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Keywords:

  • calpain;
  • melatonin;
  • melatonin receptors;
  • neurodegeneration;
  • spinal cord injury;
  • traumatic CNS injuries

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Melatonin, its receptors, and signaling
  5. Traumatic CNS injuries and melatonin efficacy
  6. Conclusions
  7. References

Abstract:  A vast literature extolling the benefits of melatonin has accumulated during the past four decades. Melatonin was previously considered of importance to seasonal reproduction and circadian rhythmicity. Currently, it appears to be a versatile anti-oxidative and anti-nitrosative agent, a molecule with immunomodulatory actions and profound oncostatic activity, and also to play a role as a potent neuroprotectant. Nowadays, melatonin is sold as a dietary supplement with differential availability as an over-the-counter aid in different countries. There is a widespread agreement that melatonin is nontoxic and safe considering its frequent, long-term usage by humans at both physiological and pharmacological doses with no reported side effects. Endeavors toward a designated drug status for melatonin may be enormously rewarding in clinics for treatment of several forms of neurotrauma where effective pharmacological intervention has not yet been attained. This mini review consolidates the data regarding the efficacy of melatonin as an unique neuroprotective agent in traumatic central nervous system (CNS) injuries. Well-documented actions of melatonin in combating traumatic CNS damage are compiled from various clinical and experimental studies. Research on traumatic brain injury and ischemia/reperfusion are briefly outlined here as they have been recently reviewed elsewhere, whereas the studies on different animal models of the experimental spinal cord injury have been extensively covered in this mini review for the first time.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Melatonin, its receptors, and signaling
  5. Traumatic CNS injuries and melatonin efficacy
  6. Conclusions
  7. References

Injury to the spinal cord causes devastating disability to individuals with loss of motor function and, depending on the severity, it may lead to paralysis. While primary injury to the spinal cord at the impact site causes irreversible damage, the secondary injury process takes time to develop and the damage may be reversible; hence, it should be the target for therapeutic modulation. Despite its limited efficacy, methylpredinisolone is the most commonly administered drug in acute spinal cord injury (SCI) and lately its benefits have been questioned [1–3]. Therefore, new therapeutic strategies including cell-based therapies, regenerative, and pharmacological interventions must be developed to ameliorate the SCI-associated dysfunction. As many diverse pathways are involved in the destruction of the spinal cord following injury, it is then imperative that an agent with multifunctional properties must be identified to combat these destructive processes in the SCI tissue. The search for such agents for treating SCI is on-going in many laboratories including ours.

In pursuit of such a multipurpose protective agent, of note, could be found in a recently published article –‘Our vanishing nights’– in National Geographic, November, 2008 issue, where the urgent need for conservation of darkness as a natural resource was emphasized. Among the profound advantages of darkness, which is being compromised by rampant light pollution, the most central to mankind and his biotic environment is the production and secretion of an unique molecule, melatonin. Melatonin, an endogenous indoleamine, produced in the pineal gland from the amino acid tryptophan is an agent with multiple beneficial actions. It is an indirect anti-oxidant and a direct free-radical scavenger with anti-inflammatory and immunomodulatory effects; hence, it may be an ideal interventional agent for the treatment of SCI and, in general, for other traumatic injuries. As the mammalian central nervous system (CNS) is extremely complex, any traumatic assault to the CNS (spinal cord and brain), even though much less frequent in annual incidence as compared to the neurological diseases, is always associated with high morbidity, mortality, and is further burdened by the enormous cost to the patient and the family. The CNS trauma has far-reaching consequences that are not only limited to the patient and the family but also include greater social and economic consequences [4]. Restoration of the loss of function in surviving patients offers a formidable biomedical challenge and depends greatly on an early intervention as well as on long-term neuroprotective/restorative agents. The present review on the efficacy of melatonin, a molecule with an extremely low toxicity record, in addressing traumatic CNS injuries certainly holds profound promise from the clinical perspective.

Melatonin, its receptors, and signaling

  1. Top of page
  2. Abstract
  3. Introduction
  4. Melatonin, its receptors, and signaling
  5. Traumatic CNS injuries and melatonin efficacy
  6. Conclusions
  7. References

Roughly, half a century ago, Aaron Lerner, a dermatologist from Yale, with his colleagues identified melatonin as the pigmentary agent of the pineal gland while exploring a treatment for skin disorders [5]. Although melatonin did not serve as a dependable treatment for vitiligo, its discovery certainly opened the gateway for its possible use in a much wider array of diseases and disorders, thus, adding substance to the three-centuries old adage for the pineal gland being ‘the seat of the soul’ as espoused by the French philosopher, René Descrates. Endogenous melatonin is synthesized in the pineal gland from the neurotransmitter serotonin in a circadian manner [6]. In mammals, the melatonin rhythm is generated by an endogenous circadian master clock in the suprachiasmatic nucleus (SCN) of the hypothalamus, which is entrained by the light/dark cycle over a 24-hr period. Exogenous administration of melatonin can also entrain the circardian clock by a direct action on SCN and, thus, it has potential to treat the disoriented circardian clock in cases such as jet-lag, shift-work, in profoundly blind subjects, and in individuals with delayed or advanced sleep phase syndromes and sleep inefficiency [7]. Melatonin is also produced at extra-pineal sites including the retina and multitude of peripheral organs such as gastrointestinal tract, skin, lymphocytes, and bone marrow [8]. Moreover, melatonin is present in every species of the animal kingdom and plants [9, 10]. Hence, it is a versatile regulator in all living organisms, including unicells [11]. It participates in a plethora of neuroendocrine and physiological processes and is appropriately referred to as a tissue factor, a paracoid, an autocoid, and an anti-oxidant and sometimes as a hormone depending on its physiological actions [12]. It has profound anti-oxidant actions against oxidative and nitrosative stress [13, 14]. It also exerts significant immunomodulatory influences [15] and modulates angiogenesis and wound healing processes [16]. Thus, melatonin, due to its ubiquity and multimodal protective mechanisms, is being considered as an important neuroprotective agent [13].

Melatonin exerts its effects through receptor-mediated and receptor-independent mechanisms, thus, manifesting enormous functional versatility and diversity [11]. The ubiquitous distribution of melatonin receptors in the CNS as well as in the peripheral organs further compliments the fact that melatonin’s actions are not compromised by morpho-physiological barriers such as the blood-brain barrier. It is likely to influence every cell with which it comes into contact [11]. At physiological concentrations, melatonin exerts receptor-mediated actions whereas the receptor-independent actions usually require higher supraphysiological/pharmacological melatonin concentrations because of the circumstances under which it is tested. Even at the higher concentrations, melatonin is well-tolerated by humans [17]. Two melatonin receptors, MT1 and MT2, which belong to the G-protein-coupled receptor superfamily, have been cloned in mammals and share some specific short amino-acid sequences, suggesting that they represent a specific subfamily [6]. A third melatonin-binding site has been purified and characterized as the enzyme quinone reductase 2, and the inhibition of this enzyme by melatonin may contribute to its anti-oxidant properties [18, 19].

A recent review provided insights into the signaling complexes associated with MT1 and MT2 receptors in various primary cell cultures, tissues, and different mammalian cell lines expressing the recombinant receptors [20]. It is crucial to relate melatonin’s efficacy to the aberrant Ca2+-homeostasis-driven signaling pathways as they form a common denominator to any traumatic CNS injury. Melatonin, with its profound effects as a scavenger of free radicals and its ability to cause radical avoidance in mitochondria, is thus, highly effective in preventing molecular mutilation due to aberrant Ca2+-homeostasis. A recent experimental study in aged mice found that oral administration of melatonin restored the metabolic function of cells with improvement in several aspects of Ca2+-signaling such as the amplitude and frequency, the size of intracellular Ca2+-pools, capacitative Ca2+-entry, and the mitochondrial potential [21, 22]. Such aberrant Ca2+-homeostasis during aging is undoubtedly a slow and gradual process that causes the accumulation of molecular debris over time. Some benefits of melatonin may also be expected when sudden neurotrauma disturbs tightly regulated Ca2+-signaling processes. This evidence comes from the experimental studies where melatonin alleviated the impaired large conductance of Ca2+-activated K+ channel activity in hippocampal neurons, which were injured as a result of intermittent hypoxia [23] or in ischemia-reperfusion injury in chronically hypoxic rats [24]. It is logical to expect translational benefits from the results of such experimental studies in clinics where usage of melatonin may be quite advantageous.

Melatonin receptors, in addition to coupling with the heterotrimeric G proteins, also physically associate with other intracellular proteins, e.g., calmodulin [25], and such interactions multiply the modulatory functions of melatonin in cell signaling [20] and cytoskeltal rearrangements [26, 27]. Moreover, melatonin receptors undergo heterodimerization as MT1/MT2, although the functional consequences of this association on receptor signaling and trafficking are currently unknown [20]. The complex field of melatonin receptor function has evolved over the past 10 yr since the cloning of the melatonin receptor subtypes; however, their pharmacology is still not fully understood, in part, because of the lack of appropriate pharmacological tools [20]. Further complexity arises from the formation of MT1 and MT2 heterodimers in cells expressing the two melatonin receptor subtypes. The GPR50 orphan receptor [28] does not bind melatonin and its endogenous ligand is still unknown [20]. Nevertheless, this receptor has been shown to behave as an antagonist of the MT1 receptor. This opens new avenues for research from a pharmacological perspective [20].

In brief, the molecular mechanisms underlying the beneficial effects of melatonin through diverse signaling processes have been extensively discussed in a series of relevant reviews [8, 11–14, 29]. The outcome of these surveys depict that melatonin may be beneficial in a multitude of disease models of the brain including traumatic CNS injuries [30–33]. An extensive overview of the use of melatonin in humans was published in the New England Journal of Medicine that extolled the many uses of melatonin from a clinical perspective [34]. The advantages of therapeutic and clinical utilization of melatonin have been repeatedly emphasized [35, 36] and such encouragement may, in due course, lead to an efficient neuroprotective intervention in CNS trauma.

One may expect dual benefits of melatonin administration in traumatic CNS injuries. Firstly, it may be important to restore the perturbed endogenous melatonin rhythm if it is disturbed by mechanical interruption of melatonin synthesis due to damage to the neural connections between the SCN and the pineal gland. Secondly, it may be a result of its multiple neuroprotective/neurorestorative actions that melatonin has at the site of injury in the CNS. Progression of traumatic CNS injuries follow an archetypal course through primary and secondary damaging events, which are distinct in their spatiotemporal windows. Because of melatonin’s multiple actions, its use as a treatment may profoundly influence both the short-term primary damaging events as well as preventing some of the long-term secondary damage (Fig. 1).

image

Figure 1.  Trauma to the spinal cord is represented as a continuous processe of tissue destruction, abortive repair, and wound healing around the injury site. Possible windows of therapeutic interventions, especially for neuroprotective/neurorestorative modalities, have been highlighted wherein agents like melatonin can act (SC, spinal cord).

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The half-life of exogenously administered melatonin in the blood is short; hence, there is a need for stable melatonin mimetics, be they synthetic ligands or receptor modulators. Updates on patented melatonin mimetics and their usage have been recently reviewed [11]. To date, these melatonin analogs have not been tested for their possible benefits in SCI or any CNS injury.

Traumatic CNS injuries and melatonin efficacy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Melatonin, its receptors, and signaling
  5. Traumatic CNS injuries and melatonin efficacy
  6. Conclusions
  7. References

Traumatic CNS injuries include traumatic brain injury (TBI) and SCI, depending on the anatomical region damaged. The current mini review will briefly summarize the changes associated with injuries to the brain (recently reviewed elsewhere [24, 30–32, 37]) and will extensively cover SCI. Emphasis will be placed on experimental SCI models to underscore melatonin’s efficacy in treating traumatic CNS injuries and the studies involving SCI will be highlighted.

Spinal cord injury

Clinically, SCI involves two components: an initial mechanical instability precipitating into a secondary injury process leading to the final neurological deficit [4]. Traumatic SCI may be a direct lesion that causes focal injury to the neural elements at the site of impact or a lesion due to stretching or compressive forces applied to spinal cord via bones and/or ligaments. In either case, the cord lesion expands with time following injury over adjoining spinal segments causing secondary injury. Primary injuries cause disruption of the blood supply to spinal cord and lead to ischemic damage. All spinal cord lesions can be broadly classified as neurologically complete or incomplete by the classical Frankel score [38] or using the more recent ASIA scale [39]. However, regardless of the mode of induction of the primary injury, SCI essentially evolves through an acute and chronic phase as inferred by a substantial body of evidence [3, 40, 41]. We provide a schematic representation of the sequence of events that occur following a traumatic SCI (Fig. 1).

Experimental SCI induction is largely guided by the objective of the investigator. Animal models of SCI may include contusion, compression, or transection. The contusion model is the choice to study physiologic responses whereas a clip or balloon compression model is preferred to study the effects of compression or the optimal timing of decompression [42]. However, to test the implementation of a device, a partial or complete transection model is preferred. A combination of models might also be an option such as initial transection mode at early stages of an experimental plan to explore axonal regeneration followed by testing the most promising therapy in clinically relevant contusion models. In our laboratory, for the past three decades, we have been using a clinically relevant contusion model to induce moderately severe injury using the weight drop method [43].

Although complete recovery after SCI is yet to be attained, research in the field over the past several decades has definitely boosted the belief of the researchers as well as the survivors in the possibility of attaining greater motor function. A recent review by Akhtar et al. (2008) has rationally pin-pointed the shortcomings in loosing the translation of experimental SCI research from bench to bed-side as the discrepancies in several aspects between the animal models and clinical trauma; these include anatomical localization, laminectomy, anesthesia, laboratory stressors, surrogate markers for behavior analysis in experimental SCI, and functional assessment scales (sensory and motor) [44]. Overcoming these pitfalls while designing the experimental SCI will certainly amplify the translational potential of experimental SCI research. Several ongoing patents on plausible SCI therapeutic interventions have been enlisted in recent publications. However, like other fields of traumatic injuries in the CNS, encouraging results obtained in experimental models of SCI have so far failed to identify any safe and effective neuroprotectants in clinical trials as confirmed recently by the International Campaign for Cures of Spinal Cord Injury and Paralysis [45]. A quest for a good neuroprotectant in SCI remains unresolved. Hence, a mini review on melatonin’s efficacy in the treatment of SCI is timely.

Melatonin efficacy in SCI

A possible correlation between the neuroprotective efficacy of melatonin and SCI originally emerged almost three decades ago as clinical case reports in which the circardian profiles of endogenous melatonin were assessed in SCI patients. Much later the experimental studies on the utility of exogenously-applied melatonin in experimental models of SCI were conducted. Hence, in the following discourse the outcomes of initial clinical case reports are considered first followed by a discussion of the results of the subsequent experimental studies.

Levels of melatonin in SCI patients differed strictly with respect to the site of injury. SCI disrupting the cervical spinal cord significantly perturbed the levels of endogenous melatonin, whereas, an injury at the levels of thoracic or lumbar did not affect it severely. These differences are explicable in terms of the central neural pathways, which connect the eyes to the pineal gland. The first clinical study revealed that lesions within the cervical spinal column caused decentralization of pineal gland because they perturbed descending sympathetic fibers and led to an absence of significant increment in nocturnal melatonin; this, clearly distinguished quadriplegic subjects from normal males and from the subject with a lesion of the lumbar spinal cord [46]. More than two decades later, it was further confirmed that neurologically complete cervical spinal cord transection results in complete loss of the circardian melatonin rhythm [47]. More complete studies on rhythms of serum melatonin in patients with spinal lesions at the cervical, thoracic, or lumbar region revealed that the cervical region of the spinal cord includes the neural pathway, which is essential for the diurnal rhythm of pineal melatonin secretion in human beings. Retrospectively, such studies clearly discerned the relationship between regional specificity of SCI lesions and changes in the endogenous profile of melatonin [48]. Such a regional bias was re-confirmed in a recent clinical study conducted using tetraplegic patients with bilateral oculosympathetic paresis showing a complete loss of the nocturnal production of melatonin [49].

A recent assessment based on the ‘Basic Nordic Sleep Questionaire’ conducted at the Karolinska University Hospital in Stockholm, on a large SCI patient population comprised of 230 patients, inferred that perturbances in the melatonin rhythm contributed to poor subjective sleep quality associated with higher ratings of pain intensity, anxiety, and depression [50]. A year later, another study confirmed the positive correlation of an altered melatonin cycle in cervical SCI patients with reduced sleep quality and documented the need for larger studies on the potential usefulness of melatonin replacement therapy in normalizing sleep in SCI patients [51].

Although the field is in its infancy, several encouraging clinical case studies suggest that melatonin may be the neuroprotectant of choice in this devastating injury. It has already been mentioned earlier that there is no neuroprotective drug in clinical practice to date that is highly useful as a treatment for this complex neurological problem. Hence, it is important to assess the outcomes of melatonin’s use in experimental models of SCI with the intent of eventually applying this information for treatment of SCI in humans.

The first experimental study to test melatonin’s efficacy in reducing neural damage in experimental SCI in animals is that of Fujimoto and colleagues [52]. They studied an acute to chronic SCI model and showed a significant protection by melatonin against neutrophil-mediated damage including lipid peroxidation, reduced levels of secondary injury, and an earlier recovery [52]. Systemically applied pharmacological doses of melatonin were shown to boost the anti-oxidant defense system in a variety of ways after acute SCI [53]. Melatonin also protected against autodestruction following SCI by reducing the levels of free iron and the products of lipid peroxidation [54].

When compared with methylprednisolone, melatonin was found to be more effective in an acute SCI model against lipid peroxidation and in preserving the structural integrity of neurons, axons, and intracellular organelles [55]. A later study uncovered the greater efficacy of melatonin compared to methylprednisolone in preserving the ultrastructural histopathological integrity of the spinal cord although the reduction of lipid peroxidation after SCI was less obvious. Furthermore, this study also verified that the neuroprotective effect of melatonin was dose-dependent [56]. A combination therapy of melatonin with methylprednisolone did show an additive effect against the accumulation of lipid peroxidation products in the subacute phase of injury, but did not show any difference in a brief chronic 10-day study following SCI in rats as evidenced by neurobehavioral, ultrastructural, and electrophysiological recovery [57]. However, more recently in a SCI model in mice, the combination therapy with melatonin and dexamethasone had a significant and important beneficial anti-inflammatory effect by blocking the possible progression of secondary injury events after SCI. This study showed that the effective dose of dexamethasone could be reduced 10-fold when it was given in combination with melatonin [58].

In comparision to other anti-oxidants such as oxytetracycline or prostaglandin E1, melatonin was found to be more potent in ameliorating secondary damage in an acute model of SCI [59]. Likewise, melatonin was more effective than octreotide, an octapeptide that mimics natural somatostatin pharmacologically and is known to reduce lipid peroxidation as well as curtailing the degree of edema and other consequences of ischemia [60]. Melatonin reduces the development of inflammation and tissue injury associated with SCI by blocking both oxidative and nitrosative stress [61]. Moreover, melatonin limits the expression and activity of matrix metalloproteinases (MMP-9 and MMP-2) thereby also reducing pro-inflammatory TNF-α expression in a mouse model of traumatic SCI [62]. The same group further demonstrated that melatonin’s protective role in SCI was related to the regulation of MAPK signaling pathways and the high-mobility group box 1 protein expression (HMGB1) in mice. They documented that melatonin treatment in SCI mice enhanced motor recovery, reduced the activation of p38 MAPK, JNK, and ERK1/2, and the expression of HMGB1 [63].

An earlier report also showed that activation of the endogenous melatonin system in the spinal cord reduced the generation, development, and maintenance of central sensitization, with a resultant inhibition of capsaicin-induced secondary mechanical allodynia and hyperalgesia [64]. To this end, it was recently confirmed in an experimental model of SCI that exogenously administered melatonin reduced mechanical allodynia by altering the expression of water channel aquaporins [65].

Complementing the data regarding the neuroprotective effects in rodent SCI models, the beneficial neurobiological effects of melatonin have also been demonstrated in the rabbit SCI models. In these reports, both preischemic and postischemic administration of melatonin in a model of ischemia/reperfusion induced SCI following temporary aortic occlusion protected against free radical damage by induction of anti-oxidant enzyme levels and/or scavenging free radicals. This mitigated the need for extensive activation of endogenous anti-oxidant enzymes [66]. Melatonin in combination with prophylactic zinc showed neuroprotection in a similar SCI model [67]. In a recent study, it has been reaffirmed that melatonin application significantly abated the severity of SCI after temporary aortic occlusion in the rabbit [68]. Further confirmation of neuroprotective efficacy of melatonin in traumatic SCI comes from a study conducted in rabbits wherein pinealectomy retarded the recovery rate after SCI, and administration of melatonin exogenously to the pinealectomized animals augmented the recovery [69].

The multifunctional efficacy of melatonin treatment after SCI has been shown in vivo by many investigations. We investigated the role of melatonin as an intervening agent for ameliorating Ca2+-mediated events, including activation of calpain in moderately severe experimental SCI [33]. Calpain, a Ca2+-dependent neutral protease, is known to be a key player in the pathogenesis of SCI. In an acute SCI regimen, immunofluorescent labeling was used to identify calpain expression in neurons, glia, or macrophages. A combination of TUNEL and double immunofluorescent labelings was used to identify neuronal apoptosis in spinal cord. Furthermore, the effect of melatonin on axonal damage was assessed using an antibody, which was specific for dephosphorylated neurofilament protein. Treatment of SCI animals with melatonin attenuated calpain expression, inflammation, axonal damage, and neuronal death, indicating that melatonin was highly neuroprotective in this situation. Moreover, examination of levels of calpain and caspase-3 expression and activity indicated significant reductions in the proteolytic events in SCI animals after treatment with melatonin. Taken together, our studies strongly suggest that melatonin may be an effective neuroprotective agent for the treatment of SCI [33], and the results are summarized (Table 1).

Table 1.   Efficacy of melatonin in diverse animal models of experimental SCI
Type of SCIMelatonin dosesInsights into melatonin efficacy in SCI
  1. SCI, spinal cord injury.

Studies in rats
Range of methods were used to induce SCI in rats, including compression, weight drop, and contusion. Both genders of Wistar and Srague-Dawley rats were used. Studies included both acute and chronic SCI spanning from days to weeks.Range of melatonin doses were used from 10 to 250 mg/kg; applied as single bolus or multiple doses; delivered mostly immediately after SCI and in some studies continued from 1 to 10 days. Melatonin was also used in combination with methylprednisolone.Melatonin was found superior to methylprednisolone but no cumulative advantage on the chronological recovery was seen with combination therapy; systemically applied pharmacological dose of melatonin boosted antioxidant defense systems after SCI; melatonin efficacy was found superior to other antioxidants in acute SCI; it was also found to be more effective than octreotide, an octapeptide that mimics natural somatostatin. Anti-inflammatory, anti-oxidative and anti-nitrosative action of melatonin were seen in SCI. Pinealectomy aggravated SCI, whereas exogenous melatonin had neurprotective effect in pinealectomized animals like that of injury-vehicle group. Melatonin reduced the expression and activity of matrix metallo-proteinases (MMP-9 and MMP-2) thereby reducing the TNF-α expression. Melatonin also reduced mechanical allodynia through regulation of aquaphorin-1 and rendered neuroprotection by attenuating proteolytic damage.
Studies in rabbits
Acute ischemic SCI induced in male New Zealand rabbits by clamping of thoraco-abdominal aorta at 1–2 sites for 20–30 min.Melatonin doses were 10 mg/kg 10 min preischemia and postischemia or in combination with zinc sulfate.Melatonin protected against acute SCI induced by ischemia/reperfusion; it showed significant neuroprotection in combination with prophylactic zinc and significantly reduced incidence of SCI after temporary aortic occlusion.
Studies in mice
Acute and chronic SCI induced by extradural aneurysm clip.Combination of melatonin (dose) with dexamethasone.Novel aspects of combination therapy as a significantly low dose of dexamethasone were effective.

Contrary to the aforementioned beneficial reports in experimental SCI, melatonin failed to render any neuroprotection in a model of iatrogenic SCI for cases of elective spine surgery, wherein preoperative (20 min), intra-operative, or postoperative (1 h) doses (10 mg/kg) were applied to incomplete SCI rats. It is important to note that three other neuroprotective drugs tested, including methylprednisolone also did not improve motor fuction or spinal cord morphometry; hence, the authors have underscored the paramount significance of a total avoidance of primary injury altogether in elective spine surgery [70].

Traumatic brain injury

Clinicians and basic scientists are in agreement that a significant barrier in finding an effective therapy in traumatic CNS injuries lies in the enormous clinical heterogeneity in all forms of neurotrauma. Recently, a major step was taken in addressing this issue by a group of prominent organizations (National Institute of Neurological Disorders and Stroke, Brain Injury Association of America, Defense and Veterans Administration Brain Injury Center, and National Institute of Disability and Rehabilitation Research) that, together, outlined a new, multidimensional classification system for TBI. This is a major modification of the existing Glasgow Coma Scale and is expected to appropriately link specific patterns of brain and neurovascular injury with beneficial therapeutic interventions, thus, facilitating clinical trials [71]. Over the years, there has been substantial evolution of the experimental models for TBI [72]. A remarkable trend in progressive development of these models has been focused on: defining a temporal window that gives an oppurtunity for interventions, testing the safety and efficacy of delivery systems of agents and cells, and providing a better understanding of the cascades of gene expression and cell interactions both acutely and chronically after injury. The published literature on the clinical and experimental background may serve as great resource to appreciate the anticipated benefits of melatonin usage in clinics for TBI.

Melatonin efficacy in TBI

The neuroprotective efficacy of melatonin in TBI or craniocerebral trauma has been recently reviewed [32]. Like other forms of neurotrauma, TBI involves multifactorial etiologies including free radical generation, which culminates in oxidative and nitrosative damage, disrupted macrocirculation and microcirculation in the vicinity of the injury, lymphocytopenia, opportunistic infections, perturbed sleep-wake cycles, suppression of nonspecific resistance, and toxicity caused by therapeutic agents. Together, these factors precipitate into the development of heterogenous clinical symptoms in the secondary phase. Melatonin has been adjudged as a protective agent against damage following TBI in several in vitro and in vivo studies [32]. Melatonin as well as its metabolites are multi-faceted free radical scavengers and are effective against both oxygen and nitrogen-based reactants and may clearly attenuate neural damage resulting from craniocerebral trauma [73, 74]. Enhanced vulnerability of brain to such oxidative or nitrosative stress that escalates the damage following TBI may be handled more deftly by melatonin compared to other anti-oxidants. Infection and inflammation complicates TBI in surviving patients. Melatonin also aids in inhibition of pro-inflammatory cytokines and activation of adhesion molecules. It would consequently reduce lymphocytopenia and infections by opportunistic organisms. Moreover, the chronobiotic capacity of melatonin may also reset the natural circadian rhythm of sleep and wakefulness, which may serve as a major advantage of melatonin’s use as a therapeutic molecule after traumatic injury. It may also reduce the toxicity and enhance the efficacy of drugs used in clinical management of TBI such as steroidal or nonsteroidal anti-inflammatory agents, anti-ulcer agents, anti-psychotics/antidepressants, anti-epileptics and also anti-anemic drugs. Similar benefits of melatonin may be seen in other traumatic injuries to CNS as well. Finally, melatonin, not being restricted by the blood-brain barrier, reportedly reduces the contusion volume and stabilizes cellular membranes preventing vasospasm and apoptosis of endothelial cells that occurs as a result of TBI [32, 75].

Melatonin efficacy in ischemia/reperfusion

The integrity of the CNS is highly vulnerable to a transitory interruption of its blood supply; this is specially true of the brain which is susceptible to focal or global ischemia. Unless ischemia is promptly reversed, reperfusion produces further cerebral damage. Ischemia/reperfusion injury is a subset of CNS damage that is unfortunately common but also occurs with equal frequency in nonneural tissues. In the CNS, interruption of the blood supply followed by reperfusion may not always be a result of traumatic assault. However, as the damage is associated with free radical-mediated attack of essential molecules, it is included in this survey.

Several recent reviews [30, 31, 37] summarize the reports that have documented the neuroprotective effects of melatonin against ischemia/reperfusion injury to the brain. Ischemia (focal or global) causes extensive destruction of neural tissue and the primary objective in the clinic is to promptly reverse it. Procedures such as acute thrombolysis or defibrinogenation, however, are effective only in selective patients, and are associated with a significant risk of complications due to bleeding. To date, a number of neuroprotectants, which were initially found effective in experimental studies for stroke therapy, failed in clinical trials. At this juncture, it may be rational to test the efficacy of melatonin. The in vivo and in vitro evidence in favor of the use of melatonin to protect against focal and global cerebral ischemia/reperfusion injury has been reviewed [31]. The benefits of conducting further experimental studies to examine any synergistic protective action by combining melatonin with thrombolysis, defibrinogenation or other neuroprotectants are emphasized. The planning of phase II and phase III trials in an attempt to define the potential benefits of melatonin as an acute stroke treatment in humans is suggested [31].

When the results of all the reports are considered, it is clear that endogenously-produced and exogenously-administered melatonin reduces the degree of tissue damage and limits the behavioral deficits associated with experimental models of stroke [37]. This further suggests that melatonin efficacy should be seriously considered for clinical trial.

The most recent updates on melatonin’s efficacy in models of stroke come from another review where the potentially widespread applications of melatonin have been emphasized [30]. These studies provide the preclinical tests for melatonin in acute stroke therapy, and its application at different treatment schedules. Advantageous characteristics of melatonin as a neuroprotective drug relates to its bioavailability, its potential for exerting wide-spread neuroprotective actions, further amplified and prolonged by its metabolites [29], its ability to reduce inflammation, its capability to protect cytoskeleton organization, and its anti-apoptotic actions. Moreover, melatonin does not interfere with the thrombolytic and neuroprotective actions of other drugs. An adequate safety profile of the drug has been underscored. The potential use of melatonin as a neuroprotective drug in clinical trials aimed at improving the acute focal or/and global cerebral ischemia has also been suggested in another review [30].

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Melatonin, its receptors, and signaling
  5. Traumatic CNS injuries and melatonin efficacy
  6. Conclusions
  7. References

This mini review emphasizes the pressing need for an effective neuroprotectant that will be useful in the treatment of acute SCI (as surmised, Fig. 2) or traumatic CNS injuries where the victims are commonly young individuals; hence, the fullest extent of functional recovery is desired. Based on the data summarized herein, the multi-functional molecule melatonin may be a useful therapeutic agent for treatment of CNS injuries. There is a wealth of well-documented experimental research to support its use. Also, melatonin is safe, nontoxic, and available in pure form for human use as a drug [76]. The results of experimental studies provide fundamental information for the effective design and execution of clinical trials using melatonin as a neuroprotective treatment for traumatic CNS injuries.

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Figure 2.  The therapeutic potentials of melatonin in the treatment of spinal cord injury (SCI).

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References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Melatonin, its receptors, and signaling
  5. Traumatic CNS injuries and melatonin efficacy
  6. Conclusions
  7. References