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Abstract

Melatonin (N-acetyl-5-methoxytryptamine) is a hormone derived from the pineal gland that has a wide range of clinical applications. While melatonin was originally assessed as a hormone specializing in regulation of the normal circadian rhythm in mammals, it now has been shown to be an effective free radical scavenger and antioxidant. Current research has focused on central nervous system (CNS) disorders, stroke in particular, for potential melatonin-based therapeutics. As of now, the realm of potential therapy regimens is focused on three main treatments: exogenously delivered melatonin, pineal gland grafting, and melatonin-mediated stem cell therapy. All therapies contain both costs and benefits, and current research is still focused on finding the best treatment plan. While comprehensive research has been conducted, more research regarding the safety of such therapies is needed in order to transition into the clinical level of testing. Antioxidants such as traditional Chinese medicine, (–)-epigallocatechin-3-gallate (EGCG), and lavender oil, which have been used for thousands of years as treatment, are now gaining recognition as effective melatonin treatment alternatives. This review will further discuss relevant studies assessing melatonin-based therapeutics and provide evidence of other natural melatonin treatment alternatives for the treatment of stroke.

Keywords

Melatonin Pineal gland Antioxidant Neuroprotection Melatonin receptors Dementia

Introduction

In recent years, melatonin has proven to be both a versatile and an effective source of clinical therapy. Derived from the pineal gland, melatonin's principal function is to regulate the normal circadian rhythm in mammals (63). Normally secreted at night, melatonin serves as an essential element in maintaining a normal light–dark cycle (2). However, in recent years, melatonin has been found in other various locations in mammals, which suggest that melatonin may have additional diverse actions. These locations include bile (69), cerebrospinal fluid (65), the anterior chamber of the eye (77), and ovarian follicular fluid (60). Moreover, within the last two decades, it has been discovered that, in addition to its other regulatory functions, melatonin is an effective free radical scavenger and antioxidant.

The central nervous system (CNS) in particular is susceptible to oxidative stress for a variety of reasons. First, the brain interacts with a majority of the oxygen that is inhaled into the body with every breath (59). This significant exposure guarantees a higher probability of oxidation in comparison to more isolated tissues. Second, the brain contains a low concentration of antioxidant molecules (59). The cause of this low concentration is the physiological barrier that the blood–brain barrier creates (59). This mechanism drastically limits the amount of antioxidants that enter the brain and other parts of the CNS. Last, the brain possesses chemicals that when mixed together create an environment that allows for abundant oxidation. This includes the brain's high concentrations of iron, ascorbic acid (vitamin C), and polyunsaturated fatty acids, which all in turn promote oxidation processes (59). Coupled with oxygen, other conditions lead to excessive production of free radicals in organisms. These include exposure to ionizing or ultraviolet radiation, transient ischemia followed by reperfusion, physical or physiological stress, and a variety of additional toxins (15). Oxidative stress has been shown to increase the severity of stroke in particular. Delivering antioxidants, such as melatonin, to targeted areas in the CNS may potentially alleviate some of the oxidative-induced stress caused by radicals (68). Using melatonin as a therapy could be achieved with various methods including direct application of the melatonin hormone into the ischemic tissue or the application of melatonin-secreting cells into the stroke-induced areas (41). In the clinic, current stroke treatments target the ischemic penumbra with anticoagulants or thrombolytics to dissolve blood clots. However, these treatments are not backed by conclusive evidence of long-lasting motor and cognitive improvement (38). With stroke remaining a leading cause of death worldwide, many researchers still search for novel treatments to rescue the CNS following ischemia. This review will further discuss relevant studies on stroke animal models using melatonin as a therapeutic. Concluding discussion will highlight other alternative medicines that mimic melatonin and the challenges of implementing current research strategies in the clinic.

Neuroprotective Effects of Melatonin in the Ischemic Brain

Melatonin's potency as a free radical scavenger is a widely accepted mechanism for its neuroprotection. The drug is both a free radical scavenger and an indirect antioxidant (47). It scavenges hydroxyl radicals (generated via the Fenton reaction from hydrogen peroxide) and peroxynitrite anions (17). It reduces lipid peroxidation in the brain produced by intoxication of free radical-generating agents (49), and it blocks singlet oxygen-induced toxicity (9). These studies demonstrate melatonin's direct protection of neural tissue from free radical toxicity. The drug's protection against neurotoxicity and its positive effects following ischemia in experimental models are well documented.

Animal stroke models have contributed to proving melatonin as a potential therapeutic. In most experimental setups, stroke is induced to experimental rats that have had their pineal gland removed since this is known to cause a drastic reduction in circulating levels of melatonin (32). It has been demonstrated that after mice are treated with melatonin (5 mg/kg) at the beginning of reperfusion, ischemic areas are decreased in both the gray and white matter in the brain (37). Melatonin also has been seen to decrease the inflammatory response (39), blood–brain barrier permeability (14), and cerebral edema formation (33) in treated stroke animals. Pretreatment by intraperitoneal injection of melatonin (5 or 15 mg/kg in 1 ml saline) given 0.5 h before MCAO results in a significant decrease in the infarction volume compared to a lower and higher dose, 1.5 and 50 mg/kg, respectively (54). Equally important, melatonin receptor type 1A (MT1) increases amniotic epithelial cell proliferation through melatonin stimulation in experimental stroke setups, further supporting the key role of melatonin in affording neuroprotection and functional effects (30).

In vitro and in vivo data suggest melatonin acts as a protective agent for glial cells, leading to functional recovery in ischemic animals. In intravenously treated ischemic animals (5 mg/kg at reperfusion onset), inflammatory response is reduced compared to the vehicle-treated control, and the melatonin-treated animals also exhibit improved behavioral outcomes (39). Interestingly, the lateral aspect of the striatum still showed clear damage in these animals, suggesting that normalization of motor behaviors may only require protection of the cortex (39). In another study, melatonin protected against the secondary cell death processes but not the functional deficits associated with interruption of cerebral blood flow since no behavioral protection during the 1-h occlusion was observed with melatonin treatment before the arterial occlusion (63). In vitro replication of this study paralleled aspects of the cellular response to ischemic injury observed in vivo demonstrated by the survival of melatonin-treated astrocytes following serum deprivation or toxin exposure, 3-NP, and sodium nitroprusside (63). Still, in other studies, pretreatment has shown to reduce cerebral infarction volume (54).

Alterations in glial cells that accompany melatonin treatment remain underexplored. Laboratory evidence suggests that improved glial cell survival after melatonin treatment may protect injured neurons, as these cells secrete trophic factors such as glial cell line-derived neurotrophic factor (GDNF) with neuroprotective effects (73). Additionally, glial cells' maintenance of neuronal cell membrane homeostasis might be aided through the cells' enveloping action, their siphoning of excess potassium or improvement of water handling capacity, and through their service as an cystine/glutamate antiporter (45). The combined effect of glial cells' trophic factors, homeostasis maintenance, and anti-glutamate toxicity render these cells effective neuroprotectors. Melatonin's protective effects aid these cells in combating brain injury.

Pineal Gland Grafts in Stroke-Induced Animal Models

Research over the last two decades has provided evidence that cell replacement therapy or more specifically intracerebral transplantation may be effective to alleviate stroke (57). In 1998, the world experienced the first-ever clinical trial of a neural transplantation therapy for stroke. This trial used human-derived cells, which experienced neuronal characteristics and were transplanted near the ischemic area of the stroke (34). The goal was for the transplanted cells to grow and eventually replace the existing damaged brain cells (34). Fortunately, this trial led to promising data and a hope for a future of intracerebral transplantation therapy for stroke victims (52). Following this lead, recent research has been focused on intracerebral transplantation of pineal gland grafts and their efficacy in melatonin-based therapies. One particular study, using an acute stroke model, demonstrated that rats receiving rat-derived pineal gland allografts yielded better motor skills as well as a decrease in the infarction volume in comparison to the control rats that did not receive any transplants (8). Conclusions for this increase in neuroprotection are associated with the increase in melatonin levels in the cerebrospinal fluid (8). The concluding results of this trial and similar allograft studies coincided with the positive data in experiments where exogenous melatonin was administered (33).

One notable discrepancy from this trial and many similar to it resulted from the sample of rats that underwent a pinealectomy in conjunction with the allograft transplantation. This group in fact did not receive any additional neuroprotection like the other group of rats (8). The most probable explanation for this stems from the dramatic increase in melatonin levels. The transplantation of the graft in conjunction with the host pineal gland resulted in extremely elevated melatonin levels, which, in turn, proved to be more effective in neuroprotection. A pinealectomy, as a result, decreased the output of melatonin and did not hit the threshold level needed to provide effective neuroprotection (63). These findings suggest that pineal gland grafts may in fact be a more effective treatment plan than the exogenous delivered melatonin because the grafts supply a steady stream of melatonin over the course of the stroke as opposed to sporadic increases in levels. While this treatment plan is still in the experimental stages, it appears that the future of melatonin-based stroke therapies will focus on a dynamic level of melatonin over the course of the stroke progression for optimal neuroprotection.

The remaining dilemma results from the pending question of whether intracerebral pineal gland grafting is more effective than exogenous melatonin treatments. The biggest difference in the two different treatment methods is the targeted line of cells. In experiments, it has been observed that pineal gland grafts particularly reduce ischemic tissue volume 2 to 3 days after the onset of stroke as opposed to on the first day. This suggests that pineal gland grafts mostly target secondary cell death as opposed to the initial stroke damage, also known as the necrotic cell death. Consequently, a chronic treatment of melatonin is needed to provide the necessary therapy (38). Comparing both treatment plans reveals the costs and the benefits of both. One example is the invasiveness of the procedure. A pineal gland graft involves a very invasive and extensive transplantation surgery, while the exogenous melatonin treatment is a minimally invasive and less physically demanding procedure. With this being said, because of the massive cell death that occurs after a stroke takes place (22), a pineal gland graft may provide a more ongoing treatment of hormone relief. Treatment for early acute stroke patients may be more effective with exogenously delivered melatonin because of the minimal invasiveness and temporary relief that it provides (40). On the contrary, pineal gland grafting may be more effective with chronic stroke because of the long-term benefits and constant secretion that it provides. Alternatively, a combination of the two regimens is being investigated for a more effective combined therapy.

A potential side effect of pineal gland graft therapy is graft rejection. Although the brain is traditionally thought of as “immune privileged,” there still is the potential that the graft could be rejected upon transplantation. This situation insists that pineal gland graft therapies would need to be accompanied by immunosuppressive agents to ensure long-term graft survival, which contain risks of their own (27). Moreover, melatonin proves to compliment immunosuppressive agents. Since the immunosuppressants weaken the immune system upon usage, the body is susceptible to infection and other side effects. Melatonin, in turn, is effective against viral (5,18) and bacterial (4) infections and can provide relief in the time of weakened immunity. In addition, in certain doses, melatonin behaves as an immunodepressive agent as well. Large pharmacological doses greater than 100 mg/kg body weight decrease the antibody production in the body (46).

In order to proceed further in the investigation of pineal gland grafts, more research needs to be conducted on the efficacy of the pineal gland grafts and their relation to melatonin. Such research could be conducted in many ways. One option would be to use melatonin antagonist molecules in conjunction with a graft transplant to investigate whether melatonin is providing all of the neuroprotection or if there is another contributor such as various growth factors (7). This experiment could also be conducted by using an antibody that specifically targets growth factors and see if neuroprotection is altered upon transplantation.

Melatonin Receptors in Stem Cells

Melatonin receptors have only recently been implicated in stem cells' mechanism of action (30). Stem cells express specific receptors modulated by the melatonin ligand: melatonin receptor 1 (MT1) and/or melatonin receptor 2 (MT2) (62,53). Postulated mechanisms of melatonin's neuroprotection in ischemic and hemorrhagic stroke include oxidative stress reduction and apoptosis prevention (6). In an experiment investigating the neural differentiation mechanisms of amniotic epithelial cells (AECs) in an in vitro model of stroke, five observations were yielded. First, it was found that AECs express the MT1 but not the MT2 receptors (30). This observation suggests that the MT1 receptor could be targeted to alter the eventual fate of AECs. In fact, another study has shown MT1 expression in neural stem cells (53), suggesting melatonin may be a pleiotropic molecule in neurodevelopment. Second, it was found that the neuroprotective effect of AECs was suppressed by antagonizing MT1, though antagonizing MT2 did not produce the same effect (30). Third, in line with previous observations, it was found that melatonin enhanced AEC proliferation and differentiation in cells expressing MT1 (51). While many studies demonstrate therapeutic benefit of exogenous melatonin treatment (42,43,35), combining melatonin and cell therapy provides a more effective treatment mechanism (8,30). Fourth, in diseases characterized by oxidative stress, treatment with AECs and melatonin should suppress neurodegeneration via an antioxidative process in addition to melatonin's positive effects on cell proliferation and differentiation (31,43,56,74). Therefore, this combined therapy is more effective than either melatonin or AEC therapy alone. Finally, it was found that neuroprotection is induced by neurotrophic factors from the AEC–melatonin therapy. Melatonin interacts with vascular endothelial growth factor (VEGF) in the periphery (61) and with brain-derived neurotrophic factor (BDNF) in the cerebellar neurons (24). The elevated VEGF levels in AECs and further evidence supporting VEGF's association with MT1 (30) and BDNF's association with MT2 (24) expands on the previous results of melatonin mechanism of action. While other studies have implicated an interaction between melatonin receptors and neurons (8,36,24,48,50), the observations of MT1 suggest that AEC and melatonin treatment, in tandem, promotes synergistic neuroprotective effects; the cell growth, trophic factor secretion, and differentiation can be enhanced or mediated by targeting the MT1 receptor. This potential method of stem cell regulation should be further tested using an in vivo model of stroke. Additionally, some drugs such as ramelteon are melatonin receptor agonists with better properties (plasma half-life, MT specificity, and high affinity) than melatonin itself (23,64), opening another area for further research.

Stroke-Induced Dementia as a Potential Target for Melatonin-Based Therapeautics

In recent years, numerous studies have reported stem cells ameliorating the neurological deficits in ischemic stroke models and decreasing the likelihood of developing dementia. Cognitive decline and vascular dementia are typically the most common consequences following a stroke (28). Cerebral ischemia plays a critical role in the pathogenesis of vascular cognitive impairment. Various mechanisms of neuronal injury suffered from cerebral ischemia have been studied, including oxidative stress, hypoxic stress, glutamate stress, formation of free radicals, and so on. Together, these factors contribute to a vicious cycle of toxicity, ultimately leading to neuronal dysfunction and cognitive impairment (78). Several transcription and neurotrophic factors, including cyclic AMP response element-binding protein (CREB) and BDNF become dysregulated in animal models and patients suffering from cerebral ischemia (78). Both CREB and BDNF are downregulated in the hippocampus tissue after an ischemic injury (78), causing a decrease in neuronal plasticity. BDNF plays an essential role in the retention of spatial learning and activity-dependent synaptic plasticity, while CREB indirectly affects the ability in memory performance through the regulation of BDNF expression (67). Increasing the CREB and BDNF levels in the hippocampus results in improved cognitive impairments and memory performance (21). Upregulated BDNF expression produces enhanced neurogenesis in the hippocampus, which correlates with the improved cognitive function (75). This BDNF elevation becomes more apparent in the ischemic hemisphere when animals are treated with stem cells compared to control (25,70). The recovery of the ischemic brain is associated with an increase in BDNF levels and an enhancement of endogenous neurogenesis (25). Additionally, stem cells cause an influx of BDNF, significantly reducing infarct volume after an ischemic attack, enhancing functional recovery, and protecting from secondary cell death (13,70). Stem cells exhibit qualities of regenerative therapy for ischemia-induced cognitive impairments and memory functions, and they have the ability to migrate in damaged tissue and differentiate into neuronal cells by secreting neurotrophic factors (29). The involvement of CREB and the upstream signaling pathways leading to the activation of BDNF in learning-associated plasticity makes them attractive therapeutic targets using stem cells to promote functional recovery in cerebral ischemic patients. As noted above, with melatonin receptors modulating stem cell fate, it is possible that melatonin can similarly alter ischemia-associated cognitive deficits, and this warrants investigation.

Natural Products or Herbal Medicines that Act Like Melatonin

Up to one third of patients seeking medical attention prefer some form of complementary and alternative medicine as alternatives to mainstream Western medical treatment. Alternative medicine involves the use of natural products, herbs, and other dietary supplements such as plant infusions. The use of melatonin as treatment for vascular dementia has recently become a focal point of research. Interestingly, indigenous populations have used a variety of other natural herbs for thousands of years, treating chronic diseases, such as stroke and dementia. Many of the herbs that were used presented similar therapeutic benefits as melatonin.

In China, traditional Chinese medicine has been used for centuries as an effective treatment for patients with vascular dementia (44). The effects of Chinese medicine on vascular dementia improved cognitive function and overall mental state after an infarction. Accumulating evidence has documented that Chinese herbal medicine repeatedly outperforms Western medicine or placebo in the treatment of vascular dementia (55). Another common herbal treatment for vascular dementia, which also has its roots in China, involves the consumption of green tea. Green tea has been associated with a reduction of cardiovascular disease, neuroprotective properties, and promotion of physiological function among other therapeutic benefits (11). In most cases, many of the listed beneficial effects have been attributed to its chatechins, particularly (–)-epigallocatechin-3-gallate (EGCG) (76). Many of the neuroprotective properties of EGCG include the promotion of neuronal plasticity and improvement of cognitive function and learning abilities (76). EGCG demonstrates many of the essential characteristics needed for an effective treatment following ischemia. A third alternative remedy against cerebral ischemia includes the use of lavender oil. A recent study proposes lavender oil displaying similar therapeutic effects as melatonin, both significantly diminishing infarct size and improving functional outcome after cerebral ischemia (71). Lavender oil exhibits neuroprotective activities, correlating with the augmentation of endogenous antioxidant defense and inhibition of oxidative stress. Brain antioxidants such as superoxide dismutase, catalase, and glutathione peroxidase increased as an antioxidant defense (72). Together, these factors may alleviate neurological function after an infarction. Although lavender oil possesses several neuroprotective characteristics, it could not suppress the apoptosis pathway (71). Last, stobadine has been highlighted as a promising antioxidant to treat cerebral ischemia. Findings suggest that although stobadine and melatonin have remarkably different chemical structures, both antioxidants exert neuroprotective activities correlating with improved energetic state of neurons in the treated tissue (19). The effect of stobadine was studied on postischemic functional recovery (26). Findings suggest that in the groups treated with stobadine, the treatment elicited improvement in synaptic transmission upon reoxygenation (19). Additionally, the treated animals were found to have improved long-term potentiation when compared to controls. The study supports the notion that stobadine demonstrates various therapeutic benefits needed for the treatment of brain ischemia and cognitive impairment. Alternative medicines are slowly regaining the lost attention they have held for centuries. An estimated number of one third of patients prefer the “natural” effects and benefits of these medications, which may substitute for melatonin's drug-like effects. Many of the alternative medicines have gained the support of numerous researchers as potent drugs for stroke therapy due to the therapeutic benefits.

It is important to note that the numerous research studies using alternative therapies to treat symptoms of PD have been studied in conjunction to dopaminergic therapy (3). Patients are searching for a more holistic approach to healthcare, complementing standard therapies with healthy living, mind–body practices, and natural products (3). In a study accessing 64 of 108 Chinese medicinal herbs, melatonin was found in excess of 10 ng/g dry mass, while melatonin levels in 43 herbs were in excess of a hundred ng/g, and in 10 herbs melatonin levels were in the μg/g range (12). These levels are significantly higher than those in the serum of mammals, which are usually in the pg/ml range (12). Moreover, many of the herbs containing the highest levels of melatonin are used to slow aging and in diseases associated with free radicals (12). Because it has been difficult to explain the alleged therapeutic effects of these Chinese herbal medicines, the findings of relatively high levels of melatonin in these herbs provide a potential pharmacological basis for their clinical use as determined over many centuries (12). Thus, their anti-inflammatory, antiapoptotic, and antioxidative properties, among others, are still continuing to make alternative medicine an attractive subject of clinical and pharmacological research.

Melatonin-Based Therapeutics Transitioning to Clinical Trials

Although impactful research has been done to develop these previously discussed therapeutic strategies, precautions must be taken to proceed into clinical trials. First, safety must be addressed. Experimental stroke animals must be investigated long term to test for any antagonistic effects of melatonin therapy. This includes behavioral side effects along with neurological inconsistencies. Investigators must examine brain tissues and other peripheral organs at various stages after treatment to look for toxic effects and accumulate a safety profile for clinical treatment. STAIR (Stroke Treatment Academic Industry Roundtable) (1) and STEP (Stem Cell Therapies as an Emerging Paradigm) (66) recommend effective protocols to move these therapies to clinical trials. Both of these guidelines are developed by stroke committees to outline the necessary actions that must be taken at the experimental and early clinical stages of testing. Some of the guidelines include multiple lab testing, testing involving additional models, and the addition of comorbidity factors, which include diabetes and aging. Incorporation of these protocols will successfully ease melatonin-based therapeutics into clinical testing. Coupled with the emphasis on safety, focus needs to be placed on melatonin's additional functions and mechanisms before it transitions into clinical study. In addition to melatonin's function in the normal circadian rhythm and its role in the antioxidant defense system, melatonin has applications in skin physiology, retinal function (58), bone physiology, and even oral health (60). As a result of these varied responsibilities and mechanisms, more research is needed to prove the safety and efficacy in clinical use. As previously mentioned, evidence has suggested that melatonin may also have immunological roles that should be considered. In vivo models have demonstrated that exogenously delivered melatonin may promote the nonspecific immune response in animal models (10). Interestingly, melatonin administration directly increases the natural killer cells and monocyte counts in the bone marrow tissue (16). In addition, antibody-dependent cellular cytotoxicity, a process where specific antibodies act in conjunction with leukocytes to promote cell lysis, has been shown to increase with melatonin treatment (20). These processes suggest some of the immune-enhancing properties of melatonin, which would affect treatments such as pineal graft melatonin therapy. Therefore, these immune-enhancing effects should be further explored before initiating melatonin therapies in a clinical setting.

Conclusion

Neurodegenerative disease including stroke remains a leading cause of death and disability around the world, creating an urgent need for novel therapies. Melatonin's properties as an antioxidant and free radical scavenger protect glial cells in the damaged brain, and these cells actively contribute to brain repair (Fig. 1). Several melatonin treatments have yielded promising results in experimental stroke models. Exogenously delivered melatonin has shown clear neuroprotective effects but exhibits marked increases and decreases in melatonin levels. On the other hand, pineal gland grafts supply a steady stream of melatonin, showing promise for chronic therapy. Additionally, stem cell treatment can be enhanced or mediated by targeting the MT1 receptor with melatonin. Stroke-induced dementia is another potential target for cell therapy, as stem cells' neuroprotection and upregulation of CRED and BDNF ameliorate cognitive impairment. Various herbal medicines demonstrate potential as melatonin substitutes due to their “natural” effects, which mimic melatonin's drug-like effects. Research has brought many of these alternative medicines into clinical trials as potent drugs for stroke therapy. Future clinical treatments exploring these methods may prove successful in ameliorating brain damage from stroke and its accompanying pathological symptoms, such as dementia.

Figure 1.

Melatonin's mechanism of action. The versatile functions of melatonin enable the drug to exert multipronged neuroprotective effects to reduce or even halt secondary cell death after stroke.

Footnotes

Acknowledgments

C.V.B. is funded by the National Institute of Neurological Disorders and Stroke 1R01NS071956-01, 1R21NS089851-01, and James and Esther King Biomedical Research Foundation 1KG01-33966.

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Melatonin as an Antioxidant for Stroke Neuroprotection

Abstract

Keywords

Introduction

Neuroprotective Effects of Melatonin in the Ischemic Brain

Pineal Gland Grafts in Stroke-Induced Animal Models

Melatonin Receptors in Stem Cells

Stroke-Induced Dementia as a Potential Target for Melatonin-Based Therapeautics

Natural Products or Herbal Medicines that Act Like Melatonin

Melatonin-Based Therapeutics Transitioning to Clinical Trials

Conclusion

Footnotes

Acknowledgments

References