Melatonin And Strokes: What's The Connection?

Melatonin is a neurohormone produced by the pineal gland and extra-pineal tissues such as the retina, gut, bone marrow, kidney, astrocytes, platelets, and glial cells. It is well known for its role in regulating sleep and mood behaviour. Melatonin has also been implicated in various neurological diseases due to its antioxidative, antiapoptotic, and anti-inflammatory properties.

Stroke is one of the most devastating neurological disabilities, and the brain's vulnerability to it proves to be fatal and a socioeconomic loss for millions of people worldwide. Ischemic stroke, caused by a blockage in a brain artery, accounts for 85% of all stroke cases and is the second leading cause of death worldwide. Hemorrhagic stroke, on the other hand, is caused by bleeding in the brain and accounts for 15% of all stroke cases.

Melatonin has been found to have neuroprotective effects against stroke, particularly ischemic stroke. Its role as a free radical scavenger and an antioxidant makes it a potent antioxidant that can protect brain cells from injury. Melatonin can reduce brain cell and neuronal death following hemorrhagic strokes and improve patient outcomes. It has also been found to improve motor skills and reduce infarct size in a rat model of acute ischemia.

While melatonin has shown promising results in reducing stroke damage, more research is needed to establish it as a standard treatment for stroke patients.

Melatonin is a neurohormone secreted by the pineal gland and extra-pineal tissues

Melatonin is synthesised from tryptophan, with the rate of its synthesis depending on the activity of two enzymes: serotonin N-acetyltransferase and tryptophan hydroxylase. Tryptophan is converted into 5-hydroxytryptophan, which then forms serotonin with the help of an enzyme called aromatic amino acid decarboxylase. Serotonin is then converted into N-acetylserotonin, which is the main step in melatonin formation. Finally, N-acetylserotonin is converted into melatonin by the enzyme hydroxyindole O-methyltransferase.

Melatonin is released directly into the peripheral circulation and the cerebrospinal fluid without being stored. It is metabolised in the liver and converted into 6-hydroxymelatonin, which is then excreted in urine.

Melatonin has been implicated in various physiological processes, including sleep and mood behaviour, and has been used in therapies for several decades. It has been found to have anti-inflammatory, antioxidant, and anticoagulopathic properties, as well as protective effects on the vascular endothelium. Melatonin has also been shown to have protective effects in various in vitro and in vivo models of neurodegenerative diseases.

Melatonin has been studied as a potential treatment for Ebola virus, with its anti-inflammatory, antioxidant, and anticoagulopathic properties, as well as its protective effects on the vascular endothelium, thought to be particularly relevant to the pathogenetic mechanisms of Ebola virus infection.

Melatonin has been found to be beneficial in several animal models of stroke

Melatonin has been found to be effective in reducing oxidative stress, promoting mitochondrial function, decreasing excitotoxicity, suppressing inflammation, and diminishing apoptosis. It can scavenge free radicals and increase the activity of antioxidant enzymes. It also stimulates the activity of NADH-coenzyme Q reductase and cytocrhome c oxidase in the electron transport chain of mitochondria, reducing electron leakage and free radical production and maintaining normal adenosine triphosphate (ATP) production.

Melatonin has also been found to reduce cerebral inflammation and infiltration of immune cells after cerebral hypoxia/ischemia. It decreases microglial/macrophage activation and reduces immune cell infiltration to the ischemic hemisphere. It also suppresses the mRNA and protein expression of tumour necrosis factor-α and intercellular adhesion molecule-1 in colon tissues.

In addition, melatonin reduces apoptosis after stroke by restoring the injury-induced reduction in phosphorylated AKT, p-Bad and Bcl-XL levels, and the binding of p-Bad and 14-3-3, as well as decreasing caspase-3 activation. It also suppresses the immunoreactivity of cytosolic cytochrome c oxidase in the ischemic cortex.

Melatonin has also been found to have long-term effects, with beneficial effects observed 120 days after global ischemia. It has been shown to counteract the pathophysiological damage caused by ischemia in the long run by preserving neuronal cells and maintaining the cytoarchitecture of dendrites.

Melatonin is a free radical scavenger and an antioxidant

The N-C=O structure in the C3 amide side chain is the functional group. The carbonyl group in the structure of N-C=O is key for melatonin to scavenge the second reactive species, and the nitrogen in the N-C=O structure is necessary for melatonin to form the new five-membered ring after its interaction with a reactive species. The methoxy group in C5 appears to keep melatonin from exhibiting prooxidative activity.

The mechanisms of melatonin's interaction with reactive species probably involve the donation of an electron to form the melatoninyl cation radical or through a radical addition at the site C3. Other possibilities include hydrogen donation from the nitrogen atom or substitution at position C2, C4 and C7 and nitrosation. Unlike classical antioxidants, melatonin is devoid of prooxidative activity, and all known intermediates generated by the interaction of melatonin with reactive species are also free radical scavengers. This phenomenon is defined as the free radical scavenging cascade reaction of the melatonin family. Due to this cascade, one melatonin molecule has the potential to scavenge up to 4 or more reactive species.

Melatonin also has the ability to repair damaged biomolecules, as shown by the fact that it converts the guanosine radical to guanosine by electron transfer. It was shown that melatonin reduced the formation of 8-hydroxy-2′-deoxyguanosine (8-OH-dG), a damaged DNA product, 60–70 times more effectively than some classic antioxidants (ascorbate and α-tocopherol).

Melatonin is a direct and indirect antioxidant. It can directly detoxify both reactive oxygen, including hydroxyl radical, hydrogen peroxide and singlet oxygen, and nitrogen species, such as nitric oxide, peroxynitrite anion, and peroxynitrous acid. It also has the ability to indirectly reduce oxidative stress by increasing the activities of antioxidative defence systems, stimulating the expression and function of a number of antioxidant enzymes, as well as glutathione, another very important non-enzymatic, low molecular weight antioxidant. It interacts synergistically with other antioxidants, and increases the efficiency of the mitochondrial electron transport chain.

Melatonin's antioxidant properties are enhanced by its metabolites, which are also free radical scavengers. The sequential scavenging of ROS by melatonin and its metabolites is known as melatonin's antioxidant cascade. The efficiency of AMK for scavenging ROS and preventing protein oxidation has been reported to be higher than that of AFMK. Therefore, it seems that at least in general, their protective activities against oxidative stress follow the order AMK > melatonin > AFMK.

Melatonin also has a chelating property, which may contribute to reducing metal-induced toxicity. It was demonstrated that the interplay of melatonin with metals such as aluminium, cadmium, copper, iron, lead, and zinc depended on concentration. Melatonin chelates both iron(III) and iron(II), which is the form that attends the Fenton reaction. If iron is bound to a protein (e.g., haemoglobin), melatonin restores the highly covalent iron such as oxyferryl (FeIV-O) haemoglobin back to iron(III), thereby re-establishing the biological activity of the protein. It is suggested that, under physiological circumstances, direct chelation mechanism would be the major chelation route for Cu(II). It was demonstrated that melatonin and its metabolites, 3OHM, AFMK, and AMK, fully inhibited the oxidative stress induced by Cu(II)-ascorbate mixtures, via Cu(II) chelation. Melatonin decreases the Cu(II)/H2O2-induced damage to proteins and protects against copper-mediated lipid peroxidation, which led to the suggestion that the antioxidant and neuroprotective effects of melatonin may involve removing toxic metals from the central nervous system.

Melatonin can be used to regulate oxidative stress and inflammation in the brain

Melatonin is a neurohormone secreted by the pineal and extra-pineal tissues, responsible for various physiological processes like sleep and mood behaviour. It has been implicated in various neurological diseases because of its antioxidative, antiapoptotic, and anti-inflammatory properties.

Oxidative stress plays a pivotal role in the pathophysiology of traumatic brain injury (TBI). TBI induces oxidative and nitrosative stress, which is involved in the progression of chronic and acute neurodegenerative diseases. Melatonin has shown regulatory effects against the TBI-induced autophagic dysfunction, regulation of mitogen-activated protein kinases, such as ERK, activation of the NLRP-3 inflammasome, and release of the inflammatory cytokines.

Melatonin is a potent antioxidant in brain injury-induced neurodegeneration. It has been well documented that oxidative stress is involved in ischemic injury, especially after reperfusion. Melatonin is effective as an antioxidant in various in vitro and in vivo models of neurodegenerative diseases not only by scavenging free radicals but also by increasing the gene expression of antioxidative enzymes like GPx, GR, and SOD.

Melatonin can also regulate the activation of the immune system, reducing chronic and acute inflammation. Melatonin exerts its anti-inflammatory effects by modulating both pro- and anti-inflammatory cytokines in various pathophysiological situations. Since different cytokines are associated with inflammatory diseases, wherein the balance between proinflammatory and anti-inflammatory molecules determines the clinical outcome to some degree, melatonin could modulate serum inflammatory parameters.

Melatonin exerts its antiapoptotic activities mainly by blocking caspase 3 cleavage and mPTP opening.

Melatonin may be able to prevent more brain damage by protecting neurons occupying the ischemic penumbra

Melatonin is a naturally-occurring indole and antioxidant primarily produced by the pineal gland. It is both lipid- and water-soluble and can readily cross the blood-brain barrier. Melatonin has been shown to significantly reduce infarct volume, edema, and oxidative damage, as well as improve electrophysiological and behavioural performance in animal stroke models.

Melatonin has been shown to reduce brain damage by reducing oxidative stress, promoting mitochondrial functions, decreasing excitotoxicity, suppressing inflammation, and diminishing apoptosis. Melatonin can also inhibit the expression of apoptotic factors, such as cytochrome c and apoptosis-inducing factor (AIF). In addition, melatonin can reduce the expression of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), which are involved in endoplasmic reticulum stress.

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