Photo: AI-generated image created by Prof. Blundell

Glutathione (GSH) is a powerful, water-soluble antioxidant composed of three amino acids: glycine, glutamate and cysteine. Found in the cytoplasm of every cell, glutathione exists in two states: reduced (GSH) and oxidised (GSSG). It plays a crucial role in protecting cells from oxidative stress by neutralising reactive oxygen species (ROS) and maintaining cellular redox balance. In recent years, glutathione has garnered attention for its potential in managing neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS) and Huntington's Disease (HD).

The role of Glutathione in cellular health

Glutathione's primary function is to protect cells from oxidative damage. It accomplishes this by donating electrons to unstable molecules, thereby neutralising them. This antioxidant defence mechanism is vital for maintaining cellular integrity and function. Glutathione also plays a role in detoxifying harmful substances, regulating immune responses, and recycling other antioxidants such as vitamins C and E back to their active forms.

Moreover, glutathione is involved in various metabolic and biochemical processes, including protein and DNA synthesis, enzyme activation, and cellular signalling pathways. It helps in the biogenesis of iron-sulfur proteins and participates in thiol-disulfide exchange reactions, essential for redox regulation and maintaining protein structure and function.

Glutathione and neurodegenerative diseases

Neurodegenerative diseases are characterised by progressive loss of neuron function and structure. Oxidative stress, mitochondrial dysfunction and abnormal protein aggregation are common pathological features of these diseases. Glutathione depletion is a significant factor in the progression of neurodegenerative disorders, as it exacerbates oxidative damage and impairs cellular defence mechanisms.

Alzheimer's Disease (AD)

• Alzheimer's disease is marked by the accumulation of amyloid-beta plaques and tau tangles, leading to neuronal death.
• Studies have shown that glutathione levels are significantly reduced in the brains of AD patients. This depletion contributes to increased oxidative stress and amyloid-beta toxicity, further damaging neurons.
• Enhancing glutathione levels in AD patients could potentially mitigate oxidative damage and improve neuronal survival.

Parkinson's Disease (PD)

• Parkinson's disease primarily affects dopaminergic neurons in the substantia nigra, leading to motor symptoms such as tremors, rigidity and bradykinesia.
• Reduced glutathione levels in the substantia nigra have been linked to impaired antioxidant defences, mitochondrial dysfunction and increased vulnerability to oxidative damage.
• Glutathione supplementation or boosting endogenous production may protect dopaminergic neurons and slow the progression of PD.

Amyotrophic Lateral Sclerosis (ALS)

• ALS is characterised by the degeneration of motor neurons, leading to muscle weakness and atrophy.
• Mutations affecting glutathione metabolism and redox balance are associated with increased oxidative stress and motor neuron degeneration in ALS patients.
• Strategies to enhance glutathione levels could potentially protect motor neurons and improve patient outcomes.

Huntington's Disease (HD)

• Huntington's disease is a genetic disorder that causes the progressive breakdown of nerve cells in the brain, leading to movement disorders, cognitive decline and psychiatric symptoms.
• Dysregulation in glutathione synthesis and redox balance is observed in HD, contributing to increased oxidative stress and neuronal damage.
• Boosting glutathione levels may help mitigate oxidative damage and improve neuronal function in HD patients.

Nutritional approaches to boost glutathione

Direct supplementation of glutathione is challenging due to its poor bioavailability and inability to cross the blood-brain barrier. Therefore, alternative strategies focus on enhancing the body's natural glutathione production through dietary modifications and supplementation with glutathione precursors.

Glutathione Precursors

• N-Acetylcysteine (NAC): NAC is a well-known glutathione precursor that supplies cysteine, the rate-limiting amino acid in glutathione synthesis. It has shown promise in protecting against neurotoxicity in animal models, though its benefits in human trials are less evident.
• γ-Glutamylcysteine: This compound is another precursor that can enhance glutathione synthesis. Like NAC, it has demonstrated neuroprotective effects in preclinical studies.

Dietary Modifications

• Certain food and nutrients can boost the body's natural glutathione production by activating the Nrf2 pathway, a key regulator of cellular antioxidant response.
• Foods rich in specific plant-based compounds and antioxidants have been shown to support glutathione levels. These include:

1.      Kaempferol: Found in kale, beans, tea, spinach and broccoli. Kaempferol has antioxidant properties that support glutathione production.

2.      Niga-ichigoside F1: This compound, found in the leaves of Rubus suavissimus, has shown potential in enhancing glutathione levels.

3.      Salacia chinensis extracts: Traditionally used for their health benefits and support in glutathione production.

4.      Hydroxytyrosol: A phenolic compound found in olives and olive oil, hydroxytyrosol has strong antioxidant properties.

5.      Curcumin: The active ingredient in turmeric, curcumin, can boost glutathione levels and has anti-inflammatory effects.

6.      Omega-3 fatty acids: Found in fish oil, it can support overall cellular health and glutathione production.

7.      Chicoric acid: Present in chicory and other plants, and has antioxidant properties that can enhance glutathione levels.

8.      Polyunsaturated fatty acids: These fatty acids, found in nuts, seeds and fish, can help maintain cellular health and support glutathione synthesis.

Vitamins

• Certain vitamins play indirect roles in maintaining glutathione balance by modulating related metabolic processes. These include:

1.    Vitamin A: Supports overall immune function and cellular health

2.    Vitamin E: Works synergistically with glutathione to protect cells from                   oxidative damage

3.    Vitamin C: Helps recycle oxidised glutathione back to its active form

4.    Vitamin B3 (Niacin): Plays a role in energy metabolism and can support

 glutathione production.

Conclusion

Glutathione is a critical antioxidant that plays an indispensable role in cellular health and defence against oxidative stress. Its significance is particularly evident in the context of neurodegenerative diseases, where glutathione depletion is a common pathological feature. By protecting neurons from oxidative damage, glutathione has the potential to slow the progression of diseases like Alzheimer's, Parkinson's, ALS and Huntington's.

While direct supplementation of glutathione poses challenges, leveraging nutritional approaches to boost its levels offers a promising strategy for supporting brain health. Incorporating glutathione precursors, antioxidant-rich foods, and essential vitamins into the diet can enhance the body's natural defence mechanisms and potentially improve outcomes for individuals suffering from neurodegenerative disorders.

Future research should continue to explore the therapeutic potential of glutathione and related compounds, aiming to develop effective interventions that harness its powerful antioxidant properties. As our understanding of glutathione's role in health and disease deepens, we can look forward to innovative treatments that enhance human health and combat the debilitating effects of neurodegenerative diseases.

Renald Blundell is a biochemist and biotechnologist with a special interest in Natural and Alternative Medicine. He is a professor at the Faculty of Medicine and Surgery,

University of Malta

Kira Copperstone is currently a medical student at the University of Malta