December 2022
Wang J, Gao S, Lenahan C, et al. Melatonin as an Antioxidant Agent in Stroke: An Updated Review. Aging Dis. 2022;13(6):1823-1844. Published 2022 Dec 1. doi:10.14336/AD.2022.0405
Overview
This updated review, including animal and human clinical studies, reports on melatonin’s use as an antioxidant in ischemic or hemorrhagic stroke. Oxidative stress plays a role in the pathogenesis of stroke but also contributes to factors that contribute to damage of the brain including inflammation, brain edema, and neuronal death. The study reviews the connection between oxidative stress and stroke as well as melatonin’s role as an antioxidant and its neuroprotective actions in stroke.
Our comments/takeaway from the article
While this article provides a deeper explanation of the role of oxidative stress in the pathophysiology of stroke, we are focused on details reported on the potential use of melatonin for stroke. Our main takeaway from this article is that melatonin continues to be highlighted in the literature for its antioxidant properties. The findings in the animal studies and limited human clinical trials are promising, though, we agree with the authors, that more studies are needed to determine the proper clinical application of melatonin in stroke patients.
Article summary
Free radicals can be divided into two groups, reactive oxygen species (ROS) and reactive nitrogen species (RNS). Antioxidants counteract free radicals. Enzymatic antioxidants include superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and thioredoxin (Trx). Non-enzymatic antioxidants include vitamin C, vitamin E, glutathione, coenzyme Q10, and melatonin.
Oxidative stress occurs when the body is unable to maintain balance between the generation of ROS/RNS and the antioxidant system to detoxify them. This results in DNA damage, lipid peroxidation, protein dysfunction, and harmful signaling pathways that can lead to mitochondrial damage, inflammation, and apoptosis. The brain is vulnerable to oxidative stress and following a stroke, the over-production of ROS/RNS causes further damage to the brain, including inflammation, brain edema, and neuronal death.
(This image, “Figure 1” by Wang, J, et al. is licensed under CC BY 4.0. / Original work)
Melatonin is a well-known antioxidant that easily crosses the blood-brain-barrier (BBB), making it a unique compound of interest in research. Melatonin’s mechanisms of action as an antioxidant include:
Directly scavenging ROS/RNS
Activating antioxidant systems. (Melatonin can contribute to maintaining glutathione levels.)
Targeting mitochondria (Scavenging free radicals produced by the mitochondria, reducing oxidative stress within the mitochondria and therefore reducing cellular death.)
Melatonin also:
Binds to heavy metals- including binding to iron to block Fenton reaction and assists metallothionine with heavy metal detoxification.
Has anti-inflammatory properties- inhibiting NF-kB activation and upregulating Nrf2.
Reduces apoptosis- by inhibiting cytochrome c (Cytc)-an apoptotic protein produced in the mitochondria.
In the manuscript, Table 1 provides a summary of the animal studies reviewed. It is important to note that the timing that melatonin was administered as well as the dose that was used was variable.
Melatonin and Ischemic Stroke
Ischemic stroke is the most common type of stroke (62.4%) that is caused by a blood clot that blocks blood flow to the cerebral artery. Animal models have shown beneficial effects in using melatonin as a preventative therapy to provide neuroprotection by reducing oxidative stress and enhancing antioxidant systems during an ischemic event. Melatonin has also been used following an ischemic stroke, reducing apoptosis and reducing inflammation. Further, long-term use of melatonin following a stroke has been shown to improve cognition.
Melatonin and Hemorrhagic Transformation
Hemorrhagic transformation (HT) occurs when blood flow is restored to the damaged vasculature following an ischemic stroke, resulting in bleeding. This event leads to increased stroke morbidity and mortality, as well as neuronal damage. Unfortunately, the drug treatment (tPA) for ischemic stroke can lead to an increased risk of HT. In animal models, when melatonin was given in combination with tPA, there was a reduction in neuronal damage, reduction in BBB permeability, and reduced risk of an HT following tPA administration.
Melatonin and Intracerebral Hemorrhage
Intracerebral hemorrhage (ICH) accounts for 27.9% of all strokes. In animal and in vivo studies melatonin has been shown to reduce brain water content, inhibit oxidative stress, reduce inflammation and apoptosis, attenuate mitochondria and BBB damage while also promoting the antioxidant system. Further, it protected oligodendrocytes and astrocytes from oxidative stress and can attenuate hyperglycemia-induced brain injury.
Melatonin and Subarachnoid Hemorrhage
Subarachnoid Hemorrhage (SH) accounts for 9.7% of all strokes. This type of stroke results in a high mortality rate and poor prognosis, with either early brain injury (within 72 hours) or delayed brain injury (occurring after the aneurysm has been treated). In animal models, melatonin has been shown to regulate cell death process (apoptosis, autophagy, and mitophagy), decrease the inflammatory response, and decrease brain edema, while also reducing oxidative stress.
Human Clinical Studies
While the use of melatonin in stroke patients is still being explored, there are some studies that provide possible clinical usefulness in the application of melatonin. Table 2 of the manuscript provides a summary of the articles included in this review. Highlights include:
Retrospective study of 300 patients treated with 2 mg per day (at night) melatonin- Significant reduction in post-stroke delirium
RCT of 20 patients treated with 30 mg per day (at night) melatonin- Shorter mechanical ventilation and ICU stays
RCT of 26 patients treated with 3 mg per day (at night) melatonin-Shorter mechanical ventilation use, reduced morphine use, and quicker improvements in Glasgow Coma Scale (GCS) scores
Retrospective study of 39 patients treated with 3-6 mg per day (at night) melatonin- No changes in mortality or incidences of delayed cerebral ischemia (DCI)
Several studies also reported that higher levels of serum melatonin levels were associated with the mortality of patients. The authors provide this explanation,
“...some researchers speculate that patients with more severe brain damage can subsequently trigger more severe oxidative stress, which is the origin of higher oxidant species production and higher serum melatonin levels (the activation of the endogenous antioxidative system attempting to maintain redox homeostasis). Therefore, endogenous melatonin may rise as a secondary factor from the primary brain injury.”
It is suggested that high serum levels may be used as a potential predictor of outcomes following a stroke. Additionally, one study also noted that high levels of 6-sulfatoxymelatonin (a melatonin metabolite measured in the urine), were indicative of post-stroke cognitive impairment in an elderly population (>60 yo).
In summary
The authors of this review conclude that while melatonin shows to be a promising antioxidant in stroke therapy, the current evidence is insufficient to determine the use of melatonin for this clinical application. They suggest additional human studies should be conducted to help determine:
The therapeutic time to administer melatonin (within 1-2 hours of insult with ongoing administration following)
The optimal dose of melatonin
The optimal time of the day to administer melatonin for this purpose, including consideration for exposure to artificial light when in the hospital and this effect on melatonin production by the pineal gland.
The optimal route of delivery (oral, injection, IV)
Its use as an add-on to tPA therapy and risk reduction for HT
Its use as a preventative supplement for those at high risk of stroke
Article review completed by Kim Ross, DCN
Content reviewed by Deanna Minich, PhD
December 18, 2022