Methylene blue (MB), as the first fully man-made medicine, has a wide range of clinical applications. Apart from its well-known applications in surgical staining, malaria, and methemoglobinemia, the anti-oxidative properties of MB recently brought new attention to this century-old drug. Mitochondrial dysfunction has been observed in systematic aging that affects many different tissues, including the brain and skin. This leads to increased oxidative stress and results in downstream phenotypes under age-related conditions. MB can bypass Complex I/III activity in mitochondria and diminish oxidative stress to some degree. MB also shows broad spectrum UV absorption capability.
MB is highly lipophilic and able to effectively cross the blood-brain barrier (BBB) . MB concentration is found to be higher in the brain than in plasma after oral administration or intravenous injection in rats . Besides, it has a strong affinity for mitochondria . Different from the other antioxidants such as MitoQ and MitoVitE, MB can reduce the production of free radicals by bypassing Complex I/III activity rather than scavenging free radicals . In fact, the membrane potential in Complex III-inhibited mitochondria can be partially restored by MB in both mice and rats . MB, acting as an electron donor, can also increase the expression of brain cytochrome oxidase and oxygen consumption in vivo . Besides, low doses of MB were shown to effectively inhibit nitric oxide (NO), which inhibits cytochrome c oxidase activity . All these properties make MB a promising drug candidate for brain diseases’ treatment.
Several studies suggest that there is an association between mitochondrial dysfunction and abnormal processing of Aβ and tau . Amyloid precursor protein (APP) can be trapped in the mitochondrial membrane and impair mitochondrial function . Overexpression of tau can also result in mitochondrial dysfunction by decreasing ATP production and increasing oxidative stress . Conversely, the damaged mitochondrial function can induce aberrant Aβ production and promote abnormal phosphorylation of tau . MB was reported to prevent Aβ and tau aggregation or dissolve existing aggregates via autophagic clearance, and therefore alleviate downstream pathological consequences . MB could directly or indirectly target β-secretase cleavage of amyloid precursor protein (APP) and regulate the generation of Aβ . MB’s role in Aβ and tau aggregation clearance may help improve mitochondrial functions in Alzheimer's Disease (AD) neurons and thus contribute to AD treatment. Besides, cytochrome oxidase activity has been shown to decline in AD , while MB can increase the enzymatic activity of cytochrome oxidase, which results in an increased oxidative metabolic capacity of neurons .
Parkinson's Disease (PD) is another neurodegenerative disease associated with aging. It is one of the most common movement diseases featured by dopaminergic neuronal damage . The pathological hallmark of PD is Lewy Bodies and Lewy Neurites, intracellular aggregates of the protein α-synuclein (α-syn) . A-syn can lead to progressive mitochondrial dysfunction when translocated to the mitochondria . Mitochondrial dysfunction is considered the primary cause of dopaminergic apoptosis via inducing oxidative stress in PD . Based on MB’s role in improving mitochondrial function, MB could be a promising treatment in PD.
In addition to its beneficial role in age-related brain disorders, MB is a promising memory enhancer. Since metabolic derangement is observed in old brains, and mitochondrial impairment accumulates over time, improving mitochondria may help neurons maintain their health and improve their functions .
Oxidative stress is involved in both intrinsic and extrinsic skin aging [83 ]. Especially when skin is exposed to certain environmental risk factors such as UV radiation, increasing oxidative damage will decrease collagen synthesis and increase collagen breakdown, leading to accelerated aging. Antioxidants such as MB can protect skin and slow down the aging process (Figure 2).
A previous study has shown that MB treatment in normal fibroblasts could increase lifespan and cell proliferation while reducing aging markers . In that study, MB increased cytochrome oxidase by 30%, enhanced oxygen consumption by 37–70%, and reversed premature senescence caused by H2O2 or cadmium, and the ratio MB/cytochrome c could be important for MB’s protective role. Interestingly, when MB was compared with common antioxidants used in skincare, including vitamin C and retinol (vitamin A), MB-treated skin cells outperformed both of them significantly in terms of promoting cell proliferation and reducing age-related markers . In addition to its potent antioxidant function, MB treatment in skin fibroblasts could stimulate the expression of ECM proteins, including upregulation of elastin and collagen 2A1, the two vital proteins for healthy, youthful skin . Another study showed that MB provides broad-spectrum absorption of UV rays and mitigates DNA double-strand breaks caused by UVB irradiation in human keratinocytes . Together, this evidence supports MB as protective and beneficial to human skin, suggesting that the inclusion of MB in daily skincare may effectively delay photoaging.
MB can facilitate wound healing. During aging, the proliferation and migration of fibroblasts are often decreased, and collagen and elastin in the ECM are degraded . Therefore, the repair capabilities of the skin decline due to structural and functional changes. Our study indicated that MB treatment could promote fibroblast migration and proliferation in the wound healing process . In skin survival burn models in rats, MB treatment could reduce necrosis progression, which might be mediated by decreasing oxidative stress through blocking nitric oxide (NO) . Moreover, MB can facilitate wound healing by reducing antimicrobial burden and decreasing hyper-granulation. MB also has a drying effect without harming healthy cells . Overall, MB was shown to improve tissue viability with little to no irritation in laboratory models.