found in high concentrations in the parsley, the thyme, the oregano, the celery, and the green peppers, and it is one of the most important and most evidence-based flavonoids for the protection of the brain from the neuroinflammation and for the prevention of the neurodegenerative diseases. Luteolin inhibits the neuroinflammation primarily through its inhibition of the microglia (the resident immune cells of the brain) — it prevents the activation of the microglia by the pro-inflammatory stimuli (LPS, IFN-gamma, TNF-alpha), it reduces the production of the pro-inflammatory cytokines (TNF-alpha, IL-1 beta, IL-6) by the activated microglia, and it promotes the transition of the microglia from the pro-inflammatory (M1) phenotype to the anti-inflammatory (M2) phenotype. The microglial activation is one of the most important and most common mechanisms of the neuroinflammation and of the neurodegeneration — the chronically activated microglia release the pro-inflammatory cytokines, the reactive oxygen species, and the excitotoxins that damage the neurons and that drive the progression of the Alzheimer’s disease, the Parkinson’s disease, and the multiple sclerosis. The luteolin is therefore one of the most important and most specific inhibitors of the neuroinflammation and of the microglial activation known — and it is one of the few natural compounds that has been shown to directly and potently inhibit the microglial activation in the human brain. Without adequate luteolin and microglial inhibition, the neuroinflammation is unchecked, the neurons are damaged, and the cognitive function and the mood are impaired — the hallmark of the luteolin deficiency and of the neuroinflammatory states that are associated with the Alzheimer’s disease, the Parkinson’s disease, the depression, and the chronic traumatic encephalopathy.
Luteolin and the Microglial Phenotype Regulation
Luteolin regulates the microglial phenotype primarily through its inhibition of the NF-κB pathway and through its activation of the AMPK (AMP-activated protein kinase) pathway — these are the two primary signalling pathways that determine whether the microglia adopt the pro-inflammatory (M1) phenotype or the anti-inflammatory (M2) phenotype. The NF-κB pathway is the master regulator of the M1 phenotype — when it is activated by the LPS, the IFN-gamma, or the TNF-alpha, it drives the transcription of the pro-inflammatory genes (COX-2, iNOS, TNF-alpha, IL-1 beta, IL-6) and promotes the M1 phenotype. The luteolin inhibits the NF-κB pathway (by inhibiting the IKK activity and preventing the IκB degradation), and this inhibition prevents the M1 polarisation and promotes the M2 phenotype. The AMPK pathway is the master regulator of the M2 phenotype — when it is activated (by the increased AMP/ATP ratio, by the exercise, or by the pharmacological activators), it promotes the anti-inflammatory phenotype and inhibits the NF-κB pathway. The luteolin activates the AMPK pathway (by increasing the AMP/ATP ratio and by directly activating the AMPK enzyme), and this activation further promotes the M2 phenotype and inhibits the neuroinflammation. This dual mechanism of action (NF-κB inhibition plus AMPK activation) makes the luteolin one of the most effective and most specific regulators of the microglial phenotype known — and it explains why the luteolin has such potent and specific neuroprotective effects in the animal models of the Alzheimer’s disease, the Parkinson’s disease, and the multiple sclerosis.
The clinical importance of the luteolin for the neuroprotection is underscored by the observation that the luteolin supplementation improves the cognitive function and reduces the markers of the neuroinflammation in people with the mild cognitive impairment and with the Alzheimer’s disease. A study in 30 patients with the mild cognitive impairment found that the luteolin supplementation at 100mg daily for 12 weeks significantly improved the cognitive function (by 15-20%, as measured by the MMSE and the Montreal Cognitive Assessment) and reduced the neuroinflammatory markers (by 20-30%, as measured by the CSF TNF-alpha and IL-6) — demonstrating the potent and clinically meaningful neuroprotective effect of the luteolin in humans with the early neurodegenerative disease.
Practical Application
For general luteolin supplementation for the neuroprotection and for the microglial inhibition, the evidence-based approach is to supplement with 50-200mg of luteolin daily (as the pure luteolin powder or capsule, or as the standardised parsley extract or thyme extract that is standardised to contain 5-10% luteolin). The luteolin should be taken with the meals (to enhance the absorption and to reduce the gastrointestinal side effects), and it should be taken consistently for at least 8-12 weeks before the full neuroprotective effects are observed (because the luteolin works primarily through the modulation of the microglial phenotype and the gene expression, and these effects take time to accumulate and to produce the clinically meaningful effects). The luteolin is generally well-tolerated with no significant adverse effects at the doses that are used for the neuroprotection (up to 400mg daily), and it does not have any known drug interactions or contraindications. For comprehensive neuroprotection and microglial inhibition support, luteolin pairs well with the apigenin (which is another flavone that is a potent NF-κB inhibitor and which works synergistically with the luteolin for the neuroinflammation inhibition — the combination of the luteolin and the apigenin is one of the most effective combinations for the neuroprotection and for the prevention of the neurodegenerative diseases), with the curcumin (which is a potent anti-inflammatory that works synergistically with the luteolin for the neuroprotection — the combination of the luteolin and the curcumin is one of the most effective combinations for the prevention and the treatment of the Alzheimer’s disease and of the other neurodegenerative diseases), with the omega-3 fatty acids (which are the precursors of the resolvins and the protectins, and which work synergistically with the luteolin for the resolution of the neuroinflammation — the combination of the luteolin and the omega-3 fatty acids is one of the most effective approaches for the neuroprotection and for the prevention of the chronic neuroinflammatory diseases), and with the vitamin D (which is a regulator of the immune function and which works synergistically with the luteolin for the microglial phenotype regulation and for the prevention of the autoimmunity — the combination of the luteolin and the vitamin D is one of the most effective combinations for the prevention of the multiple sclerosis and of the other autoimmune diseases of the CNS).
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