La melatonina: un coadyuvante potencial en el tratamiento de las demencias

SUMMARY Alzheimer’s disease is characterized by a progressive neuronal death and a lost of memory and cognition that unable the patient to perform daily tasks. Cytoskeleton alterations, identified as a major histopathologic hallmark of neurodegenerative diseases, occur in dementia. In this disease, neurons have pathologic inclusions containing fibrillar aggregates of hyperphosphorylated tau protein in absence of amyloid deposits. Abundant senile plaques and neurofibrillary tangles constitute the two major neuropathologic lesions present in hippocampal, neocortical, and forebrain cholinergic brain regions of Alzheimer’s patients. Hyperphosphorylated tau and the subsequent formation of paired helical filaments loses the capabilities for maintaining highly asymmetrical neuronal polarity. Thus, in brains with a high content of hyperphosphorylated tau, microtubules are disassembled, the highly asymmetrical neural shape is lost and an impairment of axonal transport is produced together with a lost of dendrite arborizations. In addition, brain damage caused by free radicals occurs in Alzheimer’s disease. This illness involves a reduction of the endogenous antioxidant enzyme system, increased senile-plaque formation, cytoskeletal collapse, and neuronal apoptosis induced by oxidative stress. Acetylcholinesterase inhibitors are the most commonly used compounds in the treatment of neurodegenerative diseases. However, despite their wide use in the treatment of Alzheimer’s disease, these compounds have limited therapeutic effects and cause undesirable effects. Therefore it is necessary to investigate new alternatives in the Alzheimer’s disease treatment. Considering that neurodegenerative diseases are cytoskeleton disorders, this cellular structure could be a drug target for therapeutic approaches by restoring normal cytoskeleton structure and by precluding damage caused by oxygenreactive species. In this regard, melatonin, the indole secreted by the pineal gland during the dark phase of the photoperiod, has two important properties that may be useful for the treatment of mental disorders. One is that melatonin is a potent free-radical scavenger and the other is that this indole is a cytoskeletal modulator. A neuroprotective role for melatonin was initially suggested due to its free-radical scavenger properties. Melatonin detoxifies the highly toxic hydroxyl radical as well as the peroxyl radical, peroxynitrite anion, nitric oxide, and singlet oxygen, all of which can damage brain macromolecules. Moreover, melatonin stimulates the activity of antioxidative enzymes including superoxide dismutase, glutathione peroxidase, and glutathione reductase. Also, it is a lipophilic molecule able to cross the blood-brain barrier. All these properties make melatonin a highly effective pharmacologic agent against free-radical damage in the brain. Also, it is a useful neuroprotector in dementia because it synchronize the body rhythms with the photoperiod, which are altered in Alzheimer’s disease and because normal circadian secretion of melatonin and sleep-wake cycle can be restored by the indolamine administration. Additionally, cytoskeletal modulation by melatonin is another relevant property of the indole for neurodegenerative diseases treatment. Direct assessment of melatonin effects on cytoskeletal organization in neuronal cells indicated that the indole promotes neuritogenesis in N1E-115 neuroblastoma cells at plasma melatonin concentration. Neurite formation is a complex process critical to establish synaptic connectivity that is lost in Alzheimer’s disease. Neuritogenesis takes place by a dynamic cytoskeletal organization that involves microtubule enlargement, microfilament arrangement, and intermediate-filament reorganization. In particular, microtubule assembly participates in neurite formation elicited by melatonin through antagonism to calmodulin. Also, selective activation of protein kinase C (PKC) alpha by melatonin participates in vimentin intermediate filament rearrangements and actin dynamics for neurite