Jiménez-Rubio G, Ugalde O, Ortíz–López L, Ramírez-Rodríguez G, Benítez-King G

Language: Spanish
References: 78
Page: 221-228
PDF size: 121.45 Kb.

ABSTRACT

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 outgrowth in neuroblastoma cells. In N1E-115 cells, melatonin at plasma and cerebrospinal fluid concentration caused an increase in microfilament arrays in stress fibers and their thickening, as well as increased growth cone formation, and augmented number of cells with microspikes. Recently, it was demonstrated that melatonin increased both the number of N1E-115 cells with filopodia and with long neurites through both PKC activation and Rho-associated kinase (ROCK) stimulation.
The utility of melatonin to prevent damage in the cytoskeletal structure produced by neurodegenerative processes was demonstrated in N1E-115 neuroblastoma cells cultured with okadaic acid (OA), a specific inhibitor of the serine/threonine proteins phosphatases 1 and 2A that induces molecular and structural changes similar to those found in Alzheimer’s disease. Melatonin prevented microtubule disruption followed by cell-shape changes and increased lipid peroxidation and apoptosis induced by OA. Melatonin effects on altered cytoskeletal organization induced by OA are dose-dependent and effects were observed at plasma -and cerebrospinal-fluid concentrations of the indole. These data support that melatonin can be useful in the treatment of neurodegenerative diseases by both its action on the cytoskeleton and by its free-radical scavenger properties.
At present, it is known that melatonin prevents cytoskeletal damage by reducing oxidative stress and reestablishing the normal organization of disturbed neurocytoskeletons. Our group found recently that melatonin precludes cytoskeletal damage produced by high levels of free radicals produced by hydrogen peroxide and antipsychotics. Additionally, hyperphosphorylation of tau has been shown to occur associated with high levels of oxidative stress and is considered as an important hallmark of most neurodegenerative diseases. Okadaic acid causes an extensive tau phosphorylation and paired helical filament formation in animal models and in N1E-115 cells, similarly to the ones found in neurodegeneration. Our group found that melatonin prevents these changes since, when the indole was added before, simultaneously or after OA treatment, tau hyperphosphorylation was abolished. The results strongly suggest that melatonin acts as a neurocytoskeletal protector by decreasing tau hyperphoshorylation preserving the cytoskeletal structure and also they suggest that melatonin may improve cognition by impeding neuronal damage by hyperphosphorylation and through establishing new neuronal circuits. In addition, it has been shown that melatonin modulates new neuron formation from embryonic precursor cells. New neurons formation induced by melatonin was corroborated by our group using adult hippocampal precursor cells and adult animals. We have found that melatonin modulates the survival of newly formed cells and that the surviving cells could correspond to immature neurons which could lead to a pronounced augmentation in the total number of new neurons in the adult hippocampus.
In conclusion, polarity is intrinsic to neuronal function. Current knowledge indicates that the cytoskeleton participates in the maintenance of both cell shape and polarity. Progressive loss of neuronal polarity is a major histopathologic event in the neurodegenerative diseases that precedes neuronal death and the disappearance of synaptic connectivity. Drugs that prevent the loss of polarity and cytoskeleton retraction intrinsic to these diseases as well as damage in cytoskeletal structure produced by oxidative stress can be extremely useful in treatment of neurodegenerative diseases. Melatonin is a potent free-radical scavenger that at the same time acts as a cytoskeleton regulator; thus, it is tempting to speculate that this indole could prove useful in the prevention and alleviation of these diseases. Clinical trials show that melatonin administration is followed by an alleviation of circadian disturbances and cognitive function in neurodegenerative diseases. As suggestive as this information appears, extreme and controlled clinical trials will be necessary to investigate the beneficial effects of melatonin and other drugs in the treatment of dementias.

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