Polyphenols and the NF-κB Pathway: Gaining Traction for Neurological Disorders

Neurological disorders (NDs) represent a significant global health concern with an estimated 55 million people live with Alzheimer’s disease (AD). These disorders, which also include Parkinson’s disease (PD), depression, anxiety and various other conditions affecting the nervous system, result in a range of symptoms from cognitive deficits to motor dysfunction. The nuclear factor kappa B (NF-κB) pathway, known for regulating immune responses, cell division, and apoptosis (programmed cell death), plays a crucial role in the nervous system. Dysregulation of this pathway is linked to many NDs, making it a potentially interesting target for therapeutic interventions.

The Role of NF-κB in Neurological Disorders

The NF-κB pathway can be activated through canonical and non-canonical routes** (please see note at end of blog), influencing numerous physiological processes in the central nervous system, including neurogenesis (the process by which new neurons are formed) and synaptic plasticity (the ability of synapses to strengthen or weaken over time in response to increases or decreases in their activity). Its dysregulation acts like a rogue conductor, orchestrating a cascade of inflammation and cellular stress that accelerates brain degeneration. Because of this, NF-κB tends to be a therapeutic target.

Polyphenols as Neuroprotective Agents

Polyphenols, a diverse group of natural antioxidants found mostly fruits and vegetables, have shown significant neuroprotective properties. These compounds can modulate the NF-κB pathway, offering protection against oxidative stress, inflammation, and neurotoxicity. There are many exceptional polyphenols, but some that I tend to use in practice, include curcumin, resveratrol, and quercetin.

1. Curcumin: derived from turmeric, has significant anti-inflammatory properties. It effectively suppresses cytokines and reduces inflammation by inhibiting the NF-κB pathway. Curcumin also reduces neurotoxic factors, mitigates memory impairments in Alzheimer’s disease (AD), and enhances neuronal function by targeting the PPAR-γ pathway which regulates metabolism, inflammation, and cell differentiation by activating gene expression through binding to specific ligands.
2. Resveratrol: found in grapes, is known for its antioxidant, anti-inflammatory, and anti-apoptotic properties. It has shown efficacy in restoring neuronal function post-spinal cord injury, reducing neuroinflammation, and protecting against neurotoxicity in AD. Resveratrol also exhibits antidepressant properties by mitigating neuroinflammation and oxidative stress.
3. Quercetin: a flavonoid found in many fruits and vegetables, reduces mitochondrial dysfunction, oxidative stress, and apoptosis by downregulating NF-κB, thereby preventing inflammatory responses in the brain.

Polyphenols positively influence gut microbiota composition and thereby enhance gut barrier integrity, increasing SCFA production, and influencing gut-brain axis signaling. In doing this, polyphenols contribute to both gut and brain health.

In anxiety and depression, they have been shown to counteract neuroinflammation through the Sirt1-NF-κB signaling pathway as well as by increasing levels of BDNF in the brain. BDNF is a crucial protein involved in neuroplasticity, which is essential for learning, memory, and overall brain function.

One of the easiest ways to increase polyphenol intake is by increasing intake of vegetables and fruits.

Vegetables rich in polyphenols include:

1. Artichokes: High in antioxidants and polyphenols, especially caffeoylquinic acids.
2. Spinach: Contains various polyphenols, including flavonoids like quercetin and kaempferol.
3. Red Onions: Packed with quercetin and anthocyanins.
4. Broccoli: Rich in flavonoids and glucosinolates.
5. Brussels Sprouts: Contains several polyphenols, including kaempferol and quercetin.
6. Kale: High in flavonoids and carotenoids.
7. Beets: Contains betalains and other polyphenolic compounds. Beets are also a methylation superfood – something I’ll spend more time on in upcoming blogs on reducing biological age.
8. Peppers: Especially red bell peppers, which are high in flavonoids and carotenoids.

Note:

**In the context of the NF-κB (nuclear factor kappa B) pathway, “canonical” and “non-canonical” routes refer to two different mechanisms by which this pathway can be activated and lead to gene expression changes involved in immune and inflammatory responses.