Molecular Hydrogen as a Neuroprotectant

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A potential new treatment for neurodegenerative diseases

Neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), Alzheimer’s disease (AD), and Huntington’s disease (HD), among others, are often associated with oxidative stress and neuroinflammation.[1],[2] In each of these diseases, there are similarities in the role of genetics, neurotransmitters, accumulation of toxic proteins, membrane damage, and mitochondrial dysfunction.[3],[4],[5] Especially important among these parameters is the dysfunction of mitochondria and excess oxidative stress which can result in severe nerve cell dysfunction, reducing the number of cells in the brain and spinal cord by apoptosis (programmed cell death).[3],[4],[6],[7] On a larger scale, this leads to the progressive and gradual loss of motor and cognitive function, the hallmark characteristics of neurodegenerative diseases.[8] Treatment for these conditions is minimally successful at best, but emerging data suggests antioxidant agents may improve outcomes in neurodegenerative disorders through a reduction of oxidative stress and neuroinflammation[9],[10],[11],[12]

Emerging data suggests antioxidant agents may improve outcomes in neurodegenerative disorders through a reduction of oxidative stress and neuroinflammation.

Molecular hydrogen (H₂), a colorless, odorless, tasteless, non-toxic gas, is the lightest and most abundant element in the universe. Originally thought to be inert and non-functional, this basic molecule may be a potential solution to numerous pathologies that are largely due to oxidative stress and chronic inflammation.[13],[14],[15] With more than 450 publications, reflecting over 170 different human and disease models, a broad range of clinical applications are beginning to surface – particularly in the realm of neurodegenerative disease.

Hydrogen’s “selective” antioxidant and anti-inflammatory properties

Oxidative stress and neuroinflammation are major contributing factors to central nervous system (CNS) disease such as dysfunction following brain injury, neurodegenerative disorders, psychiatric conditions, and other disease.[1] Oxidative stress arises from the strong cellular damaging potential of excess reactive oxygen species (ROS).[2],[16],[17] It is worth noting, however, that not all ROS are damaging to the body, and some are actually vital to physiological processes. For example, superoxide and hydrogen peroxide (H₂O₂) play important roles at low concentrations: they function as regulatory molecules that are involved in numerous signal transduction cascades and biological processes such as apoptosis and cell proliferation and differentiation.[18],[19] Nitric oxide (NO), another ROS, functions as a neurotransmitter and is essential for the dilation of blood vessels.[20]

The hydroxyl radical (OH^–), on the other hand, is one of the strongest of the oxidant species and reacts indiscriminately with nucleic acids, lipids, and proteins. Thus, scavenging this particular ROS is critical for the body, especially for many degenerative conditions.[21] In an important study in 2007, Ohsawa et al. demonstrated that molecular H₂, rather than being a strong reducing agent, is actually a weaker and more selective reducing agent.[22],[23] This means it reacts primarily with highly reactive and more toxic oxidants, leaving weaker (and biologically necessary) oxidants like NO and H₂O₂ present.

These and other characteristics of H₂ are particularly important to the CNS for several reasons:

• The brain, compared to other organs, is particularly vulnerable to oxidative stress due to the fact that antioxidant defenses are relatively low despite its high oxygen consumption.[24],[25]
• ROS are an important factor contributing to the development and progression of neurodegenerative diseases such as PD, AD, HD, ALS, and multiple sclerosis. ROS-induced mitochondrial damage, in particular, is associated with the onset of PD and AD.[3]
• Because of its size, neutral charge, nonreactivity, and non-polarity, H₂ readily passes through membranes (e.g., cellular membranes and the blood-brain barrier [BBB]), and into all cellular compartments and biological tissues (evidenced in part by its rapid appearance in the expired air from the lungs).[26] This means it can reach not only the cytoplasm of the neurons in the brain, but also their nucleus, mitochondria, and other organelles – all of which are susceptible to damage and altered function due to the damaging effects of ROS.

Numerous preclinical studies have shown these properties of H₂ may be beneficial for CNS disease and other pathologies. In 2007, research findings published in Nature Medicine showed that inhaled H₂ substantially decreased damage to the brain associated with ischemia/reperfusion injury.[22] In stressed cells, H₂ dissolved in a cellular nutrient medium also was shown to be protective, reducing the amount of OH^– radicals generated in both the cytoplasm and nucleus of the cells. It additionally was shown to protect the DNA from oxidation and cellular membranes from peroxidation, thus defending against apoptosis in a dose-dependent fashion.

The brain, compared to other organs, is particularly vulnerable to oxidative stress due to the fact that antioxidant defenses are relatively low despite its high oxygen consumption.

To further clarify the mechanism of H₂‘s effect in the brain, Sato et al. (2008) demonstrated that the administration of H₂-rich water dramatically attenuated superoxide formation in the brain during hypoxia-reoxygenation treatment.[27] (In excess, superoxide is damaging and may contribute to numerous diseases.) Authors of this study proposed that the decrease in superoxide may be due to the ability of H₂ to readily permeate cellular membranes (including that of the mitochondria and nucleus), reducing superoxide production by the mitochondria and protecting DNA from damage by ROS, also influencing gene transcription.[22],[27],[28]

Neuroinflammation occurs in a variety of physiological settings, such as infection, traumatic brain injury, toxin exposure, and autoimmunity.[29] Although the CNS had been thought to be an immune-privileged site protected by the BBB, some cytokines and chemokines, such as interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and chemokine (C-C motif) ligand 2 (CCL2), are known to be transported across the BBB contributing to widespread neuroinflammation.[30],[31] Many of these mediators of inflammation also have been shown to increase BBB permeability – making a bad situation even worse.[32]

What is interesting is that H₂, in addition to its established antioxidant properties, can also function as an anti-inflammatory by down-regulating the expression of these and other pro-inflammatory factors.[33],[34],[35],[36] H₂ also has been shown to play an important role in blood vessel formation which is necessary for the growth of new neurons and the connections between them[37],[38] – all things that are crucial for the healthy function and repair processes of the brain.

Alzheimer’s and Parkinson’s disease

Importantly, the CNS-protective effects of H₂ shown in preclinical research translate to improvements seen clinically in neurodegenerative disease. A double-blind, placebo-controlled pilot study investigated the therapeutic efficacy of consuming 500 mL of H₂-saturated water twice per day for 48 weeks in levodopa-medicated PD patients. A significant improvement in total UPDRS (Unified Parkinson’s Disease Rating Scale) scores for patients in the H₂‐water group was demonstrated whereas UPDRS scores in the placebo group worsened, as is typical for a neurodegenerative condition such as PD.[39] The consumption of H₂‐saturated water was also safe and well tolerated. These promising findings have prompted a larger, multicenter 72-week study (not yet completed) investigating the impact of H₂-rich water on this population.[40]

Parkinson’s patients receiving 500 mL of H₂-saturated water twice daily for 48 weeks had significant improvements in disease scores compared to placebo.

To further elucidate molecular H₂‘s potential role as a neuroprotective agent, Tan et al. (2018) reviewed the research concerning the role H₂ may play in the pathological processes contributing to AD.[41] In several animal models, treatment with H₂-rich water had a favorable impact on cognition, memory, neuroplasticity, and over-all brain function.[1],[2],[41],[42],[43] Consumption of H₂ water prevented the decline of cognition, maintaining healthy levels of proliferation of neuronal progenitors, and inhibited oxidative stress after physical and mental stress in a mouse model of dementia.[44] In an animal model of amyloid-beta-induced AD, treatment with H₂-rich saline reduced neuroinflammation and oxidative stress, improving memory function.[45] Another study concluded that consumption of H₂ water for 30 days also prevented amyloid-beta induced neuroinflammation and oxidative stress, possibly by attenuation of activation of c-Jun NH₂-terminal kinase (JNK) and nuclear factor-κB (NF-κB).[46]

There have been promising results suggesting that treatment with H₂-rich water may help reduce decline in humans with AD as well, at least in populations with a higher genetic risk of developing the disease. In a randomized double-blind placebo-controlled study, 73 subjects with mild cognitive impairment (MCI) drank approximately 300 mL of H₂-water or placebo water per day, with the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) scores assessed at baseline and after one year.[47] Although the group as a whole didn’t show a significant improvement over the placebo group in the parameters assessed, the subpopulation within the group having the APOE4 genotype variant (an established genetic risk factor for AD[48]) had significant improvements in their ADAS-cog scores as well as word recall scores.

In several animal models, treatment with H₂-rich water had a favorable impact on cognition, memory, neuroplasticity, and over-all brain function.

Additional mechanism of action for molecular hydrogen

Another potential mechanism via which consumption of H₂-rich water may deliver neuroprotective benefits also is worthy of mention. Ghrelin, a peptide hormone well known for its role in appetite and energy homeostasis, also has known neuroprotective effects.[49] It has been demonstrated that the receptor for ghrelin, growth hormone secretagogue receptor (GHSR), is highly expressed by the dopaminergic neurons of the substantia nigra (a region of the brain that experiences loss of function in PD).[50] Ghrelin has been shown to exert neuroprotective effects in PD by inhibiting activation of microglial cells (a type of immune cell in the CNS), reducing neuroinflammation and improving mitochondrial function.[51]

In a study published by Matsumoto et al. (2013), it was demonstrated that H₂-rich water induced gastric secretion of the hormone ghrelin.[52] Further supporting this, it was shown that neuroprotective efficacy of H₂ water was abolished by blocking activation of the ghrelin receptor (GHSR) and by blocking ghrelin secretion. Thus, findings that oral H₂ water exerts a neuroprotective effect through activation of the endogenous gastric ghrelin system further supports the role molecular H₂ may have in PD and other related neurodegenerative conditions.[2],[50],[51],[52]

Findings that oral H₂ water exerts a neuroprotective effect through activation of the endogenous gastric ghrelin system further supports the role molecular H₂ may have in PD and other related neurodegenerative conditions.

Given molecular H₂‘s properties as a selective antioxidant and anti-inflammatory agent and its unique ability to diffuse into all regions of the cell and all tissues (including through the blood-brain barrier), a wide array of potential health benefits exist, particularly in conditions affecting the CNS. The rapidly growing body of research on this easily administered molecule clearly makes it an exciting therapeutic agent to study in all realms of physiology and disease.

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